Keytruda

Medical Author: John P. Cunha, DO, FACOEP Last updated on RxList: 9/9/2021
Drug Description

What is Keytruda and how is it used?

Keytruda is a prescription medicine used to treat the symptoms of Melanoma and for many other cancer types such as Non Small Lung Cancer, Head and Neck Squamous Cell Cancer, Classical Hodgkin Lymphoma, and Primary Medistinal Large B-Cell Lymphoma. Keytruda may be used alone or with other medications.

Keytruda belongs to a class of drugs called Antineoplastics, Monoclonal Antibody; PD-1/PD-L1 Inhibitors.

What are the possible side effects of Keytruda?

Keytruda may cause serious side effects including:

  • shortness of breath,
  • chest pain,
  • new or worse cough,
  • diarrhea,
  • more frequent bowel movements than usual,
  • stools that are black or tarry,
  • severe stomach pain or tenderness,
  • yellowing of the skin or eyes (jaundice),
  • nausea,
  • vomiting,
  • stomach pain (upper right side),
  • dark urine,
  • loss of appetite,
  • bleeding or bruising easily,
  • rapid heartbeats,
  • weight loss,
  • weight gain,
  • sweating,
  • increased thirst or hunger,
  • increased urination,
  • hair loss,
  • feeling cold,
  • constipation,
  • your voice gets deeper,
  • muscle aches,
  • dizziness,
  • fainting,
  • headaches that will not go away or unusual headaches,
  • change in the amount or color of your urine,
  • rash,
  • changes in your eyesight,
  • severe or persistent muscle or joint pain,
  • severe muscle weakness,
  • low red blood cells (anemia),
  • chills,
  • shaking,
  • wheezing,
  • itching,
  • rash,
  • flushing,
  • fever, and
  • lightheadedness

Get medical help right away, if you have any of the symptoms listed above.

The most common side effects of Keytruda include:

  • fatigue,
  • cough,
  • shortness of breath,
  • nausea,
  • itching,
  • rash,
  • loss of skin pigmentation (vitiligo),
  • decreased appetite,
  • headache,
  • constipation,
  • joint pain,
  • back pain, and
  • diarrhea

Tell the doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Keytruda. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

DESCRIPTION

Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab is an IgG4 kappa immunoglobulin with an approximate molecular weight of 149 kDa. Pembrolizumab is produced in recombinant Chinese hamster ovary (CHO) cells.

KEYTRUDA for injection is a sterile, preservative-free, white to off-white lyophilized powder in single-dose vials. Each vial is reconstituted and diluted for intravenous infusion. Each 2 mL of reconstituted solution contains 50 mg of pembrolizumab and is formulated in L-histidine (3.1 mg), polysorbate 80 (0.4 mg), and sucrose (140 mg). May contain hydrochloric acid/sodium hydroxide to adjust pH to 5.5.

KEYTRUDA injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution that requires dilution for intravenous infusion. Each vial contains 100 mg of pembrolizumab in 4 mL of solution. Each 1 mL of solution contains 25 mg of pembrolizumab and is formulated in: L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for Injection, USP.

Indications

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INDICATIONS

Melanoma

KEYTRUDA® is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR orALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment ofpatients with NSCLC expressing PD-L1 [Tumor Proportion Score (TPS) ≥1%] as determined by an FDA-approved test [see DOSAGE AND ADMINISTRATION], with no EGFR or ALK genomic tumor aberrations, and is:

  • stage III where patients are not candidates for surgical resection or definitive chemoradiation, or
  • metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test [see DOSAGE AND ADMINISTRATION], with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Head And Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test [see DOSAGE AND ADMINISTRATION].

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL),or who have relapsed after 2 or more prior lines of therapy.

Limitations Of Use

KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test [see DOSAGE AND ADMINISTRATION], or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.

This indication is approved under accelerated approval based on tumor response rate and duration of response [see Clinical Studies]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin(BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High Or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options.

This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Limitations Of Use

The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High Or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine-and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or GEJ adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test [see DOSAGE AND ADMINISTRATION], with disease progression on or after 2 or more prior lines of therapy including fluoropyrimidine-and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy.

These indications are approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies]. Continued approval of these indications may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

  • in combination with platinum-and fluoropyrimidine-based chemotherapy, or
  • as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-approved test [see DOSAGE AND ADMINISTRATION].

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test [see DOSAGE AND ADMINISTRATION].

This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC).

This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).

KEYTRUDA, in combination with lenvatinib, is indicated for the first-line treatment of adult patients with advanced RCC.

Endometrial Carcinoma

KEYTRUDA, in combination with lenvatinib, is indicated for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.

Tumor Mutational Burden-High Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/mega base (mut/Mb)] solid tumors, as determined by an FDA-approved test [see DOSAGE AND ADMINISTRATION], that have progressed following prior treatment and who have no satisfactory alternative treatment options.

This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Limitations Of Use

The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC)or locally advanced Cscc that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA is indicated for the treatment of patients with high-riskearly-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10)as determined byan FDA-approved test [see DOSAGE AND ADMINISTRATION].

Adult Indications: Additional Dosing Regimen Of 400 mg Every 6 Weeks

KEYTRUDA is indicated for use at an additional recommended dosage of 400mg every 6weeks for all approved adult indications [see INDICATIONS AND USAGE, DOSAGE AND ADMINISTRATION]. This indication is approved under accelerated approval based on pharmacokinetic data, the relationship of exposure to efficacy, and the relationship of exposure to safety [see CLINICAL PHARMACOLOGY, Clinical Studies]. Continued approval for this dosing may be contingent upon verification and description of clinical benefit in the confirmatory trials.

QUESTION

Self-examination is important in the detection of skin cancer. See Answer
Dosage

DOSAGE AND ADMINISTRATION

Patient Selection

Patient Selection For Single-Agent Treatment

Select patients for treatment with KEYTRUDA as a single agent based on the presence of positive PD-L1 expression in:

  • stage III NSCLC who are not candidates for surgical resection or definitive chemoradiation [see Clinical Studies].
  • metastatic NSCLC [see Clinical Studies].
  • first-line treatment of metastatic orunresectable, recurrent HNSCC [see Clinical Studies].
  • metastatic urothelial carcinoma [see Clinical Studies].
  • metastatic gastric cancer [see Clinical Studies].
  • If PD-L1 expression is not detected in an archival gastric cancer specimen, evaluate the feasibility of obtaining a tumor biopsy for PD-L1 testing.
  • previously treated recurrent locally advanced ormetastatic esophageal cancer [see Clinical Studies].
  • recurrent or metastatic cervical cancer [see Clinical Studies].

For the MSI-H/dMMR indications, select patients for treatment with KEYTRUDA as a single agent based on MSI-H/dMMR status in tumor specimens [see Clinical Studies].

For the TMB-H indication, select patients for treatment with KEYTRUDA as a single agent based on TMB-H status in tumor specimens [see Clinical Studies].

Because the effect of prior chemotherapy on test results for tumor mutation burden (TMB-H), MSI-H, ordMMR in patients with high-grade gliomas is unclear, it is recommended to test for these markers in the primary tumor specimens obtained prior to initiation of temozolomide chemotherapy in patients with high-grade gliomas.

Patient Selection For Combination Therapy

For the not MSI-H/dMMR advanced endometrial carcinoma indication, select patients for treatment with KEYTRUDA in combination with lenvatinib based on MSI or MMR status in tumor specimens [see Clinical Studies].

For use of KEYTRUDA in combination with chemotherapy, select patients based on the presence of positive PD-L1 expression in locally recurrent unresectable or metastatic TNBC [see Clinical Studies].

Additional Patient Selection Information

Information on FDA-approved tests used for patient selection is available at:http://www.fda.gov/CompanionDiagnostics.

  • An FDA-approved test for the detection of MSI-H or dMMR is not currently available [see Clinical Studies].
  • An FDA-approved test for the detection of not MSI-H or dMMR is not currently available [see Clinical Studies].

Recommended Dosage

Table 1: Recommended Dosage

Indication Recommended Dosage of KEYTRUDA Duration/Timing of Treatment
Monotherapy
Adult patients with unresectable or metastatic melanoma 200 mg every 3 weeks* or 400 mg every 6 weeks* Until disease progression or unacceptable toxicity
Adjuvant treatment of adult patients with melanoma 200 mg every 3 weeks* or 400 mg every 6 weeks* Until disease recurrence, unacceptable toxicity, or up to 12 months
Adult patients with NSCLC, HNSCC, cHL, PMBCL, locally advanced or metastatic Urothelial Carcinoma, MSI-H or dMMR Cancer, MSI-H or dMMR CRC, Gastric Cancer, Esophageal Cancer, Cervical Cancer, HCC, MCC, TMB-H Cancer, or cSCC 200 mg every 3 weeks* or 400 mg every 6 weeks* Until disease progression, unacceptable toxicity, or up to 24 months
Adult patients with high-risk BCG-unresponsive NMIBC 200 mg every 3 weeks* or 400 mg every 6 weeks* Until persistent or recurrent high-risk NMIBC, disease progression, unacceptable toxicity, or up to 24 months
Pediatric patients with cHL, PMBCL, MSI-H Cancer, MCC, or TMB-H Cancer 2 mg/kg every 3 weeks (up to a maximum of 200 mg)* Until disease progression, unacceptable toxicity, or up to 24 months
Combination Therapy†
Adult patients with NSCLC, HNSCC, or Esophageal Cancer 200 mg every 3 weeks* or 400 mg every 6 weeks* Administer KEYTRUDA prior to chemotherapy when given on the same day. Until disease progression, unacceptable toxicity, or up to 24 months
Adult patients with Gastric Cancer 200 mg every 3 weeks* or 400 mg every 6 weeks* Administer KEYTRUDA prior to trastuzumab and chemotherapy when given on the same day. Until disease progression, unacceptable toxicity, or up to 24 months
Adult patients with RCC 200 mg every 3 weeks* or 400 mg every 6 weeks* Administer KEYTRUDA in combination with axitinib 5 mg orally twice daily‡ or Administer KEYTRUDA in combination with lenvatinib 20 mg orally once daily. Until disease progression, unacceptable toxicity, or for KEYTRUDA, up to 24 months
Adult patients with Endometrial Carcinoma 200 mg every 3 weeks* or 400 mg every 6 weeks* Administer KEYTRUDA in combination with lenvatinib 20 mg orally once daily. Until disease progression, unacceptable toxicity, or for KEYTRUDA, up to 24 months
Adult patients with high-risk early-stage TNBC 200 mg every 3 weeks* or 400 mg every 6 weeks Administer KEYTRUDA prior to chemotherapy when given on the same day. Neoadjuvant treatment in combination with chemotherapy for 24 weeks (8 doses of 200 mg every 3 weeks or 4 doses of 400 mg every 6 weeks) or until disease progression or unacceptable toxicity, followed by adjuvant treatment with KEYTRUDA as
a single agent for up to 27 weeks (9 doses of 200 mg every 3 weeks or 5 doses of 400 mg every 6 weeks) or until disease recurrence or unacceptable toxicity.§
Adult patients with locally recurrent unresectable or metastatic TNBC 200 mg every 3 weeks* or 400 mg every 6 weeks* Administer KEYTRUDA prior to chemotherapy when given on the same day. Until disease progression, unacceptable toxicity, or up to 24 months
* 30-minute intravenous infusion
† Refer to the Prescribing Information for the agents administered in combination with KEYTRUDA for recommended dosing information, as appropriate.
‡ When axitinib is used in combination with KEYTRUDA, dose escalation of axitinib above the initial 5 mg dose maybe considered at intervals of six weeks or longer.
§ Patients who experience disease progression or unacceptable toxicity related to KEYTRUDA with neoadjuvant treatment in combination with chemotherapy should not receive adjuvant single agent KEYTRUDA.

Dose Modifications

No dose reduction for KEYTRUDA is recommended. In general, withhold KEYTRUDA for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue KEYTRUDA for Life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids.

Dosage modifications for KEYTRUDA for adverse reactions that require management different from these general guidelines are summarized in Table2.

Table 2: Recommended Dosage Modifications for Adverse Reactions

Adverse Reaction Severity* Dosage Modification
Immune-Mediated Adverse Reactions [see WARNINGS AND PRECAUTIONS]
Pneumonitis Grade 2 Withhold†
Grade 3 or 4 Permanently discontinue
Colitis Grade 2 or 3 Withhold†
Grade 4 Permanently discontinue
Hepatitis with no tumor involvement of the liver For liver enzyme elevations in patients treated with combination therapy with axitinib, see Table 3. AST or ALT increases to more than 3 and up to 8 times ULN or Total bilirubin increases to more than 1.5 and up to 3 times ULN Withhold†
AST or ALT increases to more than 8 times ULN or Total bilirubin increases to more than 3 times ULN Permanently discontinue
Hepatitis with tumor involvement of the liver* Baseline AST or ALT is more than 1 and up to 3 times ULN and increases to more than 5 and up to 10 times ULN or Baseline AST or ALT is more than 3 and up to 5 times ULN and increases to more than 8 and up to 10 times ULN Withhold†
ALT or AST increases to more than 10 times ULN or Total bilirubin increases to more than 3 times ULN Permanently discontinue
Endocrinopathies Grade 3 or 4 Withhold until clinically stable or permanently discontinue depending on severity
Nephritis with Renal Dysfunction Grade 2 or 3 increased blood creatinine Withhold†
Grade 4 increased blood creatinine Permanently discontinue
Exfoliative Dermatologic Conditions Suspected SJS, TEN, or DRESS Withhold†
Confirmed SJS, TEN, or DRESS Permanently discontinue
Myocarditis Grade 2, 3, or 4 Permanently discontinue
Neurological Toxicities Grade 2 Withhold†
Grade 3 or 4 Permanently discontinue
Hematologic toxicity in patients with cHL orPMBCL Grade 4 Withhold until resolution to Grades 0 or 1
Other Adverse Reactions
Infusion-related reactions [see WARNINGS AND PRECAUTIONS] Grade 1 or 2 Interrupt or slow the rate of infusion
Grade 3 or 4 Permanently discontinue
* Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.0
† Resume in patients with complete or partial resolution (Grades 0 to 1) after corticosteroid taper. Permanently discontinue ifno complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg per day orless (or equivalent) within 12 weeks of initiating steroids.
‡ If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue KEYTRUDA based on recommendations for hepatitis with no liver involvement.
ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit normal

The following table represents dosage modifications that are different from those described above for KEYTRUDA or in the Full Prescribing Information for the drug administered in combination.

Table 3: Recommended Specific Dosage Modifications for Adverse Reactions for KEYTRUDA in Combination with Axitinib

Treatment Adverse Reaction Severity Dosage Modification
KEYTRUDA in combination with axitinib Liver enzyme elevations* ALT or AST increases to at least 3 times but less than 10 times ULN without concurrent total bilirubin at least 2 times ULN Withhold both KEYTRUDA and axitinib until resolution to Grades 0 or 1†
ALT or AST increases to more than 3 times ULN with concurrent total bilirubin at least 2 times ULN or ALT or AST ≥10 times ULN Permanently discontinue both KEYTRUDA and axitinib
* Consider corticosteroid therapy
† Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Consider rechallenge with a single drug or sequential rechallenge with both drugs after recovery. If rechallenging with axitinib, consider dose reduction as per the axitinib Prescribing Information.
ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normal

Recommended Dose Modifications For Adverse Reactions For KEYTRUDA In Combination With Lenvatinib

When administering KEYTRUDA in combination with lenvatinib, modify the dosage of one or both drugs. Withhold or discontinue KEYTRUDA as shown in Table 2. Refer to lenvatinib prescribing information for additional dose modification information.

Preparation And Administration

Preparation For Intravenous Infusion
  • Visually inspect the solution for particulate matter and discoloration. The solution is clear to slightly opalescent, colorless to slightly yellow. Discard the vial if visible particles are observed.
  • Dilute KEYTRUDA injection (solution) prior to intravenous administration.
  • Withdraw the required volume from the vial(s) of KEYTRUDA and transfer into an intravenous (IV) bag containing 0.9%Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Mix diluted solution by gentle inversion. Do not shake. The final concentration of the diluted solution should be between 1 mg/mL to 10 mg/mL.
  • Discard any unused portion left in the vial.
Storage Of Diluted Solution

The product does not contain a preservative. Store the diluted solution from the KEYTRUDA 100 mg/4 mL vial either:

  • At room temperature for no more than 6 hours from the time of dilution. This includes room temperature storage of the diluted solution, and the duration of infusion.
  • Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 96hours from the time of dilution. If refrigerated, allow the diluted solution to come to room temperature prior to administration. Do not shake.

Discard after 6 hours at room temperature or after96hours under refrigeration.

Do not freeze.

Administration
  • Administer diluted solution intravenously over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, low-protein binding 0.2 micron to 5 micron in-line or add-on filter.
  • Do not co-administer other drugs through the same infusion line.

HOW SUPPLIED

Dosage Forms And Strengths

  • Injection: 100 mg/4 mL (25 mg/mL) clear to slightly opalescent, colorless to slightly yellow solution in a single-dose vial

Storage And Handling

KEYTRUDA injection (clear to slightly opalescent, colorless to slightly yellow solution):

Carton containing one 100 mg/4 mL (25 mg/mL), single-dose vial (NDC 0006-3026-02)Carton containing two 100 mg/4mL (25 mg/mL), single-dose vials (NDC 0006-3026-04). Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze. Do not shake.

Manufactured by: Merck Sharp & Dohme Corp., a subsidiary of MERCK & CO ., INC., Whitehouse Station, NJ 08889, USA. Revised: Aug 2021

Side Effects & Drug Interactions

SIDE EFFECTS

The following clinically significant adverse reactions are described elsewhere in the labeling.

  • Severe and fatalimmune-mediated adverse reactions [see WARNINGS AND PRECAUTIONS].
  • Infusion-related reactions [see WARNINGS AND PRECAUTIONS].

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in the WARNINGS AND PRECAUTIONS reflect exposure to KEYTRUDA as a single agent in 2799 patients in three randomized, open-label, active-controlled trials (KEYNOTE-002,KEYNOTE-006, and KEYNOTE-010), which enrolled 912 patients with melanoma and 682 patients with NSCLC, and one single-arm trial (KEYNOTE-001), which enrolled 655patients with melanoma and550patients with NSCLC. In addition to the 2799patients, certain subsections in the WARNINGS AND PRECAUTIONS describe adverse reactions observed with exposure to KEYTRUDA as a single agentin a non-randomized, open-label, multi-cohort trial (KEYNOTE-012), a non-randomized, open-label, single-cohort trial (KEYNOTE-055), and two randomized, open-label, active-controlled trials (KEYNOTE-040 and KEYNOTE-048 single agent arms), which enrolled 909patients with HNSCC; intwo non-randomized, open-label trials (KEYNOTE-013 and KEYNOTE-087)and one randomized, open-label, active-controlled trial (KEYNOTE-204), which enrolled 389 patients with cHL; in a randomized, open-label, active-controlled trial (KEYNOTE-048 combination arm), which enrolled 276 patients with HNSCC; in combination with axitinib in a randomized, active-controlled trial (KEYNOTE 426), which enrolled 429 patients with RCC; and in post-marketing use. Across all trials, KEYTRUDA was administered at dosesof2mg/kg intravenously every 3weeks, 10mg/kg intravenously every 2weeks, 10mg/kg intravenously every 3weeks, or 200mg intravenously every 3weeks. Among the 2799patients, 41% were exposed for6 months or more and 21% were exposed for 12 months or more.

Melanoma

Ipilimumab-Naive Melanoma

The safety of KEYTRUDA for the treatment of patients with unresectable or metastatic melanoma who had not received prior ipilimumab and who had received no more than one prior systemic therapy was investigated in KEYNOTE-006. KEYNOTE-006 was a multicenter, open-label, active-controlled trial where patients were randomized (1:1:1) and received KEYTRUDA 10mg/kg every 2weeks (n=278) or KEYTRUDA 10 mg/kg every 3 weeks (n=277) until disease progression or unacceptable toxicity or ipilimumab 3 mg/kg every 3 weeks for 4 doses unless discontinued earlier for disease progression or unacceptable toxicity (n=256) [see Clinical Studies]. Patients with autoimmune disease, a medical condition that required systemic corticosteroids or other immunosuppressive medication; a history of interstitial lung disease; or active infection requiring therapy, including HIV or hepatitis B or C, were ineligible.

The median duration of exposure was 5.6 months (range: 1 day to 11.0 months) for KEYTRUDA and similar in both treatment arms. Fifty-one and 46% of patients received KEYTRUDA 10mg/kg every 2or 3 weeks, respectively, for ≥6 months. No patients in either arm received treatment for more than one year.

The study population characteristics were: median age of 62years (range:18 to 89);60%male;98% White;32% had an elevated lactate dehydrogenase (LDH) value at baseline;65% had M1c stage disease;9% with history of brain metastasis;and approximately 36% had been previously treated with systemic therapy which included a BRAF inhibitor (15%), chemotherapy (13%), and immunotherapy (6%).

In KEYNOTE-006, the adverse reaction profile was similar for the every 2week and every 3weekschedule, therefore summary safety results are provided in a pooled analysis(n=555) of both KEYTRUDA arms. Adverse reactions leading to permanent discontinuation of KEYTRUDA occurred in 9% of patients. Adverse reactions leading to discontinuation of KEYTRUDA in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 21% of patients; the most common (≥1%) was diarrhea (2.5%). Tables 4 and 5 summarize selected adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-006.

Table 4: Selected* Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-006

Adverse Reaction KEYTRUDA 10 mg/kg every 2 or 3 weeks
n=555
Ipilimumab
n=256
All Grades† (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
General
Fatigue 28 0.9 28 3.1
Skin and Subcutaneous Tissue
Rash‡ 24 0.2 23 1.2
Vitiligo§ 13 0 2 0
Musculoskeletal and Connective Tissue
Arthralgia 18 0.4 10 1.2
Back pain 12 0.9 7 0.8
Respiratory, Thoracic and Mediastinal
Cough 17 0 7 0.4
Dyspnea 11 0.9 7 0.8
Metabolism and Nutrition
Decreased appetite 16 0.5 14 0.8
Nervous System
Headache 14 0.2 14 0.8
* Adverse reactions occurring at same or higher incidence than in the ipilimumab arm
† Graded per NCI CTCAE v4.0
‡ Includes rash, rash erythematous, rash follicular, rash generalized, rash macular, rash macula papular, rash papular, rash pruritic, and exfoliative rash.
§ Includes skin hypopigmentation

Other clinically importantadverse reactionsoccurring in ≥10%ofpatients receiving KEYTRUDA were diarrhea (26%), nausea (21%), and pruritus (17%).

Table 5: Selected* Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Melanoma Patients Receiving KEYTRUDA in KEYNOTE-006

Laboratory Test† KEYTRUDA 10 mg/kg every 2 or 3 weeks Ipilimumab
All Grades‡ % Grades 3-4 % All Grades % Grades 3-4 %
Chemistry
Hyperglycemia 45 4.2 45 3.8
Hypertriglyceridemia 43 2.6 31 1.1
Hyponatremia 28 4.6 26 7
Increased AST 27 2.6 25 2.5
Hypercholesterolemia 20 1.2 13 0
Hematology
Anemia 35 3.8 33 4.0
Lymphopenia 33 7 25 6
* Laboratory abnormalities occurring at same or higher incidence than in ipilimumab arm
† Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (520 to 546 patients) and ipilimumab (237 to 247 patients); hypertriglyceridemia: KEYTRUDA n=429 and ipilimumab n=183; hypercholesterolemia: KEYTRUDA n=484 and ipilimumab n=205.
‡ Graded per NCI CTCAE v4.0

Other laboratory abnormalities occurring in ≥20% of patients receiving KEYTRUDAwere increased hypoalbuminemia (27% all Grades; 2.4% Grades3-4), increased ALT (23% all Grades; 3.1% Grades34), and increased alkaline phosphatase (21% all Grades, 2% Grades3-4).

Ipilimumab-Refractory Melanoma

The safety of KEYTRUDA inpatients with unresectable or metastatic melanoma with disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor, was investigated in KEYNOTE-002.KEYNOTE-002 was a multicenter, partially blinded (KEYTRUDA dose), randomized (1:1:1), active-controlled trial in which 528 patients received KEYTRUDA 2 mg/kg (n=178) or 10 mg/kg (n=179) every 3 weeks or investigator's choice of chemotherapy (n=171), consisting of dacarbazine (26%), temozolomide (25%), paclitaxel and carboplatin (25%), paclitaxel (16%), or carboplatin (8%) [see Clinical Studies]. Patients with autoimmune disease, severe immune-related toxicity related to ipilimumab, defined as any Grade4 toxicity or Grade3 toxicity requiring corticosteroid treatment (greaterthan 10 mg/day prednisone or equivalent dose) for greater than 12 weeks; medical conditions that required systemic corticosteroids or other immunosuppressive medication; a history of interstitial lungdisease; or an active infection requiring therapy, including HIV or hepatitis B or C, were ineligible.

The median duration of exposure to KEYTRUDA 2mg/kg every 3weeks was 3.7months (range: 1day to 16.6months) and to KEYTRUDA 10mg/kg every 3weeks was 4.8months (range: 1day to 16.8months). In the KEYTRUDA 2 mg/kg arm, 36% of patients were exposed to KEYTRUDA for ≥6 months and 4% were exposed for ≥12 months. In the KEYTRUDA 10 mg/kg arm, 41% of patients were exposed to KEYTRUDA for ≥6 months and 6% of patients were exposed to KEYTRUDA for ≥12 months.

The study population characteristics were: median age of 62years (range: 15 to 89); 61%male;98% White;41%had an elevated LDH value at baseline;83%had M1c stage disease;73% received two or more prior therapies for advanced or metastatic disease (100% received ipilimumab and 25% a BRAF inhibitor); and 15% with history of brain metastasis.

In KEYNOTE-002, the adverse reaction profile was similar for the 2 mg/kg dose and 10 mg/kg dose, therefore summary safety results are provided in a pooled analysis (n=357) of both KEYTRUDA arms. Adverse reactions resulting in permanent discontinuation occurred in 12% of patients receiving KEYTRUDA; the most common (≥1%)were generalphysical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%),and generalized edema (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 14%ofpatients; the most common (≥1%)were dyspnea (1%),diarrhea (1%), and maculo-papular rash (1%). Tables 6 and 7 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-002.

Table 6: Selected* Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-002

Adverse Reaction KEYTRUDA 2 mg/kg or 10 mg/kg every 3 weeks
n=357
Chemotherapy†
n=171
All Grades‡ (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
Skin and Subcutaneous Tissue
Pruritus 28 0 8 0
Rash§ 24 0.6 8 0
Gastrointestinal
Constipation 22 0.3 20 2.3
Diarrhea 20 0.8 20 2.3
Abdominal pain 13 1.7 8 1.2
Respiratory, Thoracic and Mediastinal
Cough 18 0 16 0
General
Pyrexia 14 0.3 9 0.6
Asthenia 10 2.0 9 1.8
Musculoskeletal and Connective Tissue
Arthralgia 14 0.6 10 1.2
* Adverse reactions occurring at same or higher incidence than in chemotherapy arm
† Chemotherapy: dacarbazine, temozolomide, carboplatin plus paclitaxel, paclitaxel, or carboplatin
‡ Graded per NCI CTCAE v4.0
§ Includes rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, and rash pruritic

Other clinically important adverse reactions occurring in patients receiving KEYTRUDA were fatigue (43%), nausea (22%), decreased appetite (20%), vomiting (13%), and peripheral neuropathy (1.7%).

Table 7: Selected* Laboratory Abnormalities Worsened from Baseline Occurring in≥20% of Melanoma Patients Receiving KEYTRUDA in KEYNOTE-002

Laboratory Test† KEYTRUDA 2 mg/kg or 10 mg/kg every 3 weeks Chemotherapy
All Grades‡ % Grades 3-4 % All Grades % Grades 3-4 %
Chemistry
Hyperglycemia 49 6 44 6
Hypoalbuminemia 37 1.9 33 0.6
Hyponatremia 37 7 24 3.8
Hypertriglyceridemia 33 0 32 0.9
Increased alkaline phosphatase 26 3.1 18 1.9
Increased AST 24 2.2 16 0.6
Decreased bicarbonate 22 0.4 13 0
Hypocalcemia 21 0.3 18 1.9
Increased ALT 21 1.8 16 0.6
* Laboratory abnormalities occurring at same or higher incidence than in chemotherapy arm.
† Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 320 to 325 patients) and chemotherapy (range: 154 to 161 patients); hypertriglyceridemia: KEYTRUDA n=247 and chemotherapy n=116; decreased bicarbonate: KEYTRUDA n=263 and chemotherapy n=123.
‡ Graded per NCI CTCAE v4.0

Other laboratory abnormalities occurring in ≥20% of patients receiving KEYTRUDA were anemia (44%allGrades; 10% Grades 3-4) and lymphopenia (40% all Grades; 9% Grades 3-4).

Adjuvant Treatment Of Resected Melanoma

The safety of KEYTRUDA as a single agent was investigated in KEYNOTE-054, a randomized (1:1)double-blind trial in which 1019 patients with completely resected stage IIIA (>1 mm lymph node metastasis), IIIB or IIIC melanoma received 200mg of KEYTRUDA by intravenous infusion every 3weeks(n=509) or placebo (n=502) for up to one year [see Clinical Studies]. Patients with active autoimmune disease or a medical condition that required immunosuppression or mucosal or ocularmelanoma were ineligible. Seventy-six percent of patients received KEYTRUDA for 6months or longer.

The study population characteristics were: median age of 54years (range: 19 to 88),25% age65 orolder; 62%male;and 94%ECOG PS of 0 and 6%ECOG PS of 1. Sixteen percent had stage IIIA, 46% had stage IIIB, 18% had stage IIIC (1-3 positive lymph nodes), and 20% had stage IIIC (≥4 positive lymph nodes).

Two patients treated with KEYTRUDA died from causes other than disease progression; causes of deathwere drug reaction with eosinophilia and systemic symptoms and autoimmune myositis with respiratory failure. Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. Adverse reactionsleading to permanent discontinuation occurred in 14% of patients receiving KEYTRUDA; the mostcommon (≥1%) were pneumonitis(1.4%), colitis (1.2%), and diarrhea (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 19% of patients; the most common (≥1%) were diarrhea (2.4%), pneumonitis (2%), increased ALT (1.4%), arthralgia (1.4%), increased AST(1.4%), dyspnea (1%), and fatigue (1%). Tables8and 9summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-054.

Table 8: Selected* Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-054

Adverse Reaction KEYTRUDA 200 mg every 3 weeks
n=509
Placebo
n=502
All Grades† (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
Gastrointestinal
Diarrhea 28 1.2 26 1.2
Nausea 17 0.2 15 0
Skin and Subcutaneous Tissue
Pruritus 19 0 12 0
Rash 13 0.2 9 0
Musculoskeletal and Connective Tissue
Arthralgia 16 1.2 14 0
Endocrine
Hypothyroidism 15 0 2.8 0
Hyperthyroidism 10 0.2 1.2 0
Respiratory, Thoracic and Mediastinal
Cough 14 0 11 0
General
Asthenia 11 0.2 8 0
Influenza like illness 11 0 8 0
Investigations
Weight loss 11 0 8 0
* Adverse reactions occurring at same or higher incidence than in placebo arm
† Graded per NCI CTCAE v4.03

Table 9: Selected* Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Melanoma Patients Receiving KEYTRUDA in KEYNOTE-054

Laboratory Test† KEYTRUDA 200 mg every 3 weeks Placebo
All Grades‡ % Grades 3-4 % All Grades % Grades 3-4 %
Chemistry
Increased ALT 27 2.4 16 0.2
Increased AST 24 1.8 15 0.4
Hematology
Lymphopenia 24 1 16 1.2
* Laboratory abnormalities occurring at same or higher incidence than placebo.
† Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 503 to 507 patients)and placebo (range: 492 to 498 patients).
‡ Graded per NCI CTCAE v4.03

NSCLC

First-Line Treatment Of Metastatic Nonsquamous NSCLC With Pemetrexed And Platinum Chemotherapy

The safety of KEYTRUDA in combination with pemetrexed and investigator's choice of platinum (either carboplatin or cisplatin) was investigated in KEYNOTE-189, a multicenter, double-blind, randomized (2:1),active-controlled trial inpatients with previously untreated, metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations [see Clinical Studies]. A total of 607 patients received KEYTRUDA 200 mg, pemetrexed and platinum every 3 weeks for 4 cycles followed by KEYTRUDA and pemetrexed (n=405) or placebo, pemetrexed, and platinum every 3weeks for 4cycles followed by placebo and pemetrexed (n=202). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.

The median duration of exposure to KEYTRUDA 200mg every 3weeks was 7.2months (range: 1day to 20.1 months). Sixty percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA for≥6 months. Seventy-two percent of patients received carboplatin.

The study population characteristics were: median age of 64years (range: 34 to 84), 49% age 65 orolder; 59% male; 94% White and 3% Asian; and 18% with history of brain metastases at baseline.

KEYTRUDA was discontinued for adverse reactions in 20% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 53% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA(≥2%) were neutropenia (13%), asthenia/fatigue (7%), anemia (7%), thrombocytopenia (5%), diarrhea (4%),pneumonia (4%), increased blood creatinine (3%), dyspnea (2%), febrile neutropenia (2%), upper respiratory tract infection (2%), increased ALT (2%), and pyrexia (2%). Tables10and 11summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE189.

Table 10: Adverse Reactions Occurring in ≥20% of Patients in KEYNOTE-189

Adverse Reaction KEYTRUDA 200 mg every 3 weeks Pemetrexed Platinum Chemotherapy
n=405
Placebo Pemetrexed Platinum Chemotherapy
n=202
All Grades* (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
Gastrointestinal
Nausea 56 3.5 52 3.5
Constipation 35 1.0 32 0.5
Diarrhea 31 5 21 3.0
Vomiting 24 3.7 23 3.0
General
Fatigue† 56 12 58 6
Pyrexia 20 0.2 15 0
Metabolism and Nutrition
Decreased appetite 28 1.5 30 0.5
Skin and Subcutaneous Tissue
Rash‡ 25 2.0 17 2.5
Respiratory, Thoracic and Mediastinal
Cough 21 0 28 0
Dyspnea 21 3.7 26 5
* Graded per NCI CTCAE v4.03
† Includes asthenia and fatigue
‡ Includes genital rash, rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular.

Table 11: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients in KEYNOTE-189

Laboratory Test* KEYTRUDA 200 mg every 3 weeks Pemetrexed Platinum Chemotherapy Placebo Pemetrexed Platinum Chemotherapy
All Grades† % Grades 3-4 % All Grades % Grades 3-4 %
Hematology
Anemia 85 17 81 18
Lymphopenia 64 22 64 25
Neutropenia 48 20 41 19
Thrombocytopenia 30 12 29 8
Chemistry
Hyperglycemia 63 9 60 7
Increased ALT 47 3.8 42 2.6
Increased AST 47 2.8 40 1.0
Hypoalbuminemia 39 2.8 39 1.1
Increased creatinine 37 4.2 25 1.0
Hyponatremia 32 7 23 6
Hypophosphatemia 30 10 28 14
Increased alkaline phosphatase 26 1.8 29 2.1
Hypocalcemia 24 2.8 17 0.5
Hyperkalemia 24 2.8 19 3.1
Hypokalemia 21 5 20 5
* Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA/pemetrexed/platinum chemotherapy (range: 381 to 401 patients) and placebo/pemetrexed/platinum chemotherapy (range: 184 to 197 patients).
† Graded per NCI CTCAE v4.03

First-Line Treatment Of Metastatic Squamous NSCLC With Carboplatin And Either Paclitaxel Or Paclitaxel Protein-Bound Chemotherapy

The safety of KEYTRUDA in combination with carboplatin and investigator's choice of either paclitaxel orpaclitaxel protein-boundwas investigated in KEYNOTE-407, a multicenter, double-blind, randomized (1:1), placebo-controlled trial in 558 patients with previously untreated, metastatic squamous NSCLC [see Clinical Studies]. Safety data are available for the first 203 patients who received KEYTRUDA and chemotherapy (n=101) or placebo and chemotherapy (n=102). Patients with autoimmune disease thatrequired systemic therapy within 2years of treatment; a medical condition that required immunosuppression;or who had received more than 30Gy of thoracic radiation within the prior 26weekswere ineligible.

The median duration of exposure to KEYTRUDA was 7months (range: 1day to 12months). Sixty-one percent of patientsin the KEYTRUDA arm were exposed to KEYTRUDA for ≥6 months. A total of 139 of 203 patients (68%) received paclitaxel and 64 patients (32%) received paclitaxel protein-bound in combination with carboplatin.

The study population characteristics were: median age of 65years (range: 40 to 83),52% age 65 or older; 78% male; 83%White; and 9% with history of brain metastases.

KEYTRUDA was discontinued for adverse reactions in 15% of patients, with no single type of adverse reaction accounting for the majority. Adverse reactions leading to interruption of KEYTRUDA occurred in 43%of patients; the most common(≥2%)were thrombocytopenia (20%), neutropenia (11%), anemia (6%), asthenia (2%), and diarrhea (2%). The most frequent (≥2%) serious adverse reactions were febrile neutropenia (6%), pneumonia (6%), and urinary tract infection (3%).

The adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs. 36%) and peripheral neuropathy (31% vs.25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

Previously Untreated NSCLC

The safety of KEYTRUDA was investigated in KEYNOTE-042, a multicenter, open-label, randomized (1:1), active-controlled trialin 1251 patients with PD-L1 expressing, previously untreated stage III NSCLC who were not candidates for surgical resection or definitive chemoradiation or metastatic NSCLC [see Clinical Studies]. Patients received KEYTRUDA 200 mg every 3 weeks (n=636) or investigator's choice of chemotherapy (n=615), consisting of pemetrexed and carboplatin followed by optional pemetrexed (n=312) or paclitaxel and carboplatin followed by optional pemetrexed (n=303)every 3 weeks. Patients with EGFR or ALK genomic tumor aberrations; autoimmune disease that required systemic therapy within 2years of treatment; a medical condition that required immunosuppression;or who had received more than 30Gy of thoracic radiation within the prior 26weeks were ineligible.

The median duration of exposure to KEYTRUDA was 5.6months (range: 1day to 27.3months). Forty-eight percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA 200 mg for ≥6 months.

The study population characteristics were:median age of 63years (range: 25 to 90), 45% age 65 orolder; 71% male;and 64% White, 30%Asian, and 2% Black. Nineteen percent were Hispanic or Latino. Eighty-seven percent had metastatic disease (stage IV), 13%had stage III disease (2% stage IIIA and11% stage IIIB), and 5% had treated brain metastases at baseline.

KEYTRUDA was discontinued for adverse reactions in 19% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3.0%), death due to unknown cause (1.6%), and pneumonia (1.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 33% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were pneumonitis (3.1%), pneumonia (3.0%), hypothyroidism (2.2%), and increased ALT (2.0%). The most frequent (≥2%) serious adverse reactions were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%).

Tables 12and 13summarize the adverse reactions and laboratory abnormalities, respectively, in patients treated with KEYTRUDA in KEYNOTE-042.

Table 12: Adverse Reactions Occurring in ≥10% of Patients in KEYNOTE-042

Adverse Reaction KEYTRUDA 200 mg every 3 weeks n=636 Chemotherapy n=615
All Grades* (%) Grades 3-5 (%) All Grades (%) Grades 3-5 (%)
General
Fatigue† 25 3.1 33 3.9
Pyrexia 10 0.3 8 0
Metabolism and Nutrition
Decreased appetite 17 1.7 21 1.5
Respiratory, Thoracic and Mediastinal
Dyspnea 17 2.0 11 0.8
Cough 16 0.2 11 0.3
Skin and Subcutaneous Tissue
Rash‡ 15 1.3 8 0.2
Gastrointestinal
Constipation 12 0 21 0.2
Diarrhea 12 0.8 12 0.5
Nausea 12 0.5 32 1.1
Endocrine
Hypothyroidism 12 0.2 1.5 0
Infections
Pneumonia 12 7 9 6
Investigations
Weight loss 10 0.9 7 0.2
* Graded per NCI CTCAE v4.03
† Includes fatigue and asthenia
‡ Includes rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular.

Table 13: Laboratory Abnormalities Worsened from Baseline in ≥20% of Patients in KEYNOTE-042

Laboratory Test* KEYTRUDA 200 mg every 3 weeks Chemotherapy
All Grades† % Grades 3-4 % All Grades % Grades 3-4 %
Chemistry
Hyperglycemia 52 4.7 51 5
Increased ALT 33 4.8 34 2.9
Hypoalbuminemia 33 2.2 29 1.0
Increased AST 31 3.6 32 1.7
Hyponatremia 31 9 32 8
Increased alkaline phosphatase 29 2.3 29 0.3
Hypocalcemia 25 2.5 19 0.7
Hyperkalemia 23 3.0 20 2.2
Increased prothrombin INR 21 2.0 15 2.9
Hematology
Anemia 43 4.4 79 19
Lymphopenia 30 7 41 13
* Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 598 to 610 patients) and chemotherapy (range: 588 to 597 patients); increased prothrombin INR: KEYTRUDA n=203 and chemotherapy n=173.
† Graded per NCI CTCAE v4.03

Previously Treated NSCLC

The safety of KEYTRUDA was investigated in KEYNOTE-010, a multicenter, open-label, randomized (1:1:1), active-controlled trial,in patients with advanced NSCLC who had documented disease progression following treatment with platinum-based chemotherapy and, if positive for EGFR or ALK genetic aberrations, appropriate therapy for these aberrations [see Clinical Studies]. A total of 991 patients received KEYTRUDA 2mg/kg (n=339) or 10mg/kg (n=343) every 3weeks or docetaxel (n=309)at 75mg/m² every 3weeks.Patients with autoimmune disease, medical conditions that required systemic corticosteroids or other immunosuppressive medication, or who had received more than 30Gy of thoracicradiation within the prior 26 weeks were ineligible.

The median duration of exposure to KEYTRUDA 2mg/kg every 3weeks was 3.5months (range: 1day to 22.4months) and to KEYTRUDA 10mg/kg every 3weeks was 3.5months (range 1day to 20.8months). The data described below reflect exposure to KEYTRUDA 2mg/kg in 31% of patients exposed to KEYTRUDA for ≥6 months. In the KEYTRUDA 10mg/kg arm, 34% of patients were exposed to KEYTRUDA for ≥6 months.

The study population characteristics were: median age of 63years (range: 20 to 88), 42% age 65 or older;61%male;72%White and 21% Asian; and 8% with advanced localized disease, 91% with metastatic disease, and 15% with history of brain metastases. Twenty-nine percent received two or more prior systemic treatments for advanced or metastatic disease.

In KEYNOTE-010, the adverse reaction profile was similar for the 2 mg/kg and 10 mg/kg dose, therefore summary safety results are provided in a pooled analysis (n=682). Treatment was discontinued for adverse reactions in 8% of patients receiving KEYTRUDA. The most common adverse events resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUD Aoccurred in 23%of patients; the most common (≥1%)were diarrhea (1%),fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). Tables 14and 15summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-010.

Table 14: Selected* Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-010

Adverse Reaction KEYTRUDA 2 or 10 mg/kg every 3 weeks
n=682
Docetaxel 75 mg/m² every 3 weeks
n=309
All Grades† (%) Grades 3-4 (%) All Grades† (%) Grades 3-4 (%)
Metabolism and Nutrition
Decreased appetite 25 1.5 23 2.6
Respiratory, Thoracic and Mediastinal
Dyspnea 23 3.7 20 2.6
Cough 19 0.6 14 0
Gastrointestinal
Nausea 20 1.3 18 0.6
Constipation 15 0.6 12 0.6
Vomiting 13 0.9 10 0.6
Skin and Subcutaneous Tissue
Rash‡ 17 0.4 8 0
Pruritus 11 0 3 0.3
Musculoskeletal and Connective Tissue
Arthralgia 11 1.0 9 0.3
Back pain 11 1.5 8 0.3
* Adverse reactions occurring at same or higher incidence than in docetaxel arm
† Graded per NCI CTCAE v4.0
‡ Includes rash, rash erythematous, rash macular, rash maculo-papular, rash papular, and rash pruritic

Other clinically important adverse reactions occurring in patients receiving KEYTRUDA were fatigue (25%), diarrhea (14%), asthenia (11%) and pyrexia (11%).

Table 15: Selected* Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% ofNSCLC Patients Receiving KEYTRUDA in KEYNOTE-010

Laboratory Test† KEYTRUDA Docetaxel
2 or 10 mg/kg every 3 weeks 75 mg/m² every 3 weeks
All Grades‡ % Grades 3-4 % All Grades‡ % Grades 3-4 %
Chemistry
Hyponatremia 32 8 27 2.9
Increased alkaline phosphatase 28 3.0 16 0.7
Increased AST 26 1.6 12 0.7
Increased ALT 22 2.7 9 0.4
* Laboratory abnormalities occurring at same or higher incidence than in docetaxel arm.
† Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 631 to 638 patients) and docetaxel(range: 274 to 277 patients).
‡ Graded per NCI CTCAE v4.0

Other laboratory abnormalities occurring in ≥20% of patients receiving KEYTRUDA were hyperglycemia (44% all Grades; 4.1% Grades 3-4), anemia (37% all Grades; 3.8% Grades3-4), hypertriglyceridemia (36% all Grades; 1.8% Grades 3-4), lymphopenia (35% all Grades; 9% Grades 3-4), hypoalbuminemia (34% all Grades; 1.6% Grades 3-4), and hypercholesterolemia (20% all Grades; 0.7% Grades3-4).

HNSCC

First-Line Treatment Of Metastatic Or Unresectable, Recurrent HNSCC

The safety of KEYTRUDA, as a single agent and in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, was investigated in KEYNOTE-048, a multicenter, open-label, randomized (1:1:1),active-controlled trial in patients with previously untreated, recurrent ormetastatic HNSCC [see Clinical Studies]. Patients with autoimmune disease that required systemic therapy within 2years of treatment or a medical condition that required immunosuppression were ineligible. A total of 576patientsreceived KEYTRUDA 200mg every 3weeks either as a single agent(n=300) or in combination with platinum and FU (n=276) every 3 weeks for 6 cycles followed by KEYTRUDA, compared to 287 patients who received cetuximab weekly in combination with platinum and FU every 3 weeks for 6 cycles followed by cetuximab.

The median duration of exposure to KEYTRUDA was 3.5months (range: 1day to 24.2months) in the KEYTRUDA single agent arm and was 5.8months (range: 3days to 24.2months) in the combination arm. Seventeen percent of patients in the KEYTRUDA single agent arm and 18% of patients in the combination arm were exposed to KEYTRUDA for ≥12 months. Fifty-seven percent of patients receiving KEYTRUDA in combination with chemotherapy started treatment with carboplatin.

KEYTRUDA was discontinued for adverse reactions in 12% of patients in the KEYTRUDA single agentarm. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA weresepsis (1.7%) and pneumonia (1.3%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 31% of patients; the most common adverse reactions leading to interruption of KEYTRUDA(≥2%) were pneumonia (2.3%), pneumonitis(2.3%), and hyponatremia (2%).

KEYTRUDA was discontinued for adverse reactions in 16% of patientsin the combination arm. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%),and septic shock (1.4%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 45% of patients; the most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were neutropenia (14%), thrombocytopenia (10%), anemia (6%), pneumonia (4.7%), and febrile neutropenia (2.9%).

Tables 16and 17summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-048.

Table 16: Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-048

Adverse Reaction KEYTRUDA 200 mg every 3 weeks
n=300
KEYTRUDA 200 mg every 3 weeks Platinum FU
n=276
Cetuximab Platinum FU
n=287
All Grades* (%) Grades 3-4 (%) All Grades* (%) Grades 3-4 (%) All Grades* (%) Grades 3-4 (%)
General
Fatigue† 33 4 49 11 48 8
Pyrexia 13 0.7 16 0.7 12 0
Mucosal inflammation 4.3 1.3 31 10 28 5
Gastrointestinal
Constipation 20 0.3 37 0 33 1.4
Nausea 17 0 51 6 51 6
Diarrhea‡ 16 0.7 29 3.3 35 3.1
Vomiting 11 0.3 32 3.6 28 2.8
Dysphagia 8 2.3 12 2.9 10 2.1
Stomatitis 3 0 26 8 28 3.5
Skin
Rash§ 20 2.3 17 0.7 70 8
Pruritus 11 0 8 0 10 0.3
Respiratory, Thoracic and Mediastinal
Cough¶ 18 0.3 22 0 15 0
Dyspnea# 14 2.0 10 1.8 8 1.0
Endocrine
Hypothyroidism 18 0 15 0 6 0
Metabolism and Nutrition
Decreased appetite 15 1.0 29 4.7 30 3.5
Weight loss 15 2 16 2.9 21 1.4
Infections
PneumoniaÞ 12 7 19 11 13 6
Nervous System
Headache 12 0.3 11 0.7 8 0.3
Dizziness 5 0.3 10 0.4 13 0.3
Peripheral sensory neuropathyβ 1 0 14 1.1 7 1
Musculoskeletal
Myalgiaa 12 1.0 13 0.4 11 0.3
Neck pain 6 0.7 10 1.1 7 0.7
Psychiatric
Insomnia 7 0.7 10 0 18 0
* Graded per NCI CTCAE v4.0
† Includes fatigue, asthenia
‡ Includes diarrhea, colitis, hemorrhagic diarrhea, microscopic colitis
§ Includes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, dermatitis contact, dermatitisexfoliative, drug eruption, erythema, erythema multiforme, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, pruritic rash, seborrheic dermatitis
¶ Includes cough, productive cough
# Includes dyspnea, exertional dyspnea
Þ Includes pneumonia, atypical pneumonia, bacterial pneumonia, staphylococcal pneumonia, aspiration pneumonia, lower respiratory tract infection, lung infection, lung infection pseudomonal
β Includes peripheral sensory neuropathy, peripheral neuropathy, hypoesthesia, dysesthesia
a Includes back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia

Table 17: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-048

Laboratory Test* KEYTRUDA 200 mg every 3 weeks KEYTRUDA 200 mg every 3 weeks Platinum FU Cetuximab Platinum FU
All Grades† (%) Grades 34 (%) All Grades† (%) Grades 34 (%) All Grades† (%) Grades 3-4 (%)
Hematology
Lymphopenia 54 25 69 35 74 45
Anemia 52 7 89 28 78 19
Thrombocytopenia 12 3.8 73 18 76 18
Neutropenia 7 1.4 67 35 71 42
Chemistry
Hyperglycemia 47 3.8 55 6 66 4.7
Hyponatremia 46 17 56 20 59 20
Hypoalbuminemia 44 3.2 47 4.0 49 1.1
Increased AST 28 3.1 24 2.0 37 3.6
Increased ALT 25 2.1 22 1.6 38 1.8
Increased alkaline phosphatase 25 2.1 27 1.2 33 1.1
Hypercalcemia 22 4.6 16 4.3 13 2.6
Hypocalcemia 22 1.1 32 4 58 7
Hyperkalemia 21 2.8 27 4.3 29 4.3
Hypophosphatemia 20 5 35 12 48 19
Hypokalemia 19 5 34 12 47 15
Increased creatinine 18 1.1 36 2.3 27 2.2
Hypomagnesemia 16 0.4 42 1.7 76 6
* Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratorymeasurement available: KEYTRUDA/chemotherapy (range: 235to 266 patients), KEYTRUDA (range: 241to 288patients), cetuximab/chemotherapy (range: 249 to 282 patients).
† Graded per NCI CTCAE v4.0

Previously Treated Recurrent Or Metastatic HNSCC

Among the 192patients with HNSCC enrolled in KEYNOTE-012 [see Clinical Studies], the median duration of exposure to KEYTRUDA was 3.3months (range: 1day to 27.9months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible forKEYNOTE-012.

The study population characteristics were: median age of 60years (range: 20 to 84), 35% age 65 or older; 83% male; and77% White, 15% Asian, and 5% Black. Sixty-one percent of patients had two or more lines of therapy in the recurrent or metastatic setting, and 95% had prior radiation therapy. Baseline ECOG PS was 0 (30%) or 1 (70%) and 86% had M1 disease.

KEYTRUDA was discontinued due to adverse reactions in 17% of patients. Serious adverse reactions occurred in 45% of patients receiving KEYTRUDA. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The incidence of adverse reactions, including serious adverse reactions, was similar between dosage regimens (10 mg/kg every 2 weeks or 200 mg every 3 weeks); therefore, summary safety results are provided in a pooled analysis. The mostcommon adverse reactions(occurring in ≥20%of patients) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in 2799patients with melanoma or NSCLC treated with KEYTRUDA as a single agent, with the exception of increased incidences of facial edema (10% all Grades; 2.1% Grades 3-4) and new or worsening hypothyroidism [see WARNINGS AND PRECAUTIONS].

Relapsed Or Refractory cHL

KEYNOTE-204

The safety of KEYTRUDA was evaluated in KEYNOTE-204 [see Clinical Studies]. Adults with relapsed or refractory cHL received KEYTRUDA 200mg intravenously every 3weeks (n=148)or brentuximab vedotin (BV) 1.8 mg/kg intravenously every 3 weeks (n=152). The trial required an ANC ≥1000/μL, platelet count ≥75,000/μL, hepatic transaminases ≤2.5 times the upper limit of normal (ULN), bilirubin ≤1.5 timesULN, and ECOG performance status of 0 or 1. The trial excluded patients with activenon-infectious pneumonitis, prior pneumonitis requiring steroids, active autoimmune disease, a medical condition requiring immunosuppression, or allogeneic HSCT within the past 5 years. The median duration of exposure to KEYTRUDA was10months (range:1day to 2.2years), with68% receiving at least6months of treatment and 48% receiving at least 1year of treatment.

Serious adverse reactions occurred in 30% of patients who received KEYTRUDA. Serious adverse reactions in ≥1% included pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three patients (2%)died from causes other than disease progression: two from complications after allogeneic HSCT and one from unknown cause.

Permanent discontinuation of KEYTRUDA due to an adverse reaction occurredin 14% of patients; 7%ofpatients discontinued treatment due to pneumonitis. Dosage interruption of KEYTRUDA due to an adverse reaction occurred in 30% of patients. Adverse reactions which required dosage interruption in ≥3% of patients were upper respiratory tract infection, pneumonitis, transaminase increase, and pneumonia.

Thirty-eight percent of patients had an adverse reaction requiring systemic corticosteroid therapy.

Table 18 summarizes adverse reactions in KEYNOTE-204.

Table 18: Adverse Reactions (≥10%) in Patients with cHL who Received KEYTRUDA in KEYNOTE-204

Adverse Reaction KEYTRUDA 200 mg every 3 weeks
N=148
Brentuximab Vedotin 1.8 mg/kg every 3 weeks
N=152
All Grades* (%) Grades 3-4 (%) All Grades* (%) Grades 3-4† (%)
Infections
Upper respiratory tract infection‡ 41 1.4 24 0
Urinary tract infection 11 0 3 0.7
Musculoskeletal and Connective Tissue
Musculoskeletal pain§ 32 0 29 1.3
Gastrointestinal
Diarrhea¶ 22 2.7 17 1.3
Nausea 14 0 24 0.7
Vomiting 14 1.4 20 0
Abdominal pain# 11 0.7 13 1.3
General
Pyrexia 20 0.7 13 0.7
FatigueÞ 20 0 22 0.7
Skin and Subcutaneous Tissue
Rashβ 20 0 19 0.7
Pruritus 18 0 12 0
Respiratory, Thoracic and Mediastinal
Cougha 20 0.7 14 0.7
Pneumonitise 11 5 3 1.3
Dyspneað 11 0.7 7 0.7
Endocrine
Hypothyroidism 19 0 3 0
Nervous System
Peripheral neuropathyø 11 0.7 43 7
Headachey 11 0 11 0
* Graded per NCI CTCAE v4.0
† Adverse reactions in BV arm were Grade 3 only.
‡ Includes acute sinusitis, nasopharyngitis, pharyngitis, pharyngotonsillitis, rhinitis, sinusitis, sinusitis bacterial, tonsillitis, upper espiratory tract infection, viral upper respiratory tract infection
 § Includes arthralgia, back pain, bone pain, musculoskeletal discomfort, musculoskeletal chestpain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity
¶ Includes diarrhea, gastroenteritis, colitis, enterocolitis
# Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper
Þ Includes fatigue, asthenia
β Includes dermatitis acneiform, dermatitis atopic, dermatitis allergic, dermatitis contact, dermatitis exfoliative, dermatitis psoriasiform, eczema, rash, rash erythematous, rash follicular, rash maculo-papular, rash papular, rash pruritic, toxic skin eruption
a Includes cough, productive cough
e Includes pneumonitis, interstitial lung disease
ð Includes dyspnea, dyspnea exertional, wheezing
ø Includes dysesthesia, hypoesthesia, neuropathy peripheral, paraesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, polyneuropathy
y Includes headache, migraine, tension headache

Clinically relevantadverse reactions in <10% of patientswho received KEYTRUDA included herpes virus infection (9%), pneumonia (8%), oropharyngeal pain (8%), hyperthyroidism (5%),hypersensitivity (4.1%), infusion reactions (3.4%),altered mental state (2.7%),and in 1.4% each, uveitis, myocarditis, thyroiditis, febrile neutropenia, sepsis, and tumor flare.

Table 19 summarizes laboratory abnormalities in KEYNOTE-204.

Table 19: Laboratory Abnormalities (≥15%) That Worsened from Baseline in Patients with cHL in KEYNOTE-204

Laboratory Abnormality* KEYTRUDA 200 mq every 3 weeks Brentuximab Vedotin 1.8 mq/kq every 3 weeks
All Grades† (%) Grades 3-4 (%) All Grades* (%) Grades 3-4 (%)
Chemistry
Hyperglycemia 46 4.1 36 2.0
Increased AST 39 5 41 3.9
Increased ALT 34 6 45 5
Hypophosphatemia 31 5 18 2.7
Increased creatinine 28 3.4 14 2.6
Hypomagnesemia 25 0 12 0
Hyponatremia 24 4.1 20 3.3
Hypocalcemia 22 2.0 16 0
Increased alkaline phosphatase 21 2.1 22 2.6
Hyperbilirubinemia 16 2.0 9 1.3
Hypoalbuminemia 16 0.7 19 0.7
Hyperkalemia 15 1.4 8 0
Hematoloqy
Lymphopenia 35 9 32 13
Thrombocytopenia 34 10 26 5
Neutropenia 28 8 43 17
Anemia 24 5 33 8
* Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 143 to 148patients)and BV (range: 146 to 152 patients); hypomagnesemia: KEYTRUDA n=53 and BV n=50.
† Graded per NCI CTCAE v4.0

KEYNOTE-087

Among the 210patients with cHL who received KEYTRUDA in KEYNOTE-087 [see Clinical Studies], the median duration of exposure to KEYTRUDA was 8.4 months (range: 1 day to 15.2 months).Serious adverse reactions occurred in 16% of patients who received KEYTRUDA. Serious adverse reactions that occurred in ≥1% of patients included pneumonia, pneumonitis, pyrexia, dyspnea, graft versus host disease(GVHD)and herpes zoster. Two patients died from causes other than disease progression; one from GVHD after subsequent allogeneic HSCT and one from septic shock.

Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 5% of patients and dosage interruption due to an adverse reaction occurred in 26%. Fifteen percent of patients had an adverse reaction requiring systemic corticosteroid therapy.Tables20and 21summarize adverse reactions and laboratory abnormalities, respectively, in KEYNOTE-087.

Table 20: Adverse Reactions (≥10%) in Patients with cHL who Received KEYTRUDA in KEYNOTE-087

Adverse Reaction KEYTRUDA 200 mg every 3 weeks
N=210
All Grades* (%) Grade 3 (%)
General
Fatigue† 26 1.0
Pyrexia 24 1.0
Respiratory, Thoracic and Mediastinal
Cough‡ 24 0.5
Dyspnea§ 11 1.0
Musculoskeletal and Connective Tissue
Musculoskeletal pain¶ 21 1.0
Arthralgia 10 0.5
Gastrointestinal
Diarrhea# 20 1.4
Vomiting 15 0
Nausea 13 0
Skin and Subcutaneous Tissue
RashÞ 20 0.5
Pruritus 11 0
Endocrine
Hypothyroidism 14 0.5
Infections
Upper respiratory tract infection 13 0
Nervous System
Headache 11 0.5
Peripheral neuropathyβ 10 0
* Graded per NCI CTCAE v4.0
† Includes fatigue, asthenia
‡ Includes cough, productive cough
§ Includes dyspnea, dyspnea exertional, wheezing
¶ Includes back pain, myalgia, bone pain, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, musculoskeletal discomfort, neck pain
# Includes diarrhea, gastroenteritis, colitis, enterocolitis
Þ Includes rash, rash maculo-papular, drug eruption, eczema, eczema asteatotic, dermatitis, dermatitis acneiform, dermatitis contact, rash erythematous, rash macular,rash papular, rash pruritic, seborrheic dermatitis, dermatitis psoriasiform
β Includes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy

Clinically relevant adverse reactions in <10% of patients who received KEYTRUDA included infusion reactions (9%), hyperthyroidism (3%), pneumonitis (3%), uveitis and myositis (1% each),and myelitis and myocarditis (0.5% each).

Table 21: Select Laboratory Abnormalities (≥15%) That Worsened from Baseline in Patients with cHL who Received KEYTRUDA in KEYNOTE-087

Laboratory Abnormality* KEYTRUDA 200 mg every 3 weeks
All Grades* (%) Grades 3-4 (%)
Chemistry
Hypertransaminasemia‡ 34 2
Increased alkaline phosphatase 17 0
Increased creatinine 15 0.5
Hematology
Anemia 30 6
Thrombocytopenia 27 4
Neutropenia 24 7
* Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 208 to 209 patients)
† Graded per NCI CTCAE v4.0
‡ Includes elevation of AST or ALT

Hyperbilirubinemia occurred in less than 15% of patients on KEYNOTE-087(10% all Grades, 2.4% Grade 3-4).

PMBCL

Among the 53patients with PMBCL who received KEYTRUDA in KEYNOTE-170 [see Clinical Studies], the median duration of exposure to KEYTRUDA was 3.5 months (range: 1 day to 22.8 months). Serious adverse reactions occurred in 26% of patients. Seriousadverse reactions that occurred in >2% of patients included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 8% of patients and dosage interruption due to an adverse reaction occurred in 15%. Twenty-five percent of patients had an adverse reaction requiring systemic corticosteroid therapy.Tables22and 23summarize adverse reactions and laboratory abnormalities, respectively, in KEYNOTE-170.

Table 22: Adverse Reactions (≥10%) in Patients with PMBCL who Received KEYTRUDA inKEYNOTE-170

Adverse Reaction KEYTRUDA 200 mg every 3 weeks
N=53
All Grades* (%) Grades 3-4 (%)
Musculoskeletal and Connective Tissue
Musculoskeletal pain† 30 0
Infections
Upper respiratory tract infection* 28 0
General
Pyrexia 28 0
Fatigue§ 23 2
Respiratory, Thoracic and Mediastinal
Cough¶ 26 2
Dyspnea 21 11
Gastrointestinal
Diarrhea# 13 2
Abdominal painÞ 13 0
Nausea 11 0
Cardiac
Arrhythmia β 11 4
Nervous System
Headache 11 0
* Graded per NCI CTCAE v4.0
† Includes arthralgia, back pain, myalgia, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, bone pain, neck pain, non-cardiac chest pain
‡ Includes nasopharyngitis, pharyngitis, rhinorrhea, rhinitis, sinusitis, upper respiratory tract infection
§ Includes fatigue, asthenia
¶ Includes allergic cough, cough,productive cough
# Includes diarrhea, gastroenteritis
Þ Includes abdominal pain, abdominal pain upper
β Includes atrial fibrillation, sinus tachycardia, supraventricular tachycardia, tachycardia

Clinically relevantadverse reactions in <10% of patients who received KEYTRUDA included hypothyroidism (8%), hyperthyroidism and pericarditis (4% each), and thyroiditis, pericardial effusion, pneumonitis, arthritis and acute kidney injury (2% each).

Table 23: Laboratory Abnormalities (≥15%) That Worsened from Baseline in Patients with PMBCL who Received KEYTRUDA in KEYNOTE-170

Laboratory Abnormality* KEYTRUDA 200 mg every 3 weeks
All Grades† (%) Grades 3-4 (%)
Hematology
Anemia 47 0
Leukopenia 35 9
Lymphopenia 32 18
Neutropenia 30 11
Chemistry
Hyperglycemia 38 4
Hypophosphatemia 29 10
Hypertransaminasemia‡ 27 4
Hypoglycemia 19 0
Increased alkaline phosphatase 17 0
Increased creatinine 17 0
Hypocalcemia 15 4
Hypokalemia 15 4
* Each test incidence is based on the number of patients who had both baseline and atleast one on-study laboratory measurement available: KEYTRUDA (range: 44 to 48 patients)
† Graded per NCI CTCAE v4.0
‡ Includes elevation of AST or ALT

Urothelial Carcinoma

Cisplatin Ineligible Patients With Urothelial Carcinoma

The safety of KEYTRUDA was investigated in KEYNOTE-052, a single-arm trial that enrolled 370patients with locally advanced or metastatic urothelial carcinoma who were not eligible for cisplatin-containing chemotherapy. Patients with autoimmune disease or medical conditions that required systemic corticosteroids or other immunosuppressive medications were ineligible [see Clinical Studies]. Patients received KEYTRUDA 200mg every 3weeks until unacceptable toxicity or either radiographic orclinical disease progression.

The median duration of exposure to KEYTRUDA was 2.8months (range: 1day to 15.8months).

KEYTRUDA was discontinued due to adverse reactions in 11% of patients. Eighteen patients (5%) died from causes other than disease progression. Five patients (1.4%) who were treated with KEYTRUDA experienced sepsis which led to death, and three patients (0.8%) experienced pneumonia which led to death. Adverse reactions leading to interruption of KEYTRUDA occurred in 22% of patients; the most common (≥1%) were liver enzyme increase, diarrhea, urinary tract infection, acute kidney injury, fatigue, jointpain, and pneumonia. Serious adverse reactions occurred in 42% of patients. The most frequent serious adverse reactions (≥2%) were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis.

Immune-related adverse reactions that required systemic glucocorticoids occurred in 8% of patients, use of hormonal supplementation due to an immune-related adverse reaction occurred in 8% of patients,and5%of patients required at least one steroid dose ≥40 mg oralprednisone equivalent.

Table 24 summarizes adverse reactions in patients on KEYTRUDA in KEYNOTE-052.

Table 24: Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-052

Adverse Reaction KEYTRUDA 200 mg every 3 weeks
N=370
All Grades* (%) Grades 3-4 (%)
General
Fatigue† 38 6
Pyrexia 11 0.5
Weight loss 10 0
Musculoskeletal and Connective Tissue
Musculoskeletal pain‡ 24 4.9
Arthralgia 10 1.1
Metabolism and Nutrition
Decreased appetite 22 1.6
Hyponatremia 10 4.1
Gastrointestinal
Constipation 21 1.1
Diarrhea§ 20 2.4
Nausea 18 1.1
Abdominal pain¶ 18 2.7
Elevated LFTs# 13 3.5
Vomiting 12 0
Skin and Subcutaneous Tissue
RashÞ 21 0.5
Pruritus 19 0.3
Edema peripheralβ 14 1.1
Infections
Urinary tract infection 19 9
Blood and Lymphatic System
Anemia 17 7
Respiratory, Thoracic, and Mediastinal
Cough 14 0
Dyspnea 11 0.5
Renal and Urinary
Increased blood creatinine 11 1.1
Hematuria 13 3.0
* Graded per NCI CTCAE v4.0
† Includes fatigue, asthenia
‡ Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, pain in extremity, spinal pain
§ Includes diarrhea, colitis, enterocolitis, gastroenteritis, frequent bowel movements
¶ Includes abdominal pain, pelvic pain, flankpain, abdominal pain lower, tumor pain, bladder pain, hepatic pain, suprapubic pain, abdominal discomfort, abdominal pain upper
# Includes autoimmune hepatitis, hepatitis, hepatitis toxic, liver injury, increased transaminases,hyperbilirubinemia, increased blood bilirubin, increased alanine aminotransferase, increased aspartate aminotransferase, increased hepatic enzymes, increased liver function tests
Þ Includes dermatitis, dermatitis bullous, eczema, erythema, rash, rash macular, rash maculo-papular, rash pruritic, rash pustular, skin reaction, dermatitis acneiform, seborrheic dermatitis, palmar-plantar erythrodysesthesia syndrome, rash generalized
β Includes edema peripheral, peripheral swelling

Previously Treated Urothelial Carcinoma

The safety of KEYTRUDA for the treatment of patients with locally advanced or metastatic urothelial carcinoma with disease progression following platinum-containing chemotherapy was investigated in KEYNOTE-045. KEYNOTE-045 was a multicenter, open-label, randomized (1:1), active-controlled trial in which 266 patients received KEYTRUDA 200 mg every 3 weeks or investigator's choice of chemotherapy (n=255), consisting of paclitaxel (n=84), docetaxel (n=84) or vinflunine (n=87) [see Clinical Studies]. Patients with autoimmune disease or a medical condition that required systemic corticosteroids orother immunosuppressive medications were ineligible.

The median duration of exposure was 3.5months (range: 1day to 20months) in patients who received KEYTRUDA and 1.5months (range: 1day to 14months) in patients who received chemotherapy.

KEYTRUDA was discontinued due to adverse reactions in 8% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Adverse reactions leading to interruption of KEYTRUDA occurred in 20%ofpatients;the most common (≥1%) were urinary tract infection (1.5%), diarrhea (1.5%), and colitis (1.1%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients. The most frequent serious adverse reactions (≥2%) in KEYTRUDA-treated patients were urinary tract infection, pneumonia, anemia, and pneumonitis. Tables 25and 26summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-045.

Table 25: Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-045

Adverse Reaction KEYTRUDA 200 mg every 3 weeks
n=266
Chemotherapy*
n=255
All Grades† (%) Grades 3-4 (%) All Grades† (%) Grades 3-4 (%)
General
Fatigue‡ 38 4.5 56 11
Pyrexia 14 0.8 13 1.2
Musculoskeletal and Connective Tissue
Musculoskeletal pain§ 32 3.0 27 2.0
Skin and Subcutaneous Tissue
Pruritus 23 0 6 0.4
Rash¶ 20 0.4 13 0.4
Gastrointestinal
Nausea 21 1.1 29 1.6
Constipation 19 1.1 32 3.1
Diarrhea# 18 2.3 19 1.6
Vomiting 15 0.4 13 0.4
Abdominal pain 13 1.1 13 2.7
Metabolism and Nutrition
Decreased appetite 21 3.8 21 1.2
Infections
Urinary tract infection 15 4.9 14 4.3
Respiratory, Thoracic and Mediastinal
CoughÞ 15 0.4 9 0
Dyspneaβ 14 1.9 12 1.2
Renal and Urinary
Hematuria a 12 2.3 8 1.6
* Chemotherapy: paclitaxel, docetaxel, or vinflunine
† Graded per NCI CTCAE v4.0
‡ Includes asthenia, fatigue, malaise, lethargy
§ Includes back pain, myalgia, bone pain, musculoskeletal pain, pain in extremity, musculoskeletal chestpain, musculoskeletal discomfort, neck pain
¶ Includes rash maculo-papular, rash, genital rash, rash erythematous, rash papular, rash pruritic, rash pustular, erythema, drug eruption, eczema, eczema asteatotic, dermatitis contact, dermatitis acneiform, dermatitis, seborrheic keratosis, lichenoid keratosis
# Includes diarrhea, gastroenteritis, colitis, enterocolitis
Þ Includes cough, productive cough
β Includes dyspnea, dyspnea exertional, wheezing
a Includes blood urine present, hematuria, chromaturia

Table 26: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Urothelial Carcinoma Patients Receiving KEYTRUDA in KEYNOTE-045

Laboratory Test* KEYTRUDA 200 mg every 3 weeks Chemotherapy
All Grades† % Grades 3-4 % All Grades† % Grades 3-4 %
Chemistry
Hyperglycemia 52 8 60 7
Anemia 52 13 68 18
Lymphopenia 45 15 53 25
Hypoalbuminemia 43 1.7 50 3.8
Hyponatremia 37 9 47 13
Increased alkaline phosphatase 37 7 33 4.9
Increased creatinine 35 4.4 28 2.9
Hypophosphatemia 29 8 34 14
Increased AST 28 4.1 20 2.5
Hyperkalemia 28 0.8 27 6
Hypocalcemia 26 1.6 34 2.1
* Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 240 to 248 patients) and chemotherapy (range: 238 to 244 patients); phosphate decreased: KEYTRUDA n=232 and chemotherapy n=222.
† Graded per NCI CTCAE v4.0

BCG-unresponsive High-risk NMIBC

The safety of KEYTRUDA was investigated in KEYNOTE-057, a multicenter, open-label, single-arm trial that enrolled 148patients with high-risk non-muscle invasive bladder cancer (NMIBC),96 of whom hadBCG-unresponsive carcinoma in situ (CIS) with or without papillary tumors. Patients received KEYTRUDA200mg every 3weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC or progressive disease, or up to 24 months of therapy without disease progression.

The median duration of exposure to KEYTRUDA was 4.3months (range:1dayto 25.6months).

KEYTRUDA was discontinued due to adverse reactions in 11% of patients. The most common adverse(>1%)reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 22%ofpatients;the most common (≥2%) were diarrhea (4%) and urinary tract infection (2%). Serious adverse reactions occurred in 28% of KEYTRUDA-treated patients. The most frequent serious adverse reactions (≥2%)in KEYTRUDA-treated patients were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%),and urinary tract infection (2%). Tables 27 and 28 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-057.

Table 27: Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-057

Adverse Reaction KEYTRUDA 200 mg every 3 weeks N=148
All Grades* (%) Grades 3-4 (%)
General
Fatigue† 29 0.7
Peripheral edema‡ 11 0
Gastrointestinal
Diarrhea§ 24 2.0
Nausea 13 0
Constipation 12 0
Skin and Subcutaneous Tissue
Rash¶ 24 0.7
Pruritus 19 0.7
Musculoskeletal and Connective Tissue
Musculoskeletal pain# 19 0
Arthralgia 14 1.4
Renal and Urinary
Hematuria 19 1.4
Respiratory, Thoracic, and Mediastinal
CoughÞ 19 0
Infections
Urinary tract infection 12 2.0
Nasopharyngitis 10 0
Endocrine
Hypothyroidism 11 0
* Graded per NCI CTCAE v4.03
† Includes asthenia, fatigue, malaise
‡ Includes edema peripheral, peripheral swelling
§ Includes diarrhea, gastroenteritis, colitis
¶ Includes rash maculo-papular, rash, rash erythematous, rash pruritic, rash pustular, erythema, eczema, eczema asteatotic, lichenoid keratosis, urticaria, dermatitis
# Includes back pain, myalgia, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, neck pain
Þ Includes cough, productive cough

Table 28: Laboratory Abnormalities Worsened from Baseline Occurring in≥20% of BCG-unresponsive NMIBC Patients Receiving KEYTRUDA inKEYNOTE-057

Laboratory Test* KEYTRUDA 200 mg every 3 weeks
All Grades† (%) Grades 3-4 (%)
Chemistry
Hyperglycemia 59 8
Increased ALT 25 3.4
Hyponatremia 24 7
Hypophosphatemia 24 6
Hypoalbuminemia 24 2.1
Hyperkalemia 23 1.4
Hypocalcemia 22 0.7
Increased AST 20 3.4
Increased creatinine 20 0.7
Hematology
Anemia 35 1.4
Lymphopenia 29 1.6
* Graded per NCI CTCAE v4.03
† Includes asthenia, fatigue, malaise
‡ Includes edema peripheral, peripheral swelling
§ Includes diarrhea, gastroenteritis, colitis
¶ Includes rash maculo-papular, rash, rash erythematous, rash pruritic, rash pustular, erythema, eczema, eczema asteatotic, lichenoid keratosis, urticaria, dermatitis
# Includes back pain, myalgia, musculoskeletal pain, pain in extremity, musculoskeletal chest pain,neck pain
Þ Includes cough, productive cough

Microsatellite Instability-High Or Mismatch Repair Deficient Colorectal Cancer

Among the 153patients with MSI-H or dMMR CRC enrolled in KEYNOTE-177 [see Clinical Studies] treated with KEYTRUDA, the median duration of exposure to KEYTRUDA was 11.1 months (range: 1day to 30.6months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with MSI-H or dMMR CRC were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent.

Gastric Cancer

First-Line Treatment Of Locally Advanced Unresectable Or Metastatic HER2-Positive Gastric Cancer With Trastuzumab And Chemotherapy

The safety analysis of Study KEYNOTE-811 included 217patientswith HER2-positive gastric cancer whoreceived KEYTRUDA 200mg, trastuzumab, and CAPOX (n=189) or FP (n=28) every 3weeks, comparedto 216patients who received placebo, trastuzumab, and CAPOX (n=187) or FP (n=29) every 3weeks [see Clinical Studies].

The median duration of exposure to KEYTRUDA was 5.8months (range: 1day to 17.7months).

The study population characteristics were: median age of63years (range:19to 84), 43% age 65 orolder; 81% male; 58% White, 35% Asian, and 0.9% Black; 44% ECOG PS of 0 and 56% ECOG PS of 1.

KEYTRUDA and placebo werediscontinued due to adverse reactions in 6% of patientsin each arm. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 58% of patients; the mostcommon adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were neutropenia (18%), thrombocytopenia (12%), diarrhea (6%), anemia (3.7%), hypokalemia (3.7%), fatigue/asthenia (3.2%), decreased appetite (3.2%), increased AST (2.8%), increased blood bilirubin (2.8%), pneumonia (2.8%), increased ALT (2.3%), and vomiting (2.3%).

In the KEYTRUDAarmversusplacebo, there was a difference of≥5% incidence between patientstreated with KEYTRUDA versus standard of care for diarrhea (53% vs 44%), and nausea (49% vs 44%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms.

There was a difference of ≥5% incidence between patients treated with KEYTRUDA versus standard ofcare for increased ALT (34% vs 29%), and increased creatinine (20% vs 10%). There were no clinicallymeaningful differences in incidence of Grade 3-4 toxicity between arms.

Previously Treated Gastric Cancer

Among the 259patients with gastric cancer enrolled inKEYNOTE-059 [see Clinical Studies (14.9)], the median duration of exposure to KEYTRUDA was 2.1 months (range: 1 day to 21.4 months). Patients with autoimmune disease or a medical condition that required immunosuppression or with clinical evidence ofascites by physical exam were ineligible. Adverse reactions occurring in patients with gastric cancer were similar to those occurring in 2799patients with melanoma or NSCLCtreated with KEYTRUDA as a single agent.

Esophageal Cancer

First-Line Treatment Of Locally Advanced Unresectable Or Metastatic Esophageal Cancer/Gastroesophageal Junction

The safety ofKEYTRUDA, in combination with cisplatin and FU chemotherapy was investigated in KEYNOTE-590, a multicenter, double-blind, randomized (1:1), placebo-controlled trialfor thefirst-line treatment in patients with metastatic orlocally advanced esophageal or gastroesophageal junction (tumors with epicenter 1 to 5 centimeters above theGEJ) carcinoma who were not candidates for surgicalresection or definitive chemoradiation [see Clinical Studies (14.10)]. A total of 740 patients received either KEYTRUDA 200 mg (n=370) or placebo (n=370) every 3weeksfor up to 35cycles, bothin combination with up to 6 cycles of cisplatin and up to 35 cycles of FU.

The median duration of exposure was 5.7 months (range: 1 day to 26 months) in the KEYTRUDAcombination arm and 5.1months (range:3daysto 27months) in the chemotherapy arm.

KEYTRUDA was discontinued for adverse reactions in 15% of patients.The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). Adverse reactions leading to interruption ofKEYTRUDA occurred in 67% of patients. The most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were neutropenia (19%), fatigue/asthenia (8%),decreased white blood cell count (5%), pneumonia (5%), decreased appetite (4.3%),anemia (3.2%), increased blood creatinine (3.2%), stomatitis (3.2%),malaise (3.0%), thrombocytopenia (3%), pneumonitis (2.7%), diarrhea (2.4%), dysphagia (2.2%), and nausea (2.2%).

Tables 29 and 30 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-590.

Table 29: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-590

Adverse Reaction KEYTRUDA 200 mg every 3 weeks Cisplatin FU
n=370
Placebo Cisplatin FU
n=370
All Grades* (%) Grades 3-4† (%) All Grades* (%) Grades 3-4† (%)
Gastrointestinal
Nausea 67 7 63 7
Constipation 40 0 40 0
Diarrhea 36 4.1 33 3
Vomiting 34 7 32 5
Stomatitis 27 6 26 3.8
General
Fatigue‡ 57 12 46 9
Metabolism and Nutrition
Decreased appetite 44 4.1 38 5
Investigations
Weight loss 24 3.0 24 5
* Graded per NCI CTCAE v4.03
† One fatal event of diarrhea was reported in each arm.
‡ Includes asthenia, fatigue

Table 30: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Esophageal Cancer Patients Receiving KEYTRUDA in KEYNOTE-590

Laboratory Test* KEYTRUDA 200 mg every 3 weeks Cisplatin FU Chemotherapy (Cisplatin and FU)
All Grades† % Grades 3-4 % All Grades† % Grades 3-4 %
Hematology
Anemia 83 21 86 24
Neutropenia 74 43 71 41
Leukopenia 72 21 73 17
Lymphopenia 55 22 53 18
Thrombocytopenia 43 5 46 8
Chemistry
Hyperglycemia 56 7 55 6
Hyponatremia 53 19 54 19
Hypoalbuminemia 52 2.8 52 2.3
Increased creatinine 45 2.5 42 2.5
Hypocalcemia 44 3.9 38 2
Hypophosphatemia 37 9 31 10
Hypokalemia 30 12 34 15
Increased alkaline phosphatase 29 1.9 29 1.7
Hyperkalemia 28 3.6 27 2.6
Increased AST 25 4.4 22 2.8
Increased ALT 23 3.6 18 1.7
* Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA/cisplatin/FU (range: 345 to 365 patients) and placebo/cisplatin/FU (range: 330 to 358 patients)
† Graded per NCI CTCAEv4.03

Previously Treated Recurrent Locally Advanced Or Metastatic Esophageal Cancer

Among the 314patients with esophageal cancer enrolled in KEYNOTE-181 [see Clinical Studies] treated with KEYTRUDA, the median duration of exposure to KEYTRUDA was 2.1months (range: 1day to 24.4months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring inpatients with esophageal cancer were similar to those occurring in 2799patients with melanoma or NSCLC treated with KEYTRUDA as a single agent.

Cervical Cancer

Among the 98patients with cervical cancer enrolled in Cohort E of KEYNOTE-158 [see Clinical Studies], the median duration of exposure to KEYTRUDA was 2.9 months (range: 1 day to 22.1 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible.

KEYTRUDA was discontinued due to adverse reactions in 8% of patients. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA. The most frequent serious adverse reactions reported included anemia (7%), fistula (4.1%), hemorrhage (4.1%), and infections [except UTIs] (4.1%).Tables31and 32summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-158.

Table 31: Adverse Reactions Occurring in ≥10% of Patients with Cervical Cancer in KEYNOTE-158

Adverse Reaction KEYTRUDA 200 mg every 3 weeks
N=98
All Grades* (%) Grades 3-4 (%)
General
Fatigue† 43 5
Pain‡ 22 2.0
Pyrexia 19 1.0
Edema peripheral§ 15 2.0
Musculoskeletal and Connective Tissue
Musculoskeletal pain¶ 27 5
Gastrointestinal
Diarrhea# 23 2.0
Abdominal painÞ 22 3.1
Nausea 19 0
Vomiting 19 1.0
Constipation 14 0
Metabolism and Nutrition
Decreased appetite 21 0
Vascular
Hemorrhageβ 19 5
Infections
UTIà 18 6
Infection (except UTI)e 16 4.1
Skin and Subcutaneous Tissue
Rashð 17 2.0
Endocrine
Hypothyroidism 11 0
Nervous System
Headache 11 2.0
Respiratory, Thoracic and Mediastinal
Dyspnea 10 1.0
* Graded per NCI CTCAE v4.0
† Includes asthenia, fatigue, lethargy, malaise
‡ Includes breast pain, cancer pain, dysesthesia, dysuria, ear pain, gingival pain, groin pain, lymph node pain, oropharyngeal pain, pain, pain of skin, pelvic pain, radicular pain, stoma site pain, toothache
§ Includes edema peripheral, peripheral swelling
¶ Includes arthralgia, back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, myositis, neck pain, non-cardiac chest pain, pain in extremity
# Includes colitis, diarrhea, gastroenteritis
Þ Includes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper
β Includes epistaxis, hematuria, hemoptysis, metrorrhagia, rectal hemorrhage, uterine hemorrhage, vaginal hemorrhage
a Includes bacterial pyelonephritis, pyelonephritis acute, urinary tract infection, urinary tract infection bacterial, urinary tract infection pseudomonal, urosepsis
e Includes cellulitis, clostridium difficile infection, device-related infection, empyema, erysipelas, herpes virus infection, infected neoplasm, infection, influenza, lower respiratory tract congestion,lung infection, oral candidiasis, oral fungal infection, osteomyelitis, pseudomonas infection, respiratory tract infection, tooth abscess, upper respiratory tract infection, uterine abscess, vulvovaginal candidiasis
ð Includes dermatitis, drug eruption, eczema, erythema, palmar-plantar erythrodysesthesia syndrome, rash, rash generalized, rash maculo-papular

Table 32: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients with Cervical Cancer in KEYNOTE-158

Laboratory Test* KEYTRUDA 200 mg every 3 weeks
All Grades† (%) Grades 3-4 (%)
Hematology
Anemia 54 24
Lymphopenia 47 9
Chemistry
Hypoalbuminemia 44 5
Increased alkaline phosphatase 42 2.6
Hyponatremia 38 13
Hyperglycemia 38 1.3
Increased AST 34 3.9
Increased creatinine 32 5
Hypocalcemia 27 0
Increased ALT 21 3.9
Hypokalemia 20 6
* Graded per NCI CTCAE v4.0
† Includes asthenia, fatigue, lethargy, malaise
‡ Includes breast pain, cancer pain, dysesthesia, dysuria, ear pain, gingival pain, groin pain, lymph node pain, oropharyngeal pain, pain, pain of skin, pelvic pain, radicular pain, stoma site pain, toothache
§ Includes edema peripheral, peripheral swelling
¶ Includes arthralgia, back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, myositis,neck pain, non-cardiac chest pain, pain in extremity
# Includes colitis, diarrhea, gastroenteritis
Þ Includes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper
β Includes epistaxis, hematuria, hemoptysis, metrorrhagia, rectal hemorrhage, uterine hemorrhage, vaginal hemorrhage
a Includes bacterial pyelonephritis, pyelonephritis acute, urinary tract infection, urinary tract infection bacterial, urinary tract infection pseudomonal, urosepsis
e Includes cellulitis, clostridium difficile infection, device-related infection, empyema, erysipelas, herpes virus infection, infected neoplasm, infection, influenza, lower respiratory tract congestion,lung infection, oral candidiasis, oral fungal infection, osteomyelitis, pseudomonas infection, respiratory tract infection, tooth abscess, upper respiratory tract infection, uterine abscess,vulvovaginal candidiasis
ð Includes dermatitis, drug eruption, eczema, erythema, palmar-plantar erythrodysesthesia syndrome, rash, rash generalized, rash maculo-papular

Other laboratory abnormalities occurring in ≥10% of patients receiving KEYTRUDA were hypophosphatemia (19% all Grades; 6% Grades3-4), increased INR (19% all Grades; 0% Grades 3-4), hypercalcemia (14% allGrades; 2.6% Grades 3-4), platelet count decreased (14% all Grades; 1.3%Grades 3-4), activated partial thromboplastin time prolonged (14% all Grades; 0% Grades 3-4),hypoglycemia (13% all Grades; 1.3% Grades3-4), white blood cell decreased (13% all Grades; 2.6% Grades 3-4), and hyperkalemia (13% all Grades; 1.3% Grades 3-4).

HCC

Among the 104patients with HCC who received KEYTRUDA in KEYNOTE-224 [see Clinical Studies], the median duration of exposure to KEYTRUDA was 4.2 months (range: 1 dayto 1.5 years).Adverse reactions occurring in patients with HCC were generally similar to those in 2799patients with melanoma or NSCLCtreated with KEYTRUDA as a single agent, with the exception of increased incidences of ascites (8% Grades 3-4) and immune-mediated hepatitis (2.9%). Laboratory abnormalities(Grades 3-4) that occurred at a higher incidence were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%).

MCC

Among the 50patients with MCC enrolled in KEYNOTE-017 [see Clinical Studies], the median duration of exposure to KEYTRUDA was 6.6months (range 1day to 23.6months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with MCC were similar to those occurring in 2799patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. Laboratory abnormalities (Grades 3-4) thatoccurred at a higher incidence were elevated AST (11%) and hyperglycemia (19%).

RCC

In Combination With Axitinib In The First-Line Treatment Of Advanced RCC (KEYNOTE-426)

The safety of KEYTRUDA in combination with axitinib was investigated in KEYNOTE-426 [see Clinical Studies]. Patients with medical conditions that required systemiccorticosteroids or other immunosuppressive medications or had a history of severe autoimmune disease other than type 1 diabetes, vitiligo, Sjogren’s syndrome, and hypothyroidism stable on hormone replacement were ineligible. Patients received KEYTRUDA 200mg intravenously every 3weeks and axitinib 5mg orally twice daily, or sunitinib 50mg once daily for 4weeks and then off treatment for 2weeks.The median duration of exposure to the combination therapy of KEYTRUDA and axitinib was 10.4months(range:1day to 21.2months).

The study population characteristics were:median age of 62years (range: 30 to 89), 40%age65 or older; 71% male; 80% White; and 80% Karnofsky Performance Status (KPS) of 90-100 and 20% KPS of 70-80.

Fatal adverse reactions occurred in 3.3% of patients receiving KEYTRUDA in combination with axitinib.These included 3 cases of cardiac arrest, 2 cases of pulmonary embolism and 1 case each of cardiac failure, death due to unknown cause, myasthenia gravis, myocarditis, Fournier’s gangrene, plasma cellmyeloma, pleural effusion, pneumonitis, and respiratory failure.

Serious adverse reactions occurred in 40% of patients receiving KEYTRUDA in combination with axitinib.Serious adverse reactions in ≥1%ofpatientsreceiving KEYTRUDA in combination with axitinib included hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%).

Permanent discontinuation due to an adverse reaction of either KEYTRUDA or axitinib occurred in 31% of patients;13% KEYTRUDA only, 13% axitinib only, and 8% both drugs. The most common adverse reaction (>1%) resulting in permanent discontinuation of KEYTRUDA, axitinib, or the combination was hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%),and cerebrovascular accident(1.2%).

Dose interruptions or reductions due to an adverse reaction, excluding temporary interruptions ofKEYTRUDA infusions due to infusion-related reactions, occurred in 76% of patients receiving KEYTRUDA in combination withaxitinib. This includes interruption of KEYTRUDA in 50% of patients.Axitinib was interrupted in 64% of patients and dose reduced in 22% of patients. The most common adverse reactions (>10%) resulting in interruption of KEYTRUDA were hepatotoxicity (14%)and diarrhea (11%), and the most common adverse reactions (>10%) resulting in either interruption or reduction ofaxitinib were hepatotoxicity (21%), diarrhea (19%), and hypertension (18%).

The most common adverse reactions (≥20%) in patients receiving KEYTRUDA and axitinib were diarrhea,fatigue/asthenia, hypertension, hypothyroidism, decreased appetite, hepatotoxicity, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation. Twenty-seven percent(27%) of patients treated with KEYTRUDA in combination with axitinib received an oral prednisone dose equivalentto ≥40 mg dailyfor an immune-mediated adverse reaction.

Tables 33and 34summarize the adverse reactions and laboratory abnormalities, respectively, thatoccurred in at least 20% of patients treated with KEYTRUDA and axitinib in KEYNOTE-426.

Table 33: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA with Axitinib in KEYNOTE-426

Adverse Reaction KEYTRUDA 200 mg every 3 weeksand Axitinib
n=429
Sunitinib
n=425
All Grades* (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
Gastrointestinal
Diarrhea† 56 11 45 5
Nausea 28 0.9 32 0.9
Constipation 21 0 15 0.2
General
Fatigue/Asthenia 52 5 51 10
Vascular
Hypertension‡ 48 24 48 20
Hepatobiliary
Hepatotoxicity§ 39 20 25 4.9
Endocrine
Hypothyroidism 35 0.2 32 0.2
Metabolism and Nutrition
Decreased appetite 30 2.8 29 0.7
Skin and Subcutaneous Tissue
Palmar-plantar erythrodysesthesia syndrome 28 5 40 3.8
Stomatitis/Mucosal inflammation 27 1.6 41 4
Rash¶ 25 1.4 21 0.7
Respiratory, Thoracic and Mediastinal
Dysphonia 25 0.2 3.3 0
Cough 21 0.2 14 0.5
* Graded per NCI CTCAE v4.03
† Includes diarrhea, colitis, enterocolitis, gastroenteritis, enteritis, enterocolitis hemorrhagic
‡ Includes hypertension, blood pressure increased, hypertensive crisis, labile hypertension
§ Includes ALT increased, AST increased, autoimmune hepatitis, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic function abnormal, hepatitis, hepatitis fulminant, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, liver function test increased, liver injury, transaminases increased
¶ Includes rash, butterfly rash, dermatitis, dermatitis acneform, dermatitis atopic, dermatitis bullous, dermatitis contact, exfoliative rash, genital rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, seborrheic dermatitis, skin discoloration, skin exfoliation, perineal rash

Table 34: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA with Axitinib in KEYNOTE-426

Laboratory Test* KEYTRUDA 200 mg every 3 weeks and Axitinib Sunitinib
All Grades† % Grades 3-4% All Grades% Grades 3-4%
Chemistry
Hyperglycemia 62 9 54 3.2
Increased ALT 60 20 44 5
Increased AST 57 13 56 5
Increased creatinine 43 4.3 40 2.4
Hyponatremia 35 8 29 8
Hyperkalemia 34 6 22 1.7
Hypoalbuminemia 32 0.5 34 1.7
Hypercalcemia 27 0.7 15 1.9
Hypophosphatemia 26 6 49 17
Increased alkaline phosphatase 26 1.7 30 2.7
Hypocalcemia‡ 22 0.2 29 0.7
Blood bilirubin increased 22 2.1 21 1.9
Activated partial thromboplastin time prolonged§ 22 1.2 14 0
Hematology
Lymphopenia 33 11 46 8
Anemia 29 2.1 65 8
Thrombocytopenia 27 1.4 78 14
* Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA/axitinib (range: 342 to 425 patients) and sunitinib (range: 345 to 422 patients).
† Graded per NCI CTCAE v4.03
‡ Corrected for albumin
§ Two patients with a Grade 3 elevated activated partial thromboplastin time prolonged (aPTT) were also reported as having an adverse reaction of hepatotoxicity.

In Combination With Lenvatinib In The First-Line Treatment Of Advanced RCC (KEYNOTE-581)

The safety of KEYTRUDA was evaluated in KEYNOTE-581 [see Clinical Studies]. Patients received KEYTRUDA 200 mg intravenously every 3 weeks in combination with lenvatinib 20 mg orally once daily (n=352),or lenvatinib 18 mg orally once daily in combination with everolimus 5 mg orally once daily (n=355), or sunitinib 50 mg orally once daily for 4 weeks then off treatment for 2 weeks (n=340).The median duration of exposure to the combination therapy of KEYTRUDA and lenvatinib was 17 months (range: 0.1 to 39).

Fatal adverse reactions occurred in 4.3% of patients treated with KEYTRUDA in combination with lenvatinib, including cardio-respiratory arrest (0.9%), sepsis (0.9%), and one case (0.3%) each of arrhythmia, autoimmune hepatitis, dyspnea, hypertensive crisis, increased blood creatinine, multiple organ dysfunction syndrome, myasthenic syndrome, myocarditis, nephritis, pneumonitis, ruptured aneurysm, and subarachnoid hemorrhage.

Serious adverse reactions occurred in 51% of patients receiving KEYTRUDA and lenvatinib. Seriousadverse reactions in ≥2%ofpatientswere hemorrhagic events(5%),diarrhea (4%),hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%),and pneumonia(2%).

Permanent discontinuation of either of KEYTRUDA, lenvatinib or both due to an adverse reaction occurred in 37%of patients receiving KEYTRUDA in combination with lenvatinib; 29% KEYTRUDA only, 26% lenvatinib only, and 13% both. Themost common adverse reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA, lenvatinib, or the combination were pneumonitis (3%), myocardial infarction (3%), hepatotoxicity (3%),acute kidney injury (3%), rash (3%), and diarrhea (2%).

Dose interruptions KEYTRUDA, lenvatinib, or both due to an adverse reaction occurred in 78% of patients receiving KEYTRUDA in combination with lenvatinib. KEYTRUDA was interrupted in 55% of patients and both drugs were interrupted in 39% of patients. The most common adverse reactions (≥3%)resulting in interruption of KEYTRUDA were diarrhea(10%), hepatotoxicity (8%), fatigue (7%), lipase increased (5%), amylase increased (4%),musculoskeletal pain (3%), hypertension (3%), rash (3%), acute kidney injury (3%), and decreased appetite (3%).

Fifteen percent (15%) of patients treated with KEYTRUDA in combination with lenvatinib received an oral prednisone equivalent to ≥40 mg daily for an immune-mediated adverse reaction.

Tables 35 and 36summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in ≥20% of patients treated with KEYTRUDA and lenvatinib in KEYNOTE-581.

Table 35: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA with Lenvatinib in KEYNOTE-581

Adverse Reaction KEYTRUDA 200 mg every 3 weeks with Lenvatinib
N=352
Sunitinib 50 mg
N=340
All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
General
Fatigue* 63 9 56 8
Gastrointestinal
Diarrhea† 62 10 50 6
Stomatitis‡ 43 2 43 2
Nausea 36 3 33 1
Abdominal pain§ 27 2 18 1
Vomiting 26 3 20 1
Constipation 25 1 19 0
Musculoskeletal and Connective Tissue
Musculoskeletal 58 4 41 3
disorders¶
Endocrine
Hypothyroidism# 57 1 32 0
Vascular
HypertensionÞ 56 29 43 20
Hemorrhagic eventsβ 27 5 26 4
Metabolism
Decreased appetitea 41 4 31 1
Skin and Subcutaneous Tissue
Rashe 37 5 17 1
Palmar-plantar erythrodysesthesia syndromeð 29 4 38 4
Investigations
Weight loss 30 8 9 0.3
Respiratory, Thoracic and Mediastinal
Dysphonia 30 0 4 0
Renal and Urinary
Proteinuriaø 30 8 13 3
Acute kidney injuryy 21 5 16 2
Hepatobiliary
Hepatotoxicity£ 25 9 21 5
Nervous System
Headache 23 1 16 1
* Includes asthenia, fatigue, lethargy, malaise
† Includes diarrhea, gastroenteritis
‡ Includes aphthous ulcer, gingival pain, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral discomfort, oral mucosal blistering, oral pain, or opharyngeal pain, pharyngeal inflammation, stomatitis
§ Includes abdominal discomfort, abdominal pain, abdominal rigidity, abdominal tenderness, epigastric discomfort, lower abdominal pain, upper abdominal pain
¶ Includes arthralgia, arthritis, back pain, bone pain, breast pain, musculoskeletal chest pain,musculoskeletal discomfort, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, pain in jaw
# Includes hypothyroidism, increased blood thyroid stimulating hormone, secondary hypothyroidism
Þ Includes essential hypertension, increased blood pressure, increased diastolic blood pressure, hypertension, hypertensive crisis, hypertensive retinopathy, labile blood pressure
β Includes all hemorrhage terms. Hemorrhage terms that occurred in 1 or more subjects in either treatment group include Anal hemorrhage, aneurysm ruptured, blood blister, blood loss anemia, blood urine present, catheter site hematoma, cerebral microhemorrhage, conjunctival hemorrhage, contusion, diarrhea hemorrhagic, disseminated intravascular coagulation, ecchymosis, epistaxis, eye hemorrhage, gastric hemorrhage, gastritis hemorrhagic, gingival bleeding, hemorrhage urinary tract, hemothorax, hematemesis, hematoma, hematochezia, hematuria, hemoptysis, hemorrhoidal hemorrhage, increased tendency to bruise, injection site hematoma, injection site hemorrhage, intra-abdominal hemorrhage, lower gastrointestinal hemorrhage, Mallory-Weiss syndrome, melaena, petechiae, rectal hemorrhage, renal hemorrhage, retroperitoneal hemorrhage, small intestinal hemorrhage, splinter hemorrhages, subcutaneous hematoma, subdural hematoma, subarachnoid hemorrhage, thrombotic thrombocytopenic purpura, tumor hemorrhage, traumatic hematoma, upper gastrointestinal hemorrhage
a Includes decreased appetite, early satiety e Includes genital rash, infusion site rash, penile rash, perineal rash, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular
ð Includes palmar erythema, palmar-plantar erythrodysesthesia syndrome, plantar erythema
ø Includes hemoglobinuria, nephrotic syndrome, proteinuria
y Includes acute kidney injury, azotemia, blood creatinine increased, creatinine renal clearance decreased, hypercreatininemia, renal failure, renal impairment, oliguria, glomerular filtration rate decreased, and nephropathy toxic
£ Includes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic failure, hepatic function abnormal, hepatocellular injury, hepatotoxicity, hyperbilirubinemia,hypertransaminasemia, immune-mediated hepatitis, liver function test increased, liver injury, transaminases increased, gamma-glutamyltransferase increased

Clinically relevant adverse reactions (<20%) that occurred in patients receiving KEYTRUDAwithlenvatinib were myocardial infarction (3%) and angina pectoris (1%).

Table 36: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% (All Grades) of Patients Receiving KEYTRUDA with Lenvatinib in KEYNOTE-581

Laboratory Test* KEYTRUDA 200 mg every 3 weeks with Lenvatinib Sunitinib 50 mg
All Grades %† Grade 3-4 %† All Grades %† Grade 3-4 %†
Chemistry
Hypertriglyceridemia 80 15 71 15
Hypercholesterolemia 64 5 43 1
Increased lipase 61 34 59 28
Increased creatinine 61 5 61 2
Increased amylase 59 17 41 9
Increased AST 58 7 57 3
Hyperglycemia 55 7 48 3
Increased ALT 52 7 49 4
Hyperkalemia 44 9 28 6
Hypoglycemia 44 2 27 1
Hyponatremia 41 12 28 9
Decreased albumin 34 0.3 22 0
Increased alkaline phosphatase 32 4 32 1
Hypocalcemia 30 2 22 1
Hypophosphatemia 29 7 50 8
Hypomagnesemia 25 2 15 3
Increased creatine phosphokinase 24 6 36 5
Hypermagnesemia 23 2 22 3
Hypercalcemia 21 1 11 1
Hematology
Lymphopenia 54 9 66 15
Thrombocytopenia 39 2 73 13
Anemia 38 3 66 8
Leukopenia 34 1 77 8
Neutropenia 31 4 72 16
* With at least one Grade increase from baseline
† Laboratory abnormality percentage is based on the number of patients who had both baseline and at least one post-baseline laboratory measurement for each parameter:KEYTRUDA with lenvatinib (range: 343 to 349 patients) and sunitinib (range: 329 to 335 patients).

Grade3 and 4 increased ALT or AST was seen in 9% of patients. Grade ≥2 increased ALTor ASTwas reported in 64 (18%)patients, ofwhom² 0 (31%)received ≥40 mg daily oralprednisone equivalent.Recurrence of Grade ≥2 increased ALTorASTwas observed on rechallenge in 10 patients receiving both KEYTRUDA and lenvatinib (n=38) and was not observed on rechallenge with KEYTRUDA alone (n=3).

Endometrial Carcinoma

The safety of KEYTRUDA in combination with lenvatinib was investigated in KEYNOTE-775, a multicenter, open-label, randomized (1:1), active-controlled trialin patientswithadvancedendometrial carcinoma previously treated with at least one prior platinum-based chemotherapy regimenin any setting,including in the neoadjuvant and adjuvant settings [see Clinical Studies]. Patients with endometrial carcinoma that isnot MSI-H ordMMRreceived KEYTRUDA 200 mg every 3 weeks in combination with lenvatinib 20mg orally once daily (n=342) or received doxorubicin or paclitaxel (n=325).

For patients with not MSI-H or dMMR tumor status, the median duration of study treatment was 7.2 months (range 1 day to 26.8 months) and the median duration of exposure to KEYTRUDA was 6.8 months (range: 1 day to 25.8 months).

Fatal adverse reactions among these patients occurred in 4.7% of those treated with KEYTRUDA and lenvatinib, including 2 cases of pneumonia, and 1 case of the following: acute kidney injury, acute myocardial infarction, colitis, decreased appetite, intestinal perforation, lower gastrointestinal hemorrhage,malignant gastrointestinal obstruction, multiple organ dysfunction syndrome, myelodysplastic syndrome, pulmonary embolism, and right ventricular dysfunction.

Serious adverse reactions occurred in 50% of these patients receiving KEYTRUDA and lenvatinib. Serious adverse reactions (≥3%) were hypertension (4.4%) and urinary tract infections (3.2%).

Discontinuation of KEYTRUDA due to an adverse reaction occurred in 15% of thesepatients. The most common adverse reaction leading to discontinuation of KEYTRUDA (≥1%) was increased ALT (1.2%).

Dose interruptions of KEYTRUDAdue to an adverse reaction occurred in 48% ofthese patients. The most common adverse reactions leading to interruption ofKEYTRUDA (≥3%) were diarrhea (8%), increased ALT (4.4%), increased AST (3.8%), and hypertension (3.5%).

Tables 37 and 38 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in combination with lenvatinib in KEYNOTE-775.

Table 37: Adverse Reactions Occurring in ≥20% of Patients with Endometrial Carcinoma in KEYNOTE-775

Adverse Reaction Endometrial Carcinoma (not MSI-H or dMMR)
KEYTRUDA 200 mg every 3 weeks and Lenvatinib
n=342
Doxorubicin or Paclitaxel
n=325
All Grades* (%) Grades 3-4 (%) All Grades* (%) Grades 3-4 (%)
Endocrine
Hypothyroidism† 67 °.9 0.9 0
Vascular
Hypertension‡ 67 39 6 2.5
Hemorrhagic events§ 25 2.6 15 0.9
General
Fatigue¶ 58 11 54 6
Gastrointestinal
Diarrhea# 55 8 20 2.8
Nausea 49 2.9 47 1.5
Vomiting 37 2.3 21 2.2
StomatitisÞ 35 2.6 26 1.2
Abdominal painβ 34 2.6 21 1.2
Constipation 27 0 25 0.6
Musculoskeletal and Connective Tissue
Musculoskeletal disordersa 53 5 27 0.6
Metabolism
Decreased appetitee 44 7 21 0
Investigations
Weight loss 34 10 6 0.3
Renal and Urinary
Proteinuriað 29 6 3.4 0.3
Infections
Urinary tract infectionø 31 5 13 1.2
Nervous System
Headache 26 0.6 9 0.3
Respiratory, Thoracic and Mediastinal
Dysphonia 22 0 0.6 0
Skin and Subcutaneous Tissue
Palmar-plantar erythrodysesthesiay 23 2.9 0.9 0
Rash£ 20 2.3 4.9 0
* Graded per NCI CTCAE v4.03
† Includes hypothyroidism, blood thyroid stimulating hormone increased, thyroiditis,secondary hypothyroidism
‡ Includes hypertension, blood pressure increased, secondary hypertension, blood pressure abnormal, hypertensive encephalopathy, blood pressure fluctuation
§ Includes epistaxis, vaginal hemorrhage, hematuria, gingival bleeding, metrorrhagia, rectal hemorrhage, contusion,hematochezia, cerebral hemorrhage, conjunctival hemorrhage, gastrointestinal hemorrhage, hemoptysis, hemorrhage urinary tract, lower gastrointestinal hemorrhage, mouth hemorrhage, petechiae, uterine hemorrhage, anal hemorrhage,blood blister, eye hemorrhage, hematoma, hemorrhage intracranial, hemorrhagic stroke, melena, stoma site hemorrhage, upper gastrointestinal hemorrhage, wound hemorrhage, blood urine present, ecchymosis, hematemesis, hemorrhage subcutaneous, hepatic hematoma, injection site bruising, intestinal hemorrhage, laryngeal hemorrhage, pulmonary hemorrhage, subdural hematoma, umbilical hemorrhage, vessel puncture site bruise
¶ Includes fatigue, asthenia, malaise, lethargy
# Includes diarrhea, gastroenteritis
Þ Includes stomatitis, mucosal inflammation, oropharyngeal pain, aphthous ulcer, mouth ulceration, cheilitis, oral mucosal erythema, tongue ulceration
β Includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, gastrointestinal pain, abdominal tenderness, epigastric discomfort
a Includes arthralgia, myalgia, back pain, pain in extremity, bone pain, neck pain, musculoskeletal pain, arthritis, musculoskeletal chest pain, musculoskeletal stiffness, non-cardiac chest pain, pain in jaw
e Includes decreased appetite, early satiety
ð Includes proteinuria, protein urine present, hemoglobinuria
ø Includes urinary tract infection, cystitis, pyelonephritis
y Includes palmar-plantar erythrodysesthesia syndrome, palmar erythema, plantar erythema
£ Includes rash, rash maculo-papular, rash pruritic, rash erythematous, rash macular, rash pustular, rash papular, rash vesicular, application site rash

Table 38: Laboratory Abnormalities Worsened from Baseline* Occurring in ≥20% (All Grades) or ≥3% (Grades 3-4) of Patients with Endometrial Carcinoma in KEYNOTE-775

Laboratory Test† Endometrial Carcinoma (not MSI-H or dMMR)
KEYTRUDA 200 mg every 3 weeks and Lenvatinib Doxorubicin or Paclitaxel
All Grades‡ % Grades 3-4 % All Grades‡ % Grades 3-4 %
Chemistry
Hypertriglyceridemia 70 6 45 1.7
Hypoalbuminemia 60 2.7 42 1.6
Increased aspartate aminotransferase 58 9 23 1.6
Hyperglycemia 58 8 45 4.4
Hypomagnesemia 53 6 32 3.8
Increased alanine aminotransferase 55 9 21 1.2
Hypercholesteremia 53 3.2 23 0.7
Hyponatremia 46 15 28 7
Increased alkaline phosphatase 43 4.7 18 0.9
Hypocalcemia 40 4.7 21 1.9
Increased lipase 36 14 13 3.9
Increased creatinine 35 4.7 18 1.9
Hypokalemia 34 10 24 5
Hypophosphatemia 26 8 17 3.2
Increased amylase 25 7 8 1
Hyperkalemia 23 2.4 12 1.2
Increased creatine kinase 19 3.7 7 0
Increased bilirubin 18 3.6 6 1.6
Hematology
Lymphopenia 50 16 65 20
Thrombocytopenia 50 8 30 4.7
Anemia 49 8 84 14
Leukopenia 43 3.5 83 43
Neutropenia 31 6 76 58
* With at least one grade increase from baseline
† Laboratory abnormality percentage is based on the number of patients who had both baseline and at least one post-baseline laboratory measurement for each parameter: KEYTRUDA and lenvatinib (range: 263 to 340 patients) and doxorubicin or paclitaxel (range: 240 to 322 patients).
‡ Graded per NCI CTCAE v4.03

TMB-H Cancer

The safety of KEYTRUDA was investigated in 105patients with TMB-H cancer enrolled in KEYNOTE-158[see Clinical Studies]. The median duration of exposure to KEYTRUDA was 4.9months (range: 0.03 to 35.2months). Adverse reactions occurring in patients with TMB-H cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

cSCC

Among the159patients with advanced cSCC (recurrent or metastatic or locally advanced disease)enrolled in KEYNOTE-629 [see Clinical Studies], the median duration of exposure to KEYTRUDAwas 6.9months (range 1day to 28.9months). Patients with autoimmune disease or a medical condition that required systemic corticosteroids or other immunosuppressive medications were ineligible. Adverse reactions occurring in patients with recurrent or metastatic cSCC or locally advanced cSCC were similar to those occurring in 2799patients with melanoma or NSCLC treated with KEYTRUDA as a single agent.Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence included lymphopenia (10%)and decreased sodium (10%).

TNBC

Neoadjuvant And Adjuvant Treatment Of High-Risk Early-Stage TNBC

The safety of KEYTRUDA in combination withneoadjuvantchemotherapy (carboplatin and paclitaxelfollowed by doxorubicin or epirubicin and cyclophosphamide)followed by surgeryand continued adjuvant treatment with KEYTRUDAas a single agent was investigated in KEYNOTE-522, a randomized (2:1),multicenter, double-blind, placebo-controlled trial in patients with newly diagnosed, previously untreated,high-risk early-stage TNBC.

A total of 778patients on the KEYTRUDA arm received at least 1 dose of KEYTRUDA in combination with neoadjuvant chemotherapy followed by KEYTRUDA as adjuvant treatment after surgery, compared to 389 patients who received at least 1 dose of placebo in combination with neoadjuvant chemotherapyfollowed by placebo as adjuvant treatment after surgery [see Clinical Studies].

The median duration of exposure to KEYTRUDA 200mg every 3weeks was 13.3months (range: 1day to 21.9 months).

Fatal adverse reactions occurred in 0.9% of patients receiving KEYTRUDA, including 1 each of adrenalcrisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, and sepsis in association with multiple organ dysfunction syndrome and myocardial infarction.

Serious adverse reactions occurred in 44% of patients receiving KEYTRUDA. Serious adverse reactions in ≥2% of patients who received KEYTRUDA included febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%).

KEYTRUDA was discontinued for adverse reactions in 20% of patients. The most common adverse reactions (≥1%) resulting in permanent discontinuation of KEYTRUDA were increased ALT (2.7%), increased AST (1.5%), and rash (1%). Adverse reactions leading to the interruption of KEYTRUDAoccurred in 57% of patients. The most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were neutropenia (26%), thrombocytopenia (6%), increased ALT(6%), increased AST (3.7%), anemia (3.5%), rash (3.2%), febrile neutropenia (2.8%), leukopenia (2.8%), upper respiratory tract infection (2.6%), pyrexia (2.2%), and fatigue (2.1%).

Tables 39 and 40 summarize the adverse reactions and laboratory abnormalities, respectively, in patientstreated with KEYTRUDA in KEYNOTE-522.

Table 39: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-522

Adverse Reaction KEYTRUDA 200 mg every 3 weeks with chemotherapy*/ KEYTRUDA
n=778
Placebo with chemotherapy*/ Placebo
n=389
All Grades† (%) Grades 3-4 (%) All Grades† (%) Grades 3-4 (%)
General
Fatigue‡ 70 8 66 3.9
Pyrexia 28 1.3 19 0.3
Gastrointestinal
Nausea 67 3.7 66 1.8
Constipation 42 0 39 0.3
Diarrhea 41 3.2 34 1.8
Stomatitis§ 34 2.7 29 1
Vomiting 31 2.7 28 1.5
Abdominal pain¶ 24 0.5 23 0.8
Skin and Subcutaneous Tissue
Alopecia 61 0 58 0
Rash# 52 5 41 0.5
Nervous System
Peripheral neuropathyÞ 41 3.3 42 2.3
Headache 30 0.5 29 1
Musculoskeletal and Connective Tissue
Arthralgia 29 0.5 31 0.3
Myalgia 20 0.5 19 0
Respiratory, Thoracic and Mediastinal
Coughβ 26 0.1 24 0
Metabolism and Nutrition
Decreased appetite 23 0.9 17 0.3
Psychiatric
Insomnia 21 0.5 19 0
* Chemotherapy: carboplatin and paclitaxel followed by doxorubicin or epirubicin andcyclophosphamide
† Graded per NCI CTCAE v4.0
‡ Includes asthenia, fatigue
§ Includes aphthous ulcer, cheilitis, lip pain, lip ulceration, mouth ulceration, mucosal inflammation, oralmucosaleruption, oral pain, stomatitis, tongue blistering, tongue ulceration
¶ Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominaltenderness
# Includesdermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, dermatitis exfoliative generalized, drug eruption, eczema, incision site rash, injection site rash, rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic, rash pustular, rash rubelliform, skin exfoliation, skin toxicity, toxic skin eruption, urticaria, vasculitic rash, viral rash
Þ Includes neuropathy peripheral, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheralsensory neuropathy
β Includes cough, productive cough, upper-airway cough syndrome

Table 40: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% ofPatients Receiving KEYTRUDA in KEYNOTE-522

Laboratory Test* KEYTRUDA 200 mg every 3 weeks with chemotherapy† /KEYTRUDA Placebo with chemotherapy† /Placebo
All Grades†% Grades 3-4% All Grades†% Grades 3-4%
Hematology
Anemia 97 22 96 19
Leukopenia 93 41 91 32
Neutropenia 88 62 89 62
Lymphopenia 80 28 74 22
Thrombocytopenia 58 11 57 9
Chemistry
Increased ALT 71 9 69 4.6
Increased AST 66 6 58 1.8
Hyperglycemia 65 5 62 2.8
Increased alkaline phosphatase 41 1 37 0.8
Hyponatremia 38 9 28 6
Hypoalbuminemia 36 1.2 30 1.5
Hypocalcemia 32 3.2 29 4.4
Hypokalemia 32 6 24 2.8
Hypophosphatemia 23 6 18 4.5
Hypercalcemia 21 3 24 3.4
* Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA in combination with chemotherapy followed by KEYTRUDA as a single agent (range: 759to 777 patients) and placebo in combination with chemotherapy followed by placebo (range: 378 to 389patients).
†Chemotherapy: carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide
†Graded per NCI CTCAE v4.0

Locally Recurrent Unresectable Or Metastatic TNBC

The safety ofKEYTRUDA in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin was investigated in KEYNOTE-355, a multicenter, double-blind, randomized (2:1), placebo-controlled trial in patients with locally recurrent unresectable or metastatic TNBC who had notbeen previously treated with chemotherapyin the metastatic setting [see Clinical Studies]. A total of 596 patients (including 34patients from a safety run-in) received KEYTRUDA 200mg every 3weeks in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin.

The median duration of exposure to KEYTRUDA was 5.7months (range: 1day to 33.0months).

Fatal adverse reactions occurred in 2.5% of patients receiving KEYTRUDA in combination withchemotherapy, includingcardio-respiratory arrest (0.7%) and septic shock (0.3%).

Serious adverse reactions occurred in 30%of patients receiving KEYTRUDA in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin. Serious adverse reactions in ≥2% of patients were pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%).

KEYTRUDA was discontinued for adverse reactions in 11% of patients. The most common adverse reactions resulting in permanentdiscontinuation ofKEYTRUDA(≥1%)were increased ALT (2.2%),increased AST (1.5%), and pneumonitis (1.2%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 50% of patients. The most common adverse reactions leading to interruption ofKEYTRUDA (≥2%) were neutropenia (22%), thrombocytopenia (14%), anemia (7%), increased ALT (6%),leukopenia (5%), increased AST (5%), decreased white blood cell count (3.9%), and diarrhea (2%).

Tables 41and 42summarize the adverse reactions and laboratory abnormalities in patients on KEYTRUDA in KEYNOTE-355.

Table 41: Adverse Reactions Occurring in ≥20% of PatientsReceiving KEYTRUDA with Chemotherapy in KEYNOTE-355

Adverse Reaction KEYTRUDA 200 mg every 3 weeks with chemotherapy
n=596
Placebo every 3 weeks with chemotherapy
n=281
All Grades* (%) Grades 3-4 (%) All Grades* (%) Grades 3-4 (%)
General
Fatigue† 48 5 49 4.3
Gastrointestinal
Nausea 44 1.7 47 1.8
Diarrhea 28 1.8 23 1.8
Constipation 28 0.5 27 0.4
Vomiting 26 2.7 22 3.2
Skin and Subcutaneous Tissue
Alopecia 34 0.8 35 1.1
Rash‡ 26 2 16 0
Respiratory, Thoracic and Mediastinal
Cough§ 23 0 20 0.4
Metabolism and Nutrition
Decreased appetite 21 0.8 14 0.4
Nervous System
Headache¶ 20 0.7 23 0.7
* Graded per NCI CTCAE v4.03
† Includes fatigue and asthenia
‡ Includes rash, rash maculo-papular, rash pruritic, rash pustular, rash macular, rash papular, butterfly rash, rash erythematous, eyelid rash
§ Includes cough, productive cough, upper-airway cough syndrome
¶ Includes headache, migraine, tension headache

Table 42: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA with Chemotherapy in KEYNOTE-355

Laboratory Test* KEYTRUDA 200 mg every 3 weeks with chemotherapy Placebo every 3 weeks with chemotherapy
All Grades† % Grades 3-4 % All Grades† % Grades 3-4 %
Hematology
Anemia 90 20 85 19
Leukopenia 85 39 86 39
Neutropenia 76 49 77 52
Lymphopenia 70 26 70 19
Thrombocytopenia 54 19 53 21
Chemistry
Increased ALT 60 11 58 8
Increased AST 57 9 55 6
Hyperglycemia 52 4.4 51 2.2
Hypoalbuminemia 37 2.2 32 2.2
Increased alkaline phosphatase 35 3.9 39 2.2
Hypocalcemia 29 3.3 27 1.8
Hyponatremia 28 5 26 6
Hypophosphatemia 21 7 18 4.8
Hypokalemia 20 4.4 18 4.0
* Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA + chemotherapy (range: 566 to 592 patients) and placebo + chemotherapy (range: 269 to 280 patients).
† Graded per NCI CTCAE v4.03

Immunogenicity

As with all therapeutic proteins, there is the potential for immunogenicity.The detection of antibodyformation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitantmedications, and underlying disease. For these reasons, comparison of incidence of antibodies to pembrolizumab in the studies described below with the incidences of antibodiesin other studies or to other products may be misleading.

Trough levels of pembrolizumab interfere with the electrochemiluminescent (ECL) assay results;therefore, a subset analysis was performed in the patients with a concentration of pembrolizumab below the drug tolerance level of the anti-product antibody assay. In clinical studies in patients treated with pembrolizumab at a dose of 2mg/kg every 3weeks, 200mg every 3weeks, or 10mg/kg every 2or 3 weeks, 27 (2.1%) of 1289 evaluable patients tested positive for treatment-emergent anti-pembrolizumab antibodies of whom six (0.5%) patients had neutralizing antibodies against pembrolizumab. There was noevidence of an altered pharmacokinetic profile or increased infusion reactions with anti-pembrolizumab binding antibody development.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of KEYTRUDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not alwayspossible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hepatobiliary: sclerosing cholangitis

DRUG INTERACTIONS

No Information provided

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Warnings & Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Severe And Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-lig and 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under WARNINGS AND PRECAUTIONS may not include all possible severe and fatal immune-mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reaction scan occur at any time after starting treatment with a PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.

Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity [see DOSAGE AND ADMINISTRATION]. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2mg/kg/day prednisone or equivalent) until improvement to Grade1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least1month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids(e.g., endocrinopathies and dermatologic reactions)are discussed below.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patientswho have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade4 (0.3%), Grade3 (0.9%), and Grade2 (1.3%) adverse reactions. Systemic corticosteroids were required in 67% (63/94) of patients with pneumonitis. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) of patients and withholding of KEYTRUDA in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence of pneumonitis. Pneumonitis resolved in 59%of the 94 patients.

In clinical studies enrolling 389adultpatients with cHL who received KEYTRUDA as a single agent, pneumonitis occurred in 31(8%) patients, including Grades3-4pneumonitisin 2.3% of patients. Patients received high-dose corticosteroids for a median duration of10days (range:2daysto 53months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 21 (5.4%) patients. Of the patients who developed pneumonitis, 42%interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77%had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus(CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade4 (<0.1%),Grade3 (1.1%), and Grade2 (0.4%) adverse reactions. Systemic corticosteroids were required in 69% (33/48) of patients with colitis. Additional immunosuppressant therapy was required in 4.2% of patients. Colitisled to permanent discontinuation of KEYTRUDA in 0.5% (15) of patients and withholding of KEYTRUDA in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence of colitis. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity And Immune-Mediated Hepatitis

KEYTRUDA As A Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7%(19/2799) of patients receiving KEYTRUDA, including Grade4 (<0.1%), Grade3 (0.4%), and Grade2 (0.1%) adverse reactions. Systemic corticosteroids were required in 68% (13/19) of patients with hepatitis. Eleven percent of these patients required additional immunosuppressant therapy. Hepatitisled to permanent discontinuation of KEYTRUDA in 0.2% (6) of patients and withholding of KEYTRUDA in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence of hepatitis.Hepatitis resolved in 79% of the 19patients.

KEYTRUDA With Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades3 and 4 ALT and AST elevations compared to KEYTRUDA alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed [see DOSAGE AND ADMINISTRATION].

With the combination of KEYTRUDA and axitinib, Grades3 and 4 increased ALT (20%) and increased AST (13%) were seen. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times ULN (Grades2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were re-challenged with either KEYTRUDA (n=3) or axitinib (n=34)administered as a single agent or with both (n=55), recurrence ofALT≥3 times ULN was observed in 1patient receiving KEYTRUDA, 16patients receiving axitinib, and 24patients receiving both KEYTRUDA and axitinib. All patients with a recurrence ofALT≥3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity [see DOSAGE AND ADMINISTRATION].

Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) adverse reactions. Systemic corticosteroids were required in 77% (17/22) of patients with adrenal insufficiency; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) of patients and withholding of KEYTRUDA in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity [see DOSAGE AND ADMINISTRATION].

Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%),Grade3 (0.3%), and Grade2 (0.2%)adverse reactions. Systemic corticosteroids were required in 94% (16/17) of patients with hypophysitis; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) of patients and withholding of KEYTRUDA in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptomimprovement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidismor institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity [see DOSAGE AND ADMINISTRATION].

Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). Nopatients discontinued KEYTRUDA due to thyroiditis. KEYTRUDA was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade3 (0.1%)and Grade2 (0.8%).Hyperthyroidism led to permanent discontinuation of KEYTRUDA in<0.1%(2) of patients and withholding of KEYTRUDA in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%)and Grade2 (6.2%). Hypothyroidism led to permanent discontinuation of KEYTRUDA in <0.1% (1) of patients and withholding of KEYTRUDA in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement.

The incidence of new or worsening hypothyroidism was higher in 1185patients with HNSCC, occurring in 16%of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade3 (0.3%)hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

Type 1 Diabetes Mellitus, Which Can present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity [see DOSAGE AND ADMINISTRATION].

Type 1 diabetes mellitus occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. Type 1 diabetes mellitusled to permanent discontinuation in <0.1% (1) of patients and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. All patients with Type 1 diabetes mellitus required long-term insulin therapy.

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3%(9/2799) of patients receiving KEYTRUDA, including Grade4 (<0.1%), Grade3 (0.1%), and Grade2 (0.1%) adverse reactions. Systemic corticosteroids were required in 89% (8/9) of patients with nephritis. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) of patients and withholding of KEYTRUDA in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence of nephritis. Nephritis resolved in 56% of the 9patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens Johnson Syndrome, DRESS,and toxic epidermal necrolysis (TEN),has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity [see DOSAGE AND ADMINISTRATION].

Immune-mediated dermatologic adverse reactions occurred in 1.4%(38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in 40% (15/38) of patients with immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions led to permanent discontinuation of KEYTRUDA in 0.1% (2) of patients and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence of immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1%(unless otherwise noted)in patients who received KEYTRUDA or were reported with the use of other PD1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions.

Cardiac/Vascular: Myocarditis, pericarditis, vasculitis

Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy

Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Haradalike syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.

Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis

Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica

Endocrine: Hypoparathyroidism

Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. For severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions, stop infusion and permanently discontinue KEYTRUDA [see DOSAGE AND ADMINISTRATION].

Complications Of Allogeneic HSCT

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease(VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occurdespite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Considerthe benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT.

Increased Mortality In Patients With Multiple Myeloma When KEYTRUDA Is Added To A Thalidomide Analogue And Dexamethasone

In two randomized trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled trials.

Embryo-Fetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Animal models link the PD-1/PD-L1 signaling pathway with maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with KEYTRUDA and for 4months after the last dose [see Use In Specific Populations].

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Immune-Mediated Adverse Reactions
  • Inform patients of the risk of immune-mediated adverse reactions that may be severe or fatal, may occur after discontinuation of treatment, and may require corticosteroid treatment and interruption ordiscontinuation of KEYTRUDA. These reactions may include:
    • Pneumonitis: Advise patients to contact their healthcare provider immediately for new or worsening cough, chest pain, or shortness of breath [see WARNINGS AND PRECAUTIONS].
    • Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see WARNINGS AND PRECAUTIONS].
    • Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, or easy bruising or bleeding [see WARNINGS AND PRECAUTIONS].
    • Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of adrenal insufficiency, hypophysitis, hypothyroidism, hyperthyroidism, or Type 1 diabetes mellitus [see WARNINGS AND PRECAUTIONS].
    • Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis [see WARNINGS AND PRECAUTIONS].
    • Severe skin reactions: Advise patients to contact their healthcare provider immediately for any signs or symptoms of severe skin reactions, SJS or TEN [see WARNINGS AND PRECAUTIONS].
    • Other immune-mediated adverse reactions:
      • Advise patients that immune-mediated adverse reactions can occur and may involve any organ system, and to contact their healthcare provider immediately for any new or worsening signs or symptoms [see WARNINGS AND PRECAUTIONS].
      • Advise patients of the risk of solid organ transplant rejection and to contact their healthcare provider immediately for signs or symptoms of organ transplant rejection [see WARNINGS AND PRECAUTIONS].
Infusion-Related Reactions
  • Advise patients to contact their healthcare provider immediately forsigns or symptoms of infusion-related reactions [see WARNINGS AND PRECAUTIONS].
Complications Of Allogeneic HSCT
  • Advise patients of the risk of post-allogeneic hematopoietic stem cell transplantation complications  [see WARNINGS AND PRECAUTIONS].
Embryo-Fetal Toxicity
  • Advise females of reproductive potentialof the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].
  • Advise females of reproductive potential to use effective contraception during treatment with KEYTRUDA and for 4 months after the last dose [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].
Lactation
  • Advise women not to breastfeed during treatment with KEYTRUDAand for 4 months after the final dose [see Use In Specific Populations].
Laboratory Tests
  • Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests [see WARNINGS AND PRECAUTIONS].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No studies have been performed to test the potential of pembrolizumab for carcinogenicity orgenotoxicity.

Fertility studies have not been conducted with pembrolizumab. In 1-month and 6-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs; however, most animals in these studies were not sexually mature.

Use In Specific Populations

Pregnancy

Risk Summary

Based on its mechanism of action, KEYTRUDAcan cause fetal harm when administered to a pregnant woman. There are no available human data informing the risk of embryo-fetal toxicity. In animalmodels, the PD-1/PD-L1 signaling pathwayis important in the maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue (see Data). Human IgG4 (immunoglobulins) are known to crossthe placenta; therefore, pembrolizumab has the potential to be transmitted from the mother to the developing fetus. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

Animal reproduction studies have not been conducted with KEYTRUDA to evaluate its effect on reproduction and fetal development. A literature-based assessment of the effects of the PD-1 pathway on reproduction demonstrated that a central function of the PD-1/PD-L1 pathway is to preserve pregnancyby maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetusand to result in an increase in fetal loss;therefore, potential risks of administering KEYTRUDA during pregnancy include increased rates ofabortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 knockout mice. Based on its mechanism of action, fetal exposure to pembrolizumab may increase the risk of developing immune-mediated disorders or of altering the normal immune response.

Lactation

Risk Summary

There are no data on the presence of pembrolizumab in either animal or human milk or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with KEYTRUDA and for 4 months after the final dose.

Females And Males Of Reproductive Potential

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating KEYTRUDA [see Use In Specific Populations].

Contraception

KEYTRUDA can cause fetal harm when administered to a pregnant woman [see WARNINGS AND PRECAUTIONS, Use In Specific Populations]. Advise females of reproductive potential to use effective contraception during treatment with KEYTRUDA and for at least 4 months following the finaldose.

Pediatric Use

The safety and effectiveness of KEYTRUDAas a single agent have been established in pediatric patientswith cHL, PMBCL, MCC, MSI-H cancer, and TMB-H cancer. Use of KEYTRUDA in pediatric patients for these indicationsis supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients [see ADVERSE REACTIONS, CLINICAL PHARMACOLOGY, Clinical Studies].

In KEYNOTE-051, 161 pediatric patients (62 pediatric patientsaged6 monthsto youngerthan 12yearsand 99 pediatric patientsaged12 to 17 years) with advanced melanoma, lymphoma, or PD-L1 positive solid tumorsreceived KEYTRUDA2 mg/kg every 3 weeks.The median duration of exposure was 2.1 months (range: 1dayto 24 months).Adversereactions that occurred at a ≥10% higher rate in pediatric patients when compared to adults included pyrexia (33%), vomiting (30%), upper respiratory tract infection (29%),and headache (25%). Laboratory abnormalities that occurred at a ≥10% higher rate in pediatric patients when compared to adults wereleukopenia (30%), neutropenia (26%), and Grade 3 anemia (17%).

The safety and effectiveness of KEYTRUDA in pediatric patients have not been established in the otherapproved indications [see INDICATIONS AND USAGE].

Geriatric Use

Of 3781patients with melanoma, NSCLC, HNSCC,or urothelial carcinoma who were treated with KEYTRUDA in clinical studies,48% were 65years and over and 17% were 75years and over. No overalldifferences in safety or effectiveness were observed between elderly patients and younger patients.

Of 389 adult patients with cHL who were treated with KEYTRUDA in clinical studies, 46 (12%) were 65 years and over. Patients aged 65 yearsand overhad a higher incidence of serious adverse reactions(50%) than patients aged younger than 65years (24%). Clinical studies of KEYTRUDAin cHL did notinclude sufficient numbers of patients aged 65 years and over to determine whether effectiveness differs from thatin younger patients.

Of 596adult patients with TNBC who were treated with KEYTRUDA in combinationwith paclitaxel,paclitaxel protein-bound, or gemcitabine and carboplatin in KEYNOTE-355, 137 (23%) were 65 years andover.No overall differences in safety or effectiveness were observed between elderly patients and younger patients.

Of 406 adult patients with endometrial carcinoma who were treated with KEYTRUDA in combination with lenvatinib in KEYNOTE-775, 201 (50%) were 65 years and over. No overall differences in safety oreffectiveness were observed between elderly patients and younger patients.

Overdosage & Contraindications

OVERDOSE

No Information provided

CONTRAINDICATIONS

None.

Clinical Pharmacology

CLINICAL PHARMACOLOGY

Mechanism Of Action

Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth.

Pharmacodynamics

Based on the modeling of dose/exposure efficacy and safety relationships and observed pharmacokinetic data from an interim analysis of 41 patients with melanoma treated with pembrolizumab 400 mg every 6 weeks, there are no anticipated clinically significant differences in efficacy and safety between pembrolizumab doses of 200 mg or 2 mg/kg every 3 weeks or 400 mg every 6 weeks.

Pharmacokinetics

The pharmacokinetics (PK) of pembrolizumab was characterized using a population PK analysis with concentration data collected from 2993 patients with various cancers who received pembrolizumab doses of 1 to 10 mg/kg every 2 weeks, 2 to 10 mg/kg every 3 weeks, or 200 mg every 3 weeks.

Steady-state concentrations of pembrolizumab were reached by 16 weeks of repeated dosing with an every 3-week regimen and the systemic accumulation was 2.1-fold. The peak concentration (Cmax), trough concentration (Cmin), and area under the plasma concentration versus time curve at steady state (AUCss) of pembrolizumab increased dose proportionally in the dose range of 2 to 10 mg/kg every 3 weeks.

Distribution

The geometric mean value (CV%) for volume of distribution at steady state is 6.0 L (20%).

Elimination

Pembrolizumab clearance (CV%) is approximately 23% lower [geometric mean, 195 mL/day (40%)] at steady state than that after the first dose [252 mL/day (37%)]; this decrease in clearance with time is not considered clinically important. The terminal half-life (t½) is 22 days (32%).

Specific Populations

The following factors had no clinically important effect on the CL of pembrolizumab: age (range: 15 to 94 years), sex, race (89% White), renal impairment (eGFR ≥ 15 mL/min/1.73 m²), mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and AST > ULN or total bilirubin between 1 and 1.5 times ULN and any AST), or tumor burden. The impact of moderate or severe hepatic impairment on the pharmacokinetics of pembrolizumab is unknown.

Pediatric Patients

Pembrolizumab concentrations with weight-based dosing at 2 mg/kg every 3 weeks in pediatric patients (10 months to 17 years) are comparable to those of adults at the same dose.

Animal Toxicology And/Or Pharmacology

In animal models, inhibition of PD-1 signaling resulted in an increased severity of some infections and enhanced inflammatory responses. M. tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-1 knockout mice have also shown decreased survival following infection with lymphocytic choriomeningitis virus (LCMV). Administration of pembrolizumab in chimpanzees with naturally occurring chronic hepatitis B infection resulted in two out of four animals with significantly increased levels of serum ALT, AST, and GGT, which persisted for at least 1 month after discontinuation of pembrolizumab.

Clinical Studies

Melanoma

Ipilimumab-Naive Melanoma

The efficacy of KEYTRUDA was investigated in KEYNOTE-006 (NCT01866319), a randomized (1:1:1), open-label, multicenter, active-controlled trial in 834 patients. Patients were randomized to receive KEYTRUDA at a dose of 10 mg/kg intravenously every 2 weeks or 10 mg/kg intravenously every 3 weeks until disease progression or unacceptable toxicity or to ipilimumab 3 mg/kg intravenously every 3 weeks for 4 doses unless discontinued earlier for disease progression or unacceptable toxicity. Patients with disease progression could receive additional doses of treatment unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at 4 to 6 weeks with repeat imaging. Randomization was stratified by line of therapy (0 vs. 1), ECOG PS (0 vs. 1), and PD-L1 expression (≥1% of tumor cells [positive] vs. <1% of tumor cells [negative]) according to an investigational use only (IUO) assay. Key eligibility criteria were unresectable or metastatic melanoma; no prior ipilimumab; and no more than one prior systemic treatment for metastatic melanoma. Patients with BRAF V600E mutation-positive melanoma were not required to have received prior BRAF inhibitor therapy. Patients with autoimmune disease; a medical condition that required immunosuppression; previous severe hypersensitivity to other monoclonal antibodies; and HIV, hepatitis B or hepatitis C infection, were ineligible. Assessment of tumor status was performed at 12 weeks, then every 6 weeks through Week 48, followed by every 12 weeks thereafter. The major efficacy outcome measures were overall survival (OS) and progression-free survival (PFS; as assessed by blinded independent central review [BICR] using Response Evaluation Criteria in Solid Tumors [RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ]). Additional efficacy outcome measures were objective response rate (ORR) and duration of response (DoR).

The study population characteristics were: median age of 62 years (range: 18 to 89); 60% male; 98% White; 66% had no prior systemic therapy for metastatic disease; 69% ECOG PS of 0; 80% had PD-L1 positive melanoma, 18% had PD-L1 negative melanoma, and 2% had unknown PD-L1 status using the IUO assay; 65% had M1c stage disease; 68% with normal LDH; 36% with reported BRAF mutation-positive melanoma; and 9% with a history of brain metastases. Among patients with BRAF mutation-positive melanoma, 139 (46%) were previously treated with a BRAF inhibitor.

The study demonstrated statistically significant improvements in OS and PFS for patients randomized to KEYTRUDA as compared to ipilimumab. Among the 91 patients randomized to KEYTRUDA 10 mg/kg every 3 weeks with an objective response, response durations ranged from 1.4+ to 8.1+ months. Among the 94 patients randomized to KEYTRUDA 10 mg/kg every 2 weeks with an objective response, response durations ranged from 1.4+ to 8.2 months. Efficacy results are summarized in Table 39 and Figure 1.

Table 39: Efficacy Results in KEYNOTE-006

Endpoint KEYTRUDA 10 mg/kg every 3 weeks
n=277
KEYTRUDA 10 mg/kg every 2 weeks
n=279
Ipilimumab 3 mg/kg every 3 weeks
n=278
OS
Deaths (%) 92 (33%) 85 (30%) 112 (40%)
Hazard ratio* (95% CI) 0.69 (0.52, 0.90) 0.63 (0.47, 0.83) ---
p-Value (stratified log-rank) 0.004 <0.001
PFS by BICR
Events (%) 157 (57%) 157 (56%) 188 (68%)
Median in months (95% CI) 4.1 (2.9, 6.9) 5.5 (3.4, 6.9) 2.8 (2.8, 2.9)
Hazard ratio* (95% CI) 0.58 (0.47, 0.72) 0.58 (0.46, 0.72) ---
p-Value (stratified log-rank) <0.001 <0.001
Best objective response by BICR
ORR (95% CI) 33% (27, 39) 34% (28, 40) 12% (8, 16)
Complete response rate 6% 5% 1%
Partial response rate 27% 29% 10%
* Hazard ratio (KEYTRUDA compared to ipilimumab) based on the stratified Cox proportional hazard model

Figure 1: Kaplan-Meier Curve for Overall Survival in KEYNOTE-006*

Kaplan-Meier Curve
for Overall Survival in KEYNOTE-006* - Illustration

Ipilimumab-Refractory Melanoma

The efficacy of KEYTRUDA was investigated in KEYNOTE-002 (NCT01704287), a multicenter, randomized (1:1:1), active-controlled trial in 540 patients randomized to receive one of two doses of KEYTRUDA in a blinded fashion or investigator’s choice chemotherapy. The treatment arms consisted of KEYTRUDA 2 mg/kg or 10 mg/kg intravenously every 3 weeks or investigator’s choice of any of the following chemotherapy regimens: dacarbazine 1000 mg/m² intravenously every 3 weeks (26%), temozolomide 200 mg/m² orally once daily for 5 days every 28 days (25%), carboplatin AUC 6 mg/mL/min intravenously plus paclitaxel 225 mg/m² intravenously every 3 weeks for four cycles then carboplatin AUC of 5 mg/mL/min plus paclitaxel 175 mg/m² every 3 weeks (25%), paclitaxel 175 mg/m² intravenously every 3 weeks (16%), or carboplatin AUC 5 or 6 mg/mL/min intravenously every 3 weeks (8%). Randomization was stratified by ECOG PS (0 vs. 1), LDH levels (normal vs. elevated [≥110% ULN]) and BRAF V600 mutation status (wild-type [WT] or V600E). The trial included patients with unresectable or metastatic melanoma with progression of disease; refractory to two or more doses of ipilimumab (3 mg/kg or higher) and, if BRAF V600 mutation-positive, a BRAF or MEK inhibitor; and disease progression within 24 weeks following the last dose of ipilimumab. The trial excluded patients with uveal melanoma and active brain metastasis. Patients received KEYTRUDA until unacceptable toxicity; disease progression that was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at 4 to 6 weeks with repeat imaging; withdrawal of consent; or physician’s decision to stop therapy for the patient. Assessment of tumor status was performed at 12 weeks after randomization, then every 6 weeks through week 48, followed by every 12 weeks thereafter. Patients on chemotherapy who experienced progression of disease were offered KEYTRUDA. The major efficacy outcomes were PFS as assessed by BICR per RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and OS. Additional efficacy outcome measures were confirmed ORR as assessed by BICR per RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and DoR.

The study population characteristics were: median age of 62 years (range: 15 to 89), 43% age 65 or older; 61% male; 98% White; and 55% ECOG PS of 0 and 45% ECOG PS of 1. Twenty-three percent of patients were BRAF V600 mutation positive, 40% had elevated LDH at baseline, 82% had M1c disease, and 73% had two or more prior therapies for advanced or metastatic disease.

The study demonstrated a statistically significant improvement in PFS for patients randomized to KEYTRUDA as compared to control arm. There was no statistically significant difference between KEYTRUDA 2 mg/kg and chemotherapy or between KEYTRUDA 10 mg/kg and chemotherapy in the OS analysis in which 55% of the patients who had been randomized to receive chemotherapy had crossed over to receive KEYTRUDA. Among the 38 patients randomized to KEYTRUDA 2 mg/kg with an objective response, response durations ranged from 1.3+ to 11.5+ months. Among the 46 patients randomized to KEYTRUDA 10 mg/kg with an objective response, response durations ranged from 1.1+ to 11.1+ months. Efficacy results are summarized in Table 40.

Table 40: Efficacy Results in KEYNOTE-002

Endpoint KEYTRUDA 2 mg/kg every 3 weeks
n=180
KEYTRUDA 10 mg/kg every 3 weeks
n=181
Chemotherapy
n=179
PFS
Number of Events, n (%) 129 (72%) 126 (70%) 155 (87%)
Progression, n (%) 105 (58%) 107 (59%) 134 (75%)
Death, n (%) 24 (13%) 19 (10%) 21 (12%)
Median in months (95% CI) 2.9 (2.8, 3.8) 2.9 (2.8, 4.7) 2.7 (2.5, 2.8)
p-Value (stratified log-rank) <0.001 <0.001
Hazard ratio* (95% CI) 0.57 (0.45, 0.73) 0.50 (0.39, 0.64)
OS†
Deaths (%) 123 (68%) 117 (65%) 128 (72%)
Hazard ratio* (95% CI) 0.86 (0.67, 1.10) 0.74 (0.57, 0.96) ---
p-Value (stratified log-rank) 0.117 0.011‡
Median in months (95% CI) 13.4 (11.0, 16.4) 14.7 (11.3, 19.5) 11.0 (8.9, 13.8)
Objective Response Rate
ORR (95% CI) 21% (15, 28) 25% (19, 32) 4% (2, 9)
Complete response rate 2% 3% 0%
Partial response rate 19% 23% 4%
* Hazard ratio (KEYTRUDA compared to chemotherapy) based on the stratified Cox proportional hazard model
† With additional follow-up of 18 months after the PFS analysis
‡ Not statistically significant compared to multiplicity adjusted significance level of 0.01

Figure 2: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-002

Kaplan-Meier Curve
for Progression-Free Survival in KEYNOTE-002 - Illustration

Adjuvant Treatment Of Resected Melanoma

The efficacy of KEYTRUDA was investigated in KEYNOTE-054 (NCT02362594), a multicenter, randomized (1:1), double-blind, placebo-controlled trial in patients with completely resected stage IIIA (>1 mm lymph node metastasis), IIIB or IIIC melanoma. Patients were randomized to KEYTRUDA 200 mg intravenously every three weeks or placebo for up to one year until disease recurrence or unacceptable toxicity. Randomization was stratified by American Joint Committee on Cancer 7th edition (AJCC) stage (IIIA vs. IIIB vs. IIIC 1-3 positive lymph nodes vs. IIIC ≥4 positive lymph nodes) and geographic region (North America, European countries, Australia, and other countries as designated). Patients must have undergone lymph node dissection and, if indicated, radiotherapy within 13 weeks prior to starting treatment. The major efficacy outcome measure was investigator-assessed recurrence-free survival (RFS) in the whole population and in the population with PD-L1 positive tumors where RFS was defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant metastasis) or death, whichever occurs first. Patients underwent imaging every 12 weeks after the first dose of KEYTRUDA for the first two years, then every 6 months from year 3 to 5, and then annually.

The study population characteristics were: median age of 54 years (range: 19 to 88), 25% age 65 or older; 62% male; and 94% ECOG PS of 0 and 6% ECOG PS of 1. Sixteen percent had stage IIIA, 46% had stage IIIB, 18% had stage IIIC (1-3 positive lymph nodes), and 20% had stage IIIC (≥4 positive lymph nodes); 50% were BRAF V600 mutation positive and 44% were BRAF wild-type; and 84% had PD-L1 positive melanoma with TPS ≥1% according to an IUO assay.

The trial demonstrated a statistically significant improvement in RFS for patients randomized to the KEYTRUDA arm compared with placebo. Efficacy results are summarized in Table 41 and Figure 3.

Table 41: Efficacy Results in KEYNOTE-054

Endpoint KEYTRUDA 200 mg every 3 weeks
n=514
Placebo
n=505
RFS
Number (%) of patients with event 135 (26%) 216 (43%)
Median in months (95% CI) NR 20.4 (16.2, NR)
Hazard ratio*† (95% CI) 0.57 (0.46, 0.70)
p-Value† (log-rank) <0.001±
* Based on the stratified Cox proportional hazard model
† Stratified by American Joint Committee on Cancer 7th edition (AJCC) stage ± p-Value is compared with 0.008 of the allocated alpha for this interim analysis.
NR = not reached

For patients with PD-L1 positive tumors, the HR was 0.54 (95% CI: 0.42, 0.69); p<0.001. The RFS benefit for KEYTRUDA compared to placebo was observed regardless of tumor PD-L1 expression.

Figure 3: Kaplan-Meier Curve for Recurrence-Free Survival in KEYNOTE-054

Kaplan-Meier Curve for Recurrence-Free Survival
in KEYNOTE-054 - Illustration

Non-Small Cell Lung Cancer

First-Line Treatment Of Metastatic Nonsquamous NSCLC With Pemetrexed And Platinum Chemotherapy

The efficacy of KEYTRUDA in combination with pemetrexed and platinum chemotherapy was investigated in KEYNOTE-189 (NCT02578680), a randomized, multicenter, double-blind, active-controlled trial conducted in 616 patients with metastatic nonsquamous NSCLC, regardless of PD-L1 tumor expression status, who had not previously received systemic therapy for metastatic disease and in whom there were no EGFR or ALK genomic tumor aberrations. Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by smoking status (never vs. former/current), choice of platinum (cisplatin vs. carboplatin), and tumor PD-L1 status (TPS <1% [negative] vs. TPS ≥1%). Patients were randomized (2:1) to one of the following treatment arms:

  • KEYTRUDA 200 mg, pemetrexed 500 mg/m², and investigator’s choice of cisplatin 75 mg/m² or carboplatin AUC 5 mg/mL/min intravenously on Day 1 of each 21-day cycle for 4 cycles followed by KEYTRUDA 200 mg and pemetrexed 500 mg/m² intravenously every 3 weeks. KEYTRUDA was administered prior to chemotherapy on Day 1.
  • Placebo, pemetrexed 500 mg/m², and investigator’s choice of cisplatin 75 mg/m² or carboplatin AUC 5 mg/mL/min intravenously on Day 1 of each 21-day cycle for 4 cycles followed by placebo and pemetrexed 500 mg/m² intravenously every 3 weeks.

Treatment with KEYTRUDA continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease as determined by the investigator, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Patients randomized to placebo and chemotherapy were offered KEYTRUDA as a single agent at the time of disease progression. Assessment of tumor status was performed at Week 6, Week 12, and then every 9 weeks thereafter. The main efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures were ORR and DoR, as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

The study population characteristics were: median age of 64 years (range: 34 to 84), 49% age 65 or older; 59% male; 94% White and 3% Asian; 56% ECOG PS of 1; and 18% with history of brain metastases. Thirty-one percent had tumor PD-L1 expression TPS <1% [negative]. Seventy-two percent received carboplatin and 12% were never smokers. A total of 85 patients in the placebo and chemotherapy arm received an anti-PD-1/PD-L1 monoclonal antibody at the time of disease progression.

The trial demonstrated a statistically significant improvement in OS and PFS for patients randomized to KEYTRUDA in combination with pemetrexed and platinum chemotherapy compared with placebo, pemetrexed, and platinum chemotherapy. Table 42 and Figure 4 summarize the efficacy results for KEYNOTE-189.

Table 42: Efficacy Results in KEYNOTE-189

Endpoint KEYTRUDA 200 mg every 3 weeks Pemetrexed Platinum Chemotherapy
n=410
Placebo Pemetrexed Platinum Chemotherapy
n=206
OS
Number (%) of patients with event 127 (31%) 108 (52%)
Median in months (95% CI) NR 11.3
(NR, NR) (8.7, 15.1)
Hazard ratio* (95% CI) 0.49 (0.38, 0.64)
p-Value† <0.0001
PFS
Number of patients with event (%) 245 (60%) 166 (81%)
Median in months (95% CI) 8.8 (7.6, 9.2) 4.9 (4.7, 5.5)
Hazard ratio* (95% CI) 0.52 (0.43, 0.64)
p-Value† <0.0001
Objective Response Rate
ORR‡ (95% CI) 48% (43, 53) 19% (14, 25)
Complete response 0.5% 0.5%
Partial response 47% 18%
p-Value§ <0.0001
Duration of Response
Median in months (range) 11.2 (1.1+, 18.0+) 7.8 (2.1+, 16.4+)
* Based on the stratified Cox proportional hazard model
† Based on a stratified log-rank test
‡ Response: Best objective response as confirmed complete response or partial response
§ Based on Miettinen and Nurminen method stratified by PD-L1 status, platinum chemotherapy, and smoking status
NR = not reached

At the protocol-specified final OS analysis, the median in the KEYTRUDA in combination with pemetrexed and platinum chemotherapy arm was 22.0 months (95% CI: 19.5, 24.5) compared to 10.6 months (95% 8.7, 13.6) in the placebo with pemetrexed and platinum chemotherapy arm, with an HR of 0.56 (95% 0.46, 0.69).

Figure 4: Kaplan-Meier Curve for Overall Survival in KEYNOTE-189*

Kaplan-Meier Curve for Overall Survival in
KEYNOTE-189* - Illustration

First-Line Treatment Of Metastatic Squamous NSCLC With Carboplatin And Either Paclitaxel Or Paclitaxel Protein-Bound Chemotherapy

The efficacy of KEYTRUDA in combination with carboplatin and investigator’s choice of either paclitaxel or paclitaxel protein-bound was investigated in KEYNOTE-407 (NCT02775435), a randomized, multi-center, double-blind, placebo-controlled trial conducted in 559 patients with metastatic squamous NSCLC, regardless of PD-L1 tumor expression status, who had not previously received systemic therapy for metastatic disease. Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by tumor PD­L1 status (TPS <1% [negative] vs. TPS ≥1%), choice of paclitaxel or paclitaxel protein-bound, and geographic region (East Asia vs. non-East Asia). Patients were randomized (1:1) to one of the following treatment arms; all study medications were administered via intravenous infusion:

  • KEYTRUDA 200 mg and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for 4 cycles, and paclitaxel 200 mg/m² on Day 1 of each 21-day cycle for 4 cycles or paclitaxel protein-bound 100 mg/m² on Days 1, 8 and 15 of each 21-day cycle for 4 cycles, followed by KEYTRUDA 200 mg every 3 weeks. KEYTRUDA was administered prior to chemotherapy on Day 1.
  • Placebo and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for 4 cycles and paclitaxel 200 mg/m² on Day 1 of each 21-day cycle for 4 cycles or paclitaxel protein-bound 100 mg/m² on Days 1, 8 and 15 of each 21-day cycle for 4 cycles, followed by placebo every 3 weeks.

Treatment with KEYTRUDA and chemotherapy or placebo and chemotherapy continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease as determined by BICR, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator. Patients randomized to the placebo and chemotherapy arm were offered KEYTRUDA as a single agent at the time of disease progression. Assessment of tumor status was performed every 6 weeks through Week 18, every 9 weeks through Week 45 and every 12 weeks thereafter. The main efficacy outcome measures were PFS and ORR as assessed by BICR using RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and OS. An additional efficacy outcome measure was DoR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

The study population characteristics were: median age of 65 years (range: 29 to 88), 55% age 65 or older; 81% male; 77% White; 71% ECOG PS of 1; and 8% with a history of brain metastases. Thirty-five percent had tumor PD-L1 expression TPS <1%; 19% were from the East Asian region; and 60% received paclitaxel.

The trial demonstrated a statistically significant improvement in OS, PFS and ORR in patients randomized to KEYTRUDA in combination with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy compared with patients randomized to placebo with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy. Table 43 and Figure 5 summarize the efficacy results for KEYNOTE-407.

Table 43: Efficacy Results in KEYNOTE-407

Endpoint KEYTRUDA 200 mg every 3 weeks Carboplatin Paclitaxel/Paclitaxel protein-bound
n=278
Placebo Carboplatin Paclitaxel/Paclitaxel protein-bound
n=281
OS
Number of events (%) 85 (31%) 120 (43%)
Median in months (95% CI) 15.9 (13.2, NE) 11.3 (9.5, 14.8)
Hazard ratio* (95% CI) 0.64 (0.49, 0.85)
p-Value† 0.0017
PFS
Number of events (%) 152 (55%) 197 (70%)
Median in months (95% CI) 6.4 (6.2, 8.3) 4.8 (4.2, 5.7)
Hazard ratio* (95% CI) 0.56 (0.45, 0.70)
p-Value† <0.0001
n=101 n=103
Objective Response Rate‡
ORR (95% CI) 58% (48, 68) 35% (26, 45)
Difference (95% CI) 23.6% (9.9, 36.4)
p-Value§ 0.0008
Duration of Response‡
Median duration of response in months (range) 7.2 (2.4, 12.4+) 4.9 (2.0, 12.4+)
* Based on the stratified Cox proportional hazard model
† Based on a stratified log-rank test
‡ ORR primary analysis and DoR analysis were conducted with the first 204 patients enrolled.
§ Based on a stratified Miettinen-Nurminen test
NE = not estimable

At the protocol-specified final OS analysis, the median in the KEYTRUDA in combination with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy arm was 17.1 months (95% CI: 14.4, 19.9) compared to 11.6 months (95% CI: 10.1, 13.7) in the placebo with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy arm, with an HR of 0.71 (95% CI: 0.58, 0.88).

Figure 5: Kaplan-Meier Curve for Overall Survival in KEYNOTE-407*

Kaplan-Meier Curve for Overall Survival in
KEYNOTE-407* - Illustration

First-Line Treatment Of Metastatic NSCLC As A Single Agent

KEYNOTE-042

The efficacy of KEYTRUDA was investigated in KEYNOTE-042 (NCT02220894), a randomized, multicenter, open-label, active-controlled trial conducted in 1274 patients with stage III NSCLC who were not candidates for surgical resection or definitive chemoradiation, or patients with metastatic NSCLC. Only patients whose tumors expressed PD-L1 (TPS ≥1%) by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx kit and who had not received prior systemic treatment for metastatic NSCLC were eligible. Patients with EGFR or ALK genomic tumor aberrations; autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of radiation in the thoracic region within the prior 26 weeks of initiation of study were ineligible. Randomization was stratified by ECOG PS (0 vs. 1), histology (squamous vs. nonsquamous), geographic region (East Asia vs. non-East Asia), and PD-L1 expression (TPS ≥50% vs. TPS 1 to 49%). Patients were randomized (1:1) to receive KEYTRUDA 200 mg intravenously every 3 weeks or investigator’s choice of either of the following platinum-containing chemotherapy regimens:

  • Pemetrexed 500 mg/m² every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for a maximum of 6 cycles followed by optional pemetrexed 500 mg/m² every 3 weeks for patients with nonsquamous histologies;
  • Paclitaxel 200 mg/m² every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for a maximum of 6 cycles followed by optional pemetrexed 500 mg/m² every 3 weeks for patients with nonsquamous histologies.

Treatment with KEYTRUDA continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator. Treatment with KEYTRUDA could be reinitiated at the time of subsequent disease progression and administered for up to 12 months. Assessment of tumor status was performed every 9 weeks. The main efficacy outcome measure was OS in the subgroup of patients with TPS ≥50% NSCLC, the subgroup of patients with TPS ≥20% NSCLC, and the overall population with TPS ≥1% NSCLC. Additional efficacy outcome measures were PFS and ORR in the subgroup of patients with TPS ≥50% NSCLC, the subgroup of patients with TPS ≥20% NSCLC, and the overall population with TPS ≥1% NSCLC as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

The study population characteristics were: median age of 63 years (range: 25 to 90), 45% age 65 or older; 71% male; and 64% White, 30% Asian, and 2% Black. Nineteen percent were Hispanic or Latino. Sixty-nine percent had ECOG PS of 1; 39% with squamous and 61% with nonsquamous histology; 87% had M1 disease and 13% had Stage IIIA (2%) or Stage IIIB (11%) and who were not candidates for surgical resection or definitive chemoradiation per investigator assessment; and 5% with treated brain metastases at baseline. Forty-seven percent of patients had TPS ≥50% NSCLC and 53% had TPS 1 to 49% NSCLC.

The trial demonstrated a statistically significant improvement in OS for patients (PD-L1 TPS ≥50%, TPS ≥20%, TPS ≥1%) randomized to KEYTRUDA as compared with chemotherapy. Table 44 and Figure 6 summarize the efficacy results in the subgroup of patients with TPS ≥50% and in all randomized patients with TPS ≥1%.

Table 44: Efficacy Results of All Randomized Patients (TPS ≥1% and TPS ≥50%) in KEYNOTE-042

Endpoint TPS ≥1% TPS ≥50%
KEYTRUDA 200 mg every 3 weeks
n=637
Chemotherapy
n=637
KEYTRUDA 200 mg every 3 weeks
n=299
Chemotherapy
n=300
OS
Number of events (%) 371 (58%) 438 (69%) 157 (53%) 199 (66%)
Median in months (95% CI) 16.7 (13.9, 19.7) 12.1 (11.3, 13.3) 20.0 (15.4, 24.9) 12.2 (10.4, 14.2)
Hazard ratio* (95% CI) 0.81 (0.71, 0.93) 0.69 (0.56, 0.85)
p-Value† 0.0036 0.0006
PFS
Number of events (%) 507 (80%) 506 (79%) 221 (74%) 233 (78%)
Median in months (95% CI) 5.4 (4.3, 6.2) 6.5 (6.3, 7.0) 6.9 (5.9, 9.0) 6.4 (6.1, 6.9)
Hazard ratio* ‡(95% CI) 1.07 (0.94, 1.21) 0.82 (0.68, 0.99)
p-Value† -‡ NS§
Objective Response Rate
ORR‡ (95% CI) 27% (24, 31) 27% (23, 30) 39% (33.9, 45.3) 32% (26.8, 37.6)
Complete response rate 0.5% 0.5% 0.7% 0.3%
Partial response rate 27% 26% 39% 32%
Duration of Response
% with duration ≥12 monthss¶ 47% 16% 42% 17%
% with duration ≥18 monthss¶ 26% 6% 25% 5%
* Based on the stratified Cox proportional hazard model
† Based on a stratified log-rank test; compared to a p-Value boundary of 0.0291
‡ Not evaluated for statistical significance as a result of the sequential testing procedure for the secondary endpoints
§ Not significant compared to a p-Value boundary of 0.0291
¶ Based on observed duration of response

The results of all efficacy outcome measures in the subgroup of patients with PD-L1 TPS ≥20% NSCLC were intermediate between the results of those with PD-L1 TPS ≥1% and those with PD-L1 TPS ≥50%. In a pre-specified exploratory subgroup analysis for patients with TPS 1-49% NSCLC, the median OS was 13.4 months (95% CI: 10.7, 18.2) for the pembrolizumab group and 12.1 months (95% CI: 11.0, 14.0) in the chemotherapy group, with an HR of 0.92 (95% CI: 0.77, 1.11).

Figure 6: Kaplan-Meier Curve for Overall Survival in all Randomized Patients in KEYNOTE-042 (TPS ≥1%)

Kaplan-Meier Curve for Overall Survival in
all Randomized Patients in KEYNOTE-042 (TPS =1%) - Illustration

KEYNOTE-024

The efficacy of KEYTRUDA was also investigated in KEYNOTE-024 (NCT02142738), a randomized, multicenter, open-label, active-controlled trial in 305 previously untreated patients with metastatic NSCLC. The study design was similar to that of KEYNOTE-042, except that only patients whose tumors had high PD-L1 expression (TPS of 50% or greater) by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx kit were eligible. Patients were randomized (1:1) to receive KEYTRUDA 200 mg intravenously every 3 weeks or investigator’s choice of any of the following platinum-containing chemotherapy regimens:

  • Pemetrexed 500 mg/m² every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for 4 to 6 cycles followed by optional pemetrexed 500 mg/m² every 3 weeks for patients with nonsquamous histologies;
  • Pemetrexed 500 mg/m² every 3 weeks and cisplatin 75 mg/m² every 3 weeks on Day 1 for 4 to 6 cycles followed by optional pemetrexed 500 mg/m² every 3 weeks for patients with nonsquamous histologies;
  • Gemcitabine 1250 mg/m² on days 1 and 8 and cisplatin 75 mg/m² every 3 weeks on Day 1 for 4 to 6 cycles;
  • Gemcitabine 1250 mg/m² on Days 1 and 8 and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for 4 to 6 cycles;
  • Paclitaxel 200 mg/m² every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for 4 to 6 cycles followed by optional pemetrexed maintenance (for nonsquamous histologies).

Patients randomized to chemotherapy were offered KEYTRUDA at the time of disease progression.

The main efficacy outcome measure was PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures were OS and ORR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

The study population characteristics were: median age of 65 years (range: 33 to 90), 54% age 65 or older; 61% male; 82% White and 15% Asian; 65% with ECOG PS of 1; 18% with squamous and 82% with nonsquamous histology and 9% with history of brain metastases. A total of 66 patients in the chemotherapy arm received KEYTRUDA at the time of disease progression.

The trial demonstrated a statistically significant improvement in both PFS and OS for patients randomized to KEYTRUDA as compared with chemotherapy. Table 45 and Figure 7 summarize the efficacy results for KEYNOTE-024.

Table 45: Efficacy Results in KEYNOTE-024

Endpoint KEYTRUDA 200 mg every 3 weeks
n=154
Chemotherapy
n=151
PFS
Number (%) of patients with event 73 (47%) 116 (77%)
Median in months (95% CI) 10.3 (6.7, NR) 6.0 (4.2, 6.2)
Hazard ratio* (95% CI) 0.50 (0.37, 0.68)
p-Value (stratified log-rank) <0.001
OS
Number (%) of patients with event 44 (29%) 64 (42%)
Median in months (95% CI)† 30.0 (18.3, NR) 14.2 (9.8, 19.0)
Hazard ratio* (95% CI) 0.60 (0.41, 0.89)
p-Value (stratified log-rank) 0.005‡
Objective Response Rate
ORR (95% CI) 45% (37, 53) 28% (21, 36)
Complete response rate 4% 1%
Partial response rate 41% 27%
p-Value (Miettinen-Nurminen) 0.001
Median duration of response in months (range) NR (1.9+, 14.5+) 6.3 (2.1+, 12.6+)
* Based on the stratified Cox proportional hazard model for the interim analysis
† Based on the protocol-specified final OS analysis conducted at 169 events, which occurred 14 months after the interim analysis.
‡ p-Value is compared with 0.0118 of the allocated alpha for the interim analysis NR = not reached

Figure 7: Kaplan-Meier Curve for Overall Survival in KEYNOTE-024*

Kaplan-Meier Curve for Overall Survival in
KEYNOTE-024* - Illustration

Previously Treated NSCLC

The efficacy of KEYTRUDA was investigated in KEYNOTE-010 (NCT01905657), a randomized, multicenter, open-label, active-controlled trial conducted in 1033 patients with metastatic NSCLC that had progressed following platinum-containing chemotherapy, and if appropriate, targeted therapy for EGFR or ALK genomic tumor aberrations. Eligible patients had PD-L1 expression TPS of 1% or greater by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx kit. Patients with autoimmune disease; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by tumor PD-L1 expression (PD-L1 expression TPS ≥50% vs. PD-L1 expression TPS=1-49%), ECOG PS (0 vs. 1), and geographic region (East Asia vs. non-East Asia). Patients were randomized (1:1:1) to receive KEYTRUDA 2 mg/kg intravenously every 3 weeks, KEYTRUDA 10 mg/kg intravenously every 3 weeks or docetaxel intravenously 75 mg/m² every 3 weeks until unacceptable toxicity or disease progression. Patients randomized to KEYTRUDA were permitted to continue until disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or confirmation of progression at 4 to 6 weeks with repeat imaging or for up to 24 months without disease progression. Assessment of tumor status was performed every 9 weeks. The main efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, in the subgroup of patients with TPS ≥50% and the overall population with TPS ≥1%. Additional efficacy outcome measures were ORR and DoR in the subgroup of patients with TPS ≥50% and the overall population with TPS ≥1%.

The study population characteristics were: median age of 63 years (range: 20 to 88), 42% age 65 or older; 61% male; 72% White and 21% Asian; 66% ECOG PS of 1; 43% with high PD-L1 tumor expression; 21% with squamous, 70% with nonsquamous, and 8% with mixed, other or unknown histology; 91% metastatic (M1) disease; 15% with history of brain metastases; and 8% and 1% with EGFR and ALK genomic aberrations, respectively. All patients had received prior therapy with a platinum-doublet regimen, 29% received two or more prior therapies for their metastatic disease.

Tables 46 and 47 and Figure 8 summarize efficacy results in the subgroup with TPS ≥50% population and in all patients, respectively.

Table 46: Efficacy Results of the Subgroup of Patients with TPS ≥50% in KEYNOTE-010

Endpoint KEYTRUDA 2 mg/kg every 3 weeks
n=139
KEYTRUDA 10 mg/kg every 3 weeks
n=151
Docetaxel 75 mg/m² every 3 weeks
n=152
OS
Deaths (%) 58 (42%) 60 (40%) 86 (57%)
Median in months (95% CI) 14.9 (10.4, NR) 17.3 (11.8, NR) 8.2 (6.4, 10.7)
Hazard ratio* (95% CI) 0.54 (0.38, 0.77) 0.50 (0.36, 0.70)
p-Value (stratified log-rank) <0.001 <0.001
PFS
Events (%) 89 (64%) 97 (64%) 118 (78%)
Median in months (95% CI) 5.2 (4.0, 6.5) 5.2 (4.1, 8.1) 4.1 (3.6, 4.3)
Hazard ratio* (95% CI) 0.58 (0.43, 0.77) 0.59 (0.45, 0.78)
p-Value (stratified log-rank) <0.001 <0.001 ---
Objective Response Rate
ORR† (95% CI) 30% (23, 39) 29% (22, 37) 8% (4, 13)
p-Value (Miettinen-Nurminen) <0.001 <0.001 ---
Median duration of response in NR NR 8.1
months (range) (0.7+, 16.8+) (2.1+, 17.8+) (2.1+, 8.8+)
* Hazard ratio (KEYTRUDA compared to docetaxel) based on the stratified Cox proportional hazard model
† All responses were partial responses NR = not reached

Table 47: Efficacy Results of All Randomized Patients (TPS ≥1%) in KEYNOTE-010

Endpoint KEYTRUDA 2 mg/kg every 3 weeks
n=344
KEYTRUDA 10 mg/kg every 3 weeks
n=346
Docetaxel 75 mg/m² every 3 weeks
n=343
OS
Deaths (%) 172 (50%) 156 (45%) 193 (56%)
Median in months (95% CI) 10.4 (9.4, 11.9) 12.7 (10.0, 17.3) 8.5 (7.5, 9.8)
Hazard ratio* (95% CI) 0.71 (0.58, 0.88) 0.61 (0.49, 0.75)
p-Value (stratified log-rank) <0.001 <0.001
PFS
Events (%) 266 (77%) 255 (74%) 257 (75%)
Median in months (95% CI) 3.9 (3.1, 4.1) 4.0 (2.6, 4.3) 4.0 (3.1, 4.2)
Hazard ratio* (95% CI) 0.88 (0.73, 1.04) 0.79 (0.66, 0.94)
p-Value (stratified log-rank) 0.068 0.005
Objective Response Rate
ORR† (95% CI) 18% (14, 23) 19% (15, 23) 9% (7, 13)
p-Value (Miettinen-Nurminen) <0.001 <0.001
Median duration of response in NR NR 6.2
months (range) (0.7+, 20.1+) (2.1+, 17.8+) (1.4+, 8.8+)
* Hazard ratio (KEYTRUDA compared to docetaxel) based on the stratified Cox proportional hazard model
† All responses were partial responses NR = not reached

Figure 8: Kaplan-Meier Curve for Overall Survival in all Randomized Patients in KEYNOTE-010 (TPS ≥1%)

Kaplan-Meier Curve for Overall Survival in all Randomized Patients in KEYNOTE-010 (TPS =1%) - Illustration

Head And Neck Squamous Cell Cancer

First-Line Treatment Of Metastatic Or Unresectable, Recurrent HNSCC

The efficacy of KEYTRUDA was investigated in KEYNOTE-048 (NCT02358031), a randomized, multicenter, open-label, active-controlled trial conducted in 882 patients with metastatic HNSCC who had not previously received systemic therapy for metastatic disease or with recurrent disease who were considered incurable by local therapies. Patients with active autoimmune disease that required systemic therapy within two years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by tumor PD-L1 expression (TPS ≥50% or <50%) according to the PD-L1 IHC 22C3 pharmDx kit, HPV status according to p16 IHC (positive or negative), and ECOG PS (0 vs. 1). Patients were randomized 1:1:1 to one of the following treatment arms:

  • KEYTRUDA 200 mg intravenously every 3 weeks
  • KEYTRUDA 200 mg intravenously every 3 weeks, carboplatin AUC 5 mg/mL/min intravenously every 3 weeks or cisplatin 100 mg/m² intravenously every 3 weeks, and FU 1000 mg/m²/day as a continuous intravenous infusion over 96 hours every 3 weeks (maximum of 6 cycles of platinum and FU)
  • Cetuximab 400 mg/m² intravenously as the initial dose then 250 mg/m² intravenously once weekly, carboplatin AUC 5 mg/mL/min intravenously every 3 weeks or cisplatin 100 mg/m² intravenously every 3 weeks, and FU 1000 mg/m²/day as a continuous intravenous infusion over 96 hours every 3 weeks (maximum of 6 cycles of platinum and FU)

Treatment with KEYTRUDA continued until RECIST v1.1-defined progression of disease as determined by the investigator, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed at Week 9 and then every 6 weeks for the first year, followed by every 9 weeks through 24 months. A retrospective re-classification of patients’ tumor PD-L1 status according to CPS using the PD-L1 IHC 22C3 pharmDx kit was conducted using the tumor specimens used for randomization.

The main efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ) sequentially tested in the subgroup of patients with CPS ≥20, the subgroup of patients with CPS ≥1, and the overall population.

The study population characteristics were: median age of 61 years (range: 20 to 94), 36% age 65 or older; 83% male; 73% White, 20% Asian and 2.4% Black; 61% had ECOG PS of 1; and 79% were former/current smokers. Twenty-two percent of patients’ tumors were HPV-positive, 23% had PD-L1 TPS ≥50%, and 95% had Stage IV disease (Stage IVA 19%, Stage IVB 6%, and Stage IVC 70%). Eighty-five percent of patients’ tumors had PD-L1 expression of CPS ≥1 and 43% had CPS ≥20.

The trial demonstrated a statistically significant improvement in OS for patients randomized to KEYTRUDA in combination with chemotherapy compared to those randomized to cetuximab in combination with chemotherapy at a pre-specified interim analysis in the overall population. Table 48 and Figure 9 summarize efficacy results for KEYTRUDA in combination with chemotherapy.

Table 48: Efficacy Results* for KEYTRUDA plus Platinum/Fluorouracil in KEYNOTE-048

Endpoint KEYTRUDA 200 mg every 3 weeks Platinum FU
n=281
Cetuximab Platinum FU
n=278
OS
Number (%) of patients with event 197 (70%) 223 (80%)
Median in months (95% CI) 13.0 (10.9, 14.7) 10.7 (9.3, 11.7)
Hazard ratio† (95% CI) 0.77 (0.63, 0.93)
p-Value‡ 0.0067
PFS
Number of patients with event (%) 244 (87%) 253 (91 %)
Median in months (95% CI) 4.9 (4.7, 6.0) 5.1 (4.9, 6.0)
Hazard ratio† (95% CI) 0.92 (0.77, 1.10)
p-Value‡ 0.3394
Objective Response Rate
ORR§ (95% CI) 36% (30.0, 41.5) 36% (30.7, 42.3)
Complete response rate 6% 3%
Partial response rate 30% 33%
Duration of Response
Median in months (range) 6.7 (1.6+, 30.4+) 4.3 (1.2+, 27.9+)
* Results at a pre-specified interim analysis
† Based on the stratified Cox proportional hazard model
‡ Based on stratified log-rank test § Response: Best objective response as confirmed complete response or partial response

At the pre-specified final OS analysis for the ITT population, the hazard ratio was 0.72 (95% CI: 0.60, 0.87). In addition, KEYNOTE-048 demonstrated a statistically significant improvement in OS for the subgroups of patients with PD-L1 CPS ≥1 (HR=0.65, 95% CI: 0.53, 0.80) and CPS ≥20 (HR=0.60, 95% CI: 0.45, 0.82).

Figure 9: Kaplan-Meier Curve for Overall Survival for KEYTRUDA plus Platinum/Fluorouracil in KEYNOTE-048*

Kaplan-Meier Curve for Overall Survival for
KEYTRUDA plus Platinum/Fluorouracil in KEYNOTE-048* - Illustration

The trial also demonstrated a statistically significant improvement in OS for the subgroup of patients with PD-L1 CPS ≥1 randomized to KEYTRUDA as a single agent compared to those randomized to cetuximab in combination with chemotherapy at a pre-specified interim analysis. At the time of the interim and final analyses, there was no significant difference in OS between the KEYTRUDA single agent arm and the control arm for the overall population.

Table 49 summarizes efficacy results for KEYTRUDA as a single agent in the subgroups of patients with CPS ≥1 HNSCC and CPS ≥20 HNSCC. Figure 10 summarizes the OS results in the subgroup of patients with CPS ≥1 HNSCC.

Table 49: Efficacy Results* for KEYTRUDA as a Single Agent in KEYNOTE-048 (CPS ≥1 and CPS ≥20)

Endpoint CPS ≥1 CPS ≥20
KEYTRUDA 200 mg every 3 weeks
n=257
Cetuximab Platinum FU
n=255
KEYTRUDA 200 mg every 3 weeks
n=133
Cetuximab Platinum FU
n=122
OS
Number of events (%) 177 (69%) 206 (81%) 82 (62%) 95 (78%)
Median in months (95% CI) 12.3 (10.8, 14.9) 10.3 (9.0,11.5) 14.9 (11.6, 21.5) 10.7 (8.8, 12.8)
Hazard ratio† (95% CI) 0.78 (0.64, 0.96) 0.61 (0.45, 0.83)
p-Value‡ 0.0171 0.0015
PFS
Number of events (%) 225 (88%) 231 (91%) 113 (85%) 111 (91 %)
Median in months (95% CI) 3.2 (2.2, 3.4) 5.0 (4.8, 5.8) 3.4 (3.2, 3.8) 5.0 (4.8, 6.2)
Hazard ratio† (95% CI) 1.15 (0.95, 1.38) 0.97 (0.74, 1.27)
Objective Response Rate
ORR§ (95% CI) 19% (14.5, 24.4) 35% (29.1, 41.1) 23% (16.4, 31.4) 36% (27.6, 45.3)
Complete response rate 5% 3% 8% 3%
Partial response rate 14% 32% 16% 33%
Duration of Response
Median in months (range) 20.9 (1.5+, 34.8+) 4.5 (1.2+, 28.6+) 20.9 (2.7, 34.8+) 4.2 (1.2+, 22.3+)
* Results at a pre-specified interim analysis
† Based on the stratified Cox proportional hazard model
‡ Based on a stratified log-rank test
§ Response: Best objective response as confirmed complete response or partial response

At the pre-specified final OS analysis comparing KEYTRUDA as a single agent to cetuximab in combination with chemotherapy, the hazard ratio for the subgroup of patients with CPS ≥1 was 0.74 (95% CI: 0.61, 0.90) and the hazard ratio for the subgroup of patients with CPS ≥20 was 0.58 (95% CI: 0.44, 0.78).

In an exploratory subgroup analysis for patients with CPS 1-19 HNSCC at the time of the pre-specified final OS analysis, the median OS was 10.8 months (95% CI: 9.0, 12.6) for KEYTRUDA as a single agent and 10.1 months (95% CI: 8.7, 12.1) for cetuximab in combination with chemotherapy, with an HR of 0.86 (95% CI: 0.66, 1.12).

Figure 10: Kaplan-Meier Curve for Overall Survival for KEYTRUDA as a Single Agent in KEYNOTE-048 (CPS ≥1)*

Kaplan-Meier Curve for Overall Survival for
KEYTRUDA as a Single Agent in KEYNOTE-048 (CPS =1)* - Illustration

Previously Treated Recurrent Or Metastatic HNSCC

The efficacy of KEYTRUDA was investigated in KEYNOTE-012 (NCT01848834), a multicenter, non-randomized, open-label, multi-cohort study that enrolled 174 patients with recurrent or metastatic HNSCC who had disease progression on or after platinum-containing chemotherapy administered for recurrent or metastatic HNSCC or following platinum-containing chemotherapy administered as part of induction, concurrent, or adjuvant therapy. Patients with active autoimmune disease, a medical condition that required immunosuppression, evidence of interstitial lung disease, or ECOG PS ≥2 were ineligible.

Patients received KEYTRUDA 10 mg/kg every 2 weeks (n=53) or 200 mg every 3 weeks (n=121) until unacceptable toxicity or disease progression that was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Treatment with pembrolizumab could be reinitiated for subsequent disease progression and administered for up to 1 additional year. Assessment of tumor status was performed every 8 weeks. The major efficacy outcome measures were ORR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR, and DoR.

The study population characteristics were median age of 60 years, 32% age 65 or older; 82% male; 75% White, 16% Asian, and 6% Black; 87% had M1 disease; 33% had HPV positive tumors; 63% had prior cetuximab; 29% had an ECOG PS of 0 and 71% had an ECOG PS of 1; and the median number of prior lines of therapy administered for the treatment of HNSCC was 2.

The ORR was 16% (95% CI: 11, 22) with a complete response rate of 5%. The median follow-up time was 8.9 months. Among the 28 responding patients, the median DoR had not been reached (range: 2.4+ to 27.7+ months), with 23 patients having responses of 6 months or longer. The ORR and DoR were similar irrespective of dosage regimen (10 mg/kg every 2 weeks or 200 mg every 3 weeks) or HPV status.

Classical Hodgkin Lymphoma

KEYNOTE-204

The efficacy of KEYTRUDA was investigated in KEYNOTE-204 (NCT02684292), a randomized, open-label, active controlled trial conducted in 304 patients with relapsed or refractory cHL. The trial enrolled adults with relapsed or refractory disease after at least one multi-agent chemotherapy regimen. Patients were randomized (1:1) to receive:

  • KEYTRUDA 200 mg intravenously every 3 weeks or
  • Brentuximab vedotin (BV) 1.8 mg/kg intravenously every 3 weeks

Treatment was continued until unacceptable toxicity, disease progression, or a maximum of 35 cycles (up to approximately 2 years). Disease assessment was performed every 12 weeks. Randomization was stratified by prior autologous HSCT (yes vs. no) and disease status after frontline therapy (primary refractory vs. relapse <12 months after completion vs. relapse ≥12 months after completion). The main efficacy measure was PFS as assessed by BICR using 2007 revised International Working Group criteria.

The study population characteristics were: median age of 35 years (range: 18 to 84); 57% male; 77% White, 9% Asian, 3.9% Black. The median number of prior therapies was 2 (range: 1 to 10) in the KEYTRUDA arm and 3 (range: 1 to 11) in the BV arm, with 18% in both arms having 1 prior line. Forty-two percent of patients were refractory to the last prior therapy, 29% had primary refractory disease, 37% had prior autologous HSCT, 5% had received prior BV, and 39% had prior radiation therapy.

Efficacy is summarized in Table 50 and Figure 11.

Table 50: Efficacy Results in Patients with cHL in KEYNOTE-204

Endpoint KEYTRUDA 200 mg every 3 weeks
n=151
Brentuximab Vedotin 1.8 mg/kg every 3 weeks
n=153
PFS
Number of patients with event (%) 81 (54%) 88 (58%)
Median in months (95% CI)* 13.2 (10.9, 19.4) 8.3 (5.7, 8.8)
Hazard ratio† (95% CI) 0.65 (0.48, 0.88)
p-Value‡ 0.0027
Objective Response Rate
ORR§ (95% CI) 66% (57, 73) 54% (46, 62)
Complete response 25% 24%
Partial response 41% 30%
Duration of Response
Median in months (range)* 20.7 (0.0+, 33.2+) 13.8 (0.0+, 33.9+)
* Based on Kaplan-Meier estimates.
† Based on the stratified Cox proportional hazard model.
‡ Based on a stratified log-rank test. One-sided p-value, with a prespecified boundary of 0.0043.
§ Difference in ORR is not statistically significant.
+ Denotes a censored value.

Figure 11: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-204

Kaplan-Meier Curve for Progression-Free
Survival in KEYNOTE-204 - Illustration

KEYNOTE-087

The efficacy of KEYTRUDA was investigated in KEYNOTE-087 (NCT02453594), a multicenter, non-randomized, open-label trial in 210 patients with relapsed or refractory cHL. Patients with active, non­infectious pneumonitis, an allogeneic HSCT within the past 5 years (or >5 years but with symptoms of GVHD), active autoimmune disease, a medical condition that required immunosuppression, or an active infection requiring systemic therapy were ineligible for the trial. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression, or for up to 24 months in patients who did not progress. Disease assessment was performed every 12 weeks. The major efficacy outcome measures (ORR, Complete Response Rate, and DoR) were assessed by BICR according to the 2007 revised International Working Group (IWG) criteria.

The study population characteristics were: median age of 35 years (range: 18 to 76), 9% age 65 or older; 54% male; 88% White; and 49% ECOG PS of 0 and 51% ECOG PS of 1. The median number of prior lines of therapy administered for the treatment of cHL was 4 (range: 1 to 12). Fifty-eight percent were refractory to the last prior therapy, including 35% with primary refractory disease and 14% whose disease was chemo-refractory to all prior regimens. Sixty-one percent of patients had undergone prior autologous HSCT, 83% had received prior brentuximab vedotin and 36% of patients had prior radiation therapy.

Efficacy results for KEYNOTE-087 are summarized in Table 51.

Table 51: Efficacy Results in Patients with cHL in KEYNOTE-087

Endpoint KEYTRUDA 200 mg every 3 weeks
n=210*
Objective Response Rate
ORR (95% CI) 69% (62, 75)
Complete response rate 22%
Partial response rate 47%
Duration of Response
Median in months (range) 11.1 (0.0+, 11.1)†
* Median follow-up time of 9.4 months
† Based on patients (n=145) with a response by independent review

Primary Mediastinal Large B-Cell Lymphoma

The efficacy of KEYTRUDA was investigated in KEYNOTE-170 (NCT02576990), a multicenter, open-label, single-arm trial in 53 patients with relapsed or refractory PMBCL. Patients were not eligible if they had active non-infectious pneumonitis, allogeneic HSCT within the past 5 years (or >5 years but with symptoms of GVHD), active autoimmune disease, a medical condition that required immunosuppression, or an active infection requiring systemic therapy. Patients were treated with KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression, or for up to 24 months for patients who did not progress. Disease assessments were performed every 12 weeks and assessed by BICR according to the 2007 revised IWG criteria. The efficacy outcome measures were ORR and DoR.

The study population characteristics were: median age of 33 years (range: 20 to 61 years); 43% male; 92% White; and 43% ECOG PS of 0 and 57% ECOG PS of 1. The median number of prior lines of therapy administered for the treatment of PMBCL was 3 (range 2 to 8). Thirty-six percent had primary refractory disease, 49% had relapsed disease refractory to the last prior therapy, and 15% had untreated relapse. Twenty-six percent of patients had undergone prior autologous HSCT, and 32% of patients had prior radiation therapy. All patients had received rituximab as part of a prior line of therapy.

For the 24 responders, the median time to first objective response (complete or partial response) was 2.8 months (range 2.1 to 8.5 months). Efficacy results for KEYNOTE-170 are summarized in Table 52.

Table 52: Efficacy Results in Patients with PMBCL in KEYNOTE-170

Endpoint KEYTRUDA 200 mg every 3 weeks
n=53*
Objective Response Rate
ORR (95% CI) 45% (32, 60)
Complete response rate 11%
Partial response rate 34%
Duration of Response
Median in months (range) NR (1.1+, 19.2+)†
* Median follow-up time of 9.7 months
† Based on patients (n=24) with a response by independent review NR = not reached

Urothelial Carcinoma

Cisplatin Ineligible Patients With Urothelial Carcinoma

The efficacy of KEYTRUDA was investigated in KEYNOTE-052 (NCT02335424), a multicenter, open-label, single-arm trial in 370 patients with locally advanced or metastatic urothelial carcinoma who were not eligible for cisplatin-containing chemotherapy. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity or disease progression. Patients with initial radiographic disease progression could receive additional doses of treatment during confirmation of progression unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Patients without disease progression could be treated for up to 24 months. Tumor response assessments were performed at 9 weeks after the first dose, then every 6 weeks for the first year, and then every 12 weeks thereafter. The major efficacy outcome measures were ORR and DoR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

The study population characteristics were: median age of 74 years; 77% male; and 89% White. Eighty-seven percent had M1 disease, and 13% had M0 disease. Eighty-one percent had a primary tumor in the lower tract, and 19% of patients had a primary tumor in the upper tract. Eighty-five percent of patients had visceral metastases, including 21% with liver metastases. Reasons for cisplatin ineligibility included: 50% with baseline creatinine clearance of <60 mL/min, 32% with ECOG PS of 2, 9% with ECOG PS of 2 and baseline creatinine clearance of <60 mL/min, and 9% with other reasons (Class III heart failure, Grade 2 or greater peripheral neuropathy, and Grade 2 or greater hearing loss). Ninety percent of patients were treatment naïve, and 10% received prior adjuvant or neoadjuvant platinum-based chemotherapy.

Among the 370 patients, 30% (n = 110) had tumors that expressed PD-L1 with a CPS ≥10. PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx kit. The study population characteristics of these 110 patients were: median age of 73 years; 68% male; and 87% White. Eighty-two percent had M1 disease, and 18% had M0 disease. Eighty-one percent had a primary tumor in the lower tract, and 18% of patients had a primary tumor in the upper tract. Seventy-six percent of patients had visceral metastases, including 11% with liver metastases. Reasons for cisplatin ineligibility included: 45% with baseline creatinine clearance of <60 mL/min, 37% with ECOG PS of 2, 10% with ECOG PS of 2 and baseline creatinine clearance of <60 mL/min, and 8% with other reasons (Class III heart failure, Grade 2 or greater peripheral neuropathy, and Grade 2 or greater hearing loss). Ninety percent of patients were treatment naïve, and 10% received prior adjuvant or neoadjuvant platinum-based chemotherapy.

The median follow-up time for 370 patients treated with KEYTRUDA was 7.8 months (range 0.1 to 20 months). Efficacy results are summarized in Table 53.

Table 53: Efficacy Results in KEYNOTE-052

Endpoint KEYTRUDA 200 mg every 3 weeks
All Subjects n=370 PD-L1 CPS <10 n=260* PD-L1 CPS ≥10 n=110
Objective Response Rate
ORR (95% CI) 29% (24, 34) 21% (16, 26) 47% (38, 57)
Complete response rate 7% 3% 15%
Partial response rate 22% 18% 32%
Duration of Response
Median in months (range) NR (1.4+, 17.8+) NR (1.4+, 16.3+) NR (1.4+, 17.8+)
* Includes 9 subjects with unknown PD-L1 status
+ Denotes ongoing response NR = not reached

Previously Untreated Urothelial Carcinoma

KEYNOTE-361 (NCT02853305) is an ongoing, multicenter, randomized study in previously untreated patients with metastatic urothelial carcinoma who are eligible for platinum-containing chemotherapy. The study compares KEYTRUDA with or without platinum-based chemotherapy (i.e., cisplatin or carboplatin with gemcitabine) to platinum-based chemotherapy alone. The trial also enrolled a third arm of monotherapy with KEYTRUDA to compare to platinum-based chemotherapy alone. The independent Data Monitoring Committee (iDMC) for the study conducted a review of early data and found that in patients classified as having low PD-L1 expression (CPS <10), those treated with KEYTRUDA monotherapy had decreased survival compared to those who received platinum-based chemotherapy. The iDMC recommended to stop further accrual of patients with low PD-L1 expression in the monotherapy arm, however, no other changes were recommended, including any change of therapy for patients who had already been randomized to and were receiving treatment in the monotherapy arm.

Previously Treated Urothelial Carcinoma

The efficacy of KEYTRUDA was investigated in KEYNOTE-045 (NCT02256436), a multicenter, randomized (1:1), active-controlled trial in 542 patients with locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression.

Patients were randomized to receive either KEYTRUDA 200 mg every 3 weeks (n=270) or investigator’s choice of any of the following chemotherapy regimens all given intravenously every 3 weeks (n=272): paclitaxel 175 mg/m² (n=90), docetaxel 75 mg/m² (n=92), or vinflunine 320 mg/m² (n=90). Treatment continued until unacceptable toxicity or disease progression. Patients with initial radiographic disease progression could receive additional doses of treatment during confirmation of progression unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Patients without disease progression could be treated for up to 24 months. Assessment of tumor status was performed at 9 weeks after randomization, then every 6 weeks through the first year, followed by every 12 weeks thereafter. The major efficacy outcomes were OS and PFS as assessed by BICR per RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures were ORR as assessed by BICR per RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and DoR.

The study population characteristics were: median age of 66 years (range: 26 to 88), 58% age 65 or older; 74% male; 72% White and 23% Asian; 42% ECOG PS of 0 and 56% ECOG PS of 1; and 96% M1 disease and 4% M0 disease. Eighty-seven percent of patients had visceral metastases, including 34% with liver metastases. Eighty-six percent had a primary tumor in the lower tract and 14% had a primary tumor in the upper tract. Fifteen percent of patients had disease progression following prior platinum-containing neoadjuvant or adjuvant chemotherapy. Twenty-one percent had received 2 or more prior systemic regimens in the metastatic setting. Seventy-six percent of patients received prior cisplatin, 23% had prior carboplatin, and 1% were treated with other platinum-based regimens.

The study demonstrated statistically significant improvements in OS and ORR for patients randomized to KEYTRUDA as compared to chemotherapy. There was no statistically significant difference between KEYTRUDA and chemotherapy with respect to PFS. The median follow-up time for this trial was 9.0 months (range: 0.2 to 20.8 months). Table 54 and Figure 12 summarize the efficacy results for KEYNOTE-045.

Table 54: Efficacy Results in KEYNOTE-045

KEYTRUDA 200 mg every 3 weeks
n=270
Chemotherapy
n=272
OS
Deaths (%) 155 (57%) 179 (66%)
Median in months (95% CI) 10.3 (8.0, 11.8) 7.4 (6.1, 8.3)
Hazard ratio* (95% CI) 0.73 (0.59, 0.91)
p-Value (stratified log-rank) 0.004
PFS by BICR
Events (%) 218 (81%) 219 (81%)
Median in months (95% CI) 2.1 (2.0, 2.2) 3.3 (2.3, 3.5)
Hazard ratio* (95% CI) 0.98 (0.81, 1.19)
p-Value (stratified log-rank) 0.833
Objective Response Rate
ORR (95% CI) 21% (16, 27) 11% (8, 16)
Complete response rate 7% 3%
Partial response rate 14% 8%
p-Value (Miettinen-Nurminen) 0.002
Median duration of response in months (range) NR (1.6+, 15.6+) 4.3 (1.4+, 15.4+)
* Hazard ratio (KEYTRUDA compared to chemotherapy) based on the stratified Cox proportional hazard model
+ Denotes ongoing response
NR = not reached

Figure 12: Kaplan-Meier Curve for Overall Survival in KEYNOTE-045

 Kaplan-Meier Curve for Overall Survival in KEYNOTE-045 - Illustration

BCG-Unresponsive High-Risk Non-Muscle Invasive Bladder Cancer

The efficacy of KEYTRUDA was investigated in KEYNOTE-057 (NCT02625961), a multicenter, open-label, single-arm trial in 96 patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. BCG-unresponsive high-risk NMIBC was defined as persistent disease despite adequate BCG therapy, disease recurrence after an initial tumor-free state following adequate BCG therapy, or T1 disease following a single induction course of BCG. Adequate BCG therapy was defined as administration of at least five of six doses of an initial induction course plus either of: at least two of three doses of maintenance therapy or at least two of six doses of a second induction course. Prior to treatment, all patients had undergone transurethral resection of bladder tumor (TURBT) to remove all resectable disease (Ta and T1 components). Residual CIS (Tis components) not amenable to complete resection was allowed. The trial excluded patients with muscle invasive (i.e., T2, T3, T4) locally advanced non-resectable or metastatic urothelial carcinoma, concurrent extra-vesical (i.e., urethra, ureter or renal pelvis) non-muscle invasive transitional cell carcinoma of the urothelium, or autoimmune disease or a medical condition that required immunosuppression.

Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC, or progressive disease. Assessment of tumor status was performed every 12 weeks for two years and then every 24 weeks for three years, and patients without disease progression could be treated for up to 24 months. The major efficacy outcome measures were complete response (as defined by negative results for cystoscopy [with TURBT/biopsies as applicable], urine cytology, and computed tomography urography [CTU] imaging) and duration of response.

The study population characteristics were: median age of 73 years (range: 44 to 92); 44% age ≥75; 84% male; 67% White; and 73% and 27% with an ECOG performance status of 0 or 1, respectively. Tumor pattern at study entry was CIS with T1 (13%), CIS with high grade TA (25%), and CIS (63%). Baseline high-risk NMIBC disease status was 27% persistent and 73% recurrent. The median number of prior instillations of BCG was 12.

The median follow-up time was 28.0 months (range: 4.6 to 40.5 months). Efficacy results are summarized in Table 55.

Table 55: Efficacy Results in KEYNOTE-057

Endpoint KEYTRUDA 200 mg every 3 weeks
n=96
Complete Response Rate (95% CI) 41% (31, 51)
Duration of Response*
Median in months (range) 16.2 (0.0+, 30.4+)
% (n) with duration ≥12 months 46% (18)
* Based on patients (n=39) that achieved a complete response; reflects period from the time complete response was achieved
+ Denotes ongoing response

Microsatellite Instability-High Or Mismatch Repair Deficient Cancer

The efficacy of KEYTRUDA was investigated in patients with MSI-H or mismatch repair deficient (dMMR), solid tumors enrolled in one of five uncontrolled, open-label, multi-cohort, multi-center, single-arm trials. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible across the five trials. Patients received either KEYTRUDA 200 mg every 3 weeks or KEYTRUDA 10 mg/kg every 2 weeks. Treatment continued until unacceptable toxicity or disease progression that was either symptomatic, rapidly progressive, required urgent intervention, or occurred with a decline in performance status. A maximum of 24 months of treatment with KEYTRUDA was administered. For the purpose of assessment of anti-tumor activity across these 5 trials, the major efficacy outcome measures were ORR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and DoR.

Table 56: MSI-H Trials

Study Design and Patient Population Number of Patients MSI-H/dMMR Testing Dosage Prior Therapy
KEYNOTE-016 NCT01876511
  • prospective, investigator-initiated
  • 6 sites
  • patients with CRC and other tumors
28 CRC 30 non-CRC local PCR or IHC 10 mg/kg every 2 weeks
  • CRC: ≥ 2 prior regimens
  • Non-CRC: ≥1 prior regimen
KEYNOTE-164 NCT02460198
  • prospective international multi-center
  •   CRC
61 local PCR or IHC 200 mg every 3 weeks Prior fluoropyrimidine, oxaliplatin, and irinotecan +/- anti-VEGF/EGFR mAb
KEYNOTE-012 NCT01848834
  • retrospectively identified patients with PD-L1-positive gastric, bladder, or triple-negative breast cancer
6 central PCR 10 mg/kg every 2 weeks ≥1 prior regimen
KEYNOTE-028 NCT02054806
  • retrospectively identified patients with PD-L1-positive esophageal, biliary, breast, endometrial, or CRC
5 central PCR 10 mg/kg every 2 weeks ≥1 prior regimen
KEYNOTE-158 NCT02628067
  • prospective international multi-center enrollment of patients with MSI-H/dMMR non-CRC
  • retrospectively identified patients who were enrolled in specific rare tumor non-CRC cohorts
19 local PCR or IHC (central PCR for patients in rare tumor non-CRC cohorts) 200 mg every 3 weeks ≥1 prior regimen
Total 149
CRC = colorectal cancer
PCR = polymerase chain reaction
IHC = immunohistochemistry

A total of 149 patients with MSI-H or dMMR cancers were identified across the five trials. Among these 149 patients, the baseline characteristics were: median age of 55 years, 36% age 65 or older; 56% male; 77% White, 19% Asian, and 2% Black; and 36% ECOG PS of 0 and 64% ECOG PS of 1. Ninety-eight percent of patients had metastatic disease and 2% had locally advanced, unresectable disease. The median number of prior therapies for metastatic or unresectable disease was two. Eighty-four percent of patients with metastatic CRC and 53% of patients with other solid tumors received two or more prior lines of therapy.

The identification of MSI-H or dMMR tumor status for the majority of patients (135/149) was prospectively determined using local laboratory-developed, polymerase chain reaction (PCR) tests for MSI-H status or immunohistochemistry (IHC) tests for dMMR. Fourteen of the 149 patients were retrospectively identified as MSI-H by testing tumor samples from a total of 415 patients using a central laboratory developed PCR test. Forty-seven patients had dMMR cancer identified by IHC, 60 had MSI-H identified by PCR, and 42 were identified using both tests.

Efficacy results are summarized in Tables 57 and 58.

Table 57: Efficacy Results for Patients with MSI-H/dMMR Cancer

Endpoint KEYTRUDA
n=149
Objective Response Rate
ORR (95% CI) 39.6% (31.7, 47.9)
Complete response rate 7.4%
Partial response rate 32.2%
Duration of Response
Median in months (range) NR (1.6+, 22.7+)
% with duration ≥6 months 78%
NR = not reached

Table 58: Response by Tumor Type

N Objective Response Rate n (%) 95% CI Duration of Response range (months)
CRC 90 32 (36%)
(26%, 46%)
(1.6+, 22.7+)
Non-CRC 59 27 (46%)
(33%, 59%)
(1.9+, 22.1+)
Endometrial cancer 14 5 (36%)
(13%, 65%)
(4.2+, 17.3+)
Biliary cancer 11 3 (27%)
(6%, 61 %)
(11.6+, 19.6+)
Gastric or GE junction cancer 9 5 (56%)
(21%, 86%)
(5.8+, 22.1+)
Pancreatic cancer 6 5 (83%)
(36%, 100%)
(2.6+, 9.2+)
Small intestinal cancer 8 3 (38%)
(9%, 76%)
(1.9+, 9.1+)
Breast cancer 2 PR, PR (7.6, 15.9)
Prostate cancer 2 PR, SD 9.8+
Bladder cancer 1 NE
Esophageal cancer 1 PR 18.2+
Sarcoma 1 PD
Thyroid cancer 1 NE
Retroperitoneal adenocarcinoma 1 PR 7.5+
Small cell lung cancer 1 CR 8.9+
Renal cell cancer 1 PD
CR = complete response
PR = partial response
SD = stable disease
PD = progressive disease
NE = not evaluable

Microsatellite Instability-High Or Mismatch Repair Deficient Colorectal Cancer

The efficacy of KEYTRUDA was investigated in KEYNOTE-177 (NCT02563002), a multicenter, randomized, open-label, active-controlled trial that enrolled 307 patients with previously untreated unresectable or metastatic MSI-H or dMMR CRC. MSI or MMR tumor status was determined locally using polymerase chain reaction (PCR) or immunohistochemistry (IHC), respectively. Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible.

Patients were randomized (1:1) to receive KEYTRUDA 200 mg intravenously every 3 weeks or investigator’s choice of the following chemotherapy regimens given intravenously every 2 weeks:

  • mFOLFOX6 (oxaliplatin, leucovorin, and FU) or mFOLFOX6 in combination with either bevacizumab or cetuximab: Oxaliplatin 85 mg/m², leucovorin 400 mg/m² (or levoleucovorin 200 mg/m²), and FU 400 mg/m² bolus on Day 1, then FU 2400 mg/m² over 46-48 hours. Bevacizumab 5 mg/kg on Day 1 or cetuximab 400 mg/m² on first infusion, then 250 mg/m² weekly.
  • FOLFIRI (irinotecan, leucovorin, and FU) or FOLFIRI in combination with either bevacizumab or cetuximab: Irinotecan 180 mg/m², leucovorin 400 mg/m² (or levoleucovorin 200 mg/m²), and FU 400 mg/m² bolus on Day 1, then FU 2400 mg/m² over 46-48 hours. Bevacizumab 5 mg/kg on Day 1 or cetuximab 400 mg/m² on first infusion, then 250 mg/m² weekly.

Treatment with KEYTRUDA or chemotherapy continued until RECIST v1.1-defined progression of disease as determined by the investigator or unacceptable toxicity. Patients treated with KEYTRUDA without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every 9 weeks. Patients randomized to chemotherapy were offered KEYTRUDA at the time of disease progression. The main efficacy outcome measures were PFS (as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ) and OS. Additional efficacy outcome measures were ORR and DoR.

A total of 307 patients were enrolled and randomized to KEYTRUDA (n=153) or chemotherapy (n=154). The baseline characteristics of these 307 patients were: median age of 63 years (range: 24 to 93), 47% age 65 or older; 50% male; 75% White and 16% Asian; 52% had an ECOG PS of 0 and 48% had an ECOG PS of 1; and 27% received prior adjuvant or neoadjuvant chemotherapy. Among 154 patients randomized to receive chemotherapy,143 received chemotherapy per the protocol. Of the 143 patients, 56% received mFOLFOX6, 44% received FOLFIRI, 70% received bevacizumab plus mFOLFOX6 or FOLFIRI, and 11% received cetuximab plus mFOLFOX6 or FOLFIRI.

The trial demonstrated a statistically significant improvement in PFS for patients randomized to KEYTRUDA compared with chemotherapy. At the time of the PFS analysis, the overall survival data were not mature (66% of the required number of events for the OS final analysis). The median follow-up time was 27.6 months (range: 0.2 to 48.3 months). Table 59 and Figure 13 summarize the key efficacy measures for KEYNOTE-177.

Table 59: Efficacy Results in Patients with MSI-H or dMMR CRC in KEYNOTE-177

Endpoint KEYTRUDA 200 mg every 3 weeks
n=153
Chemotherapy
n=154
PFS
Number (%) of patients with event 82 (54%) 113 (73%)
Median in months (95% CI) 16.5 (5.4, 32.4) 8.2 (6.1, 10.2)
Hazard ratio* (95% CI) 0.60 (0.45, 0.80)
p-Value† 0.0004
Objective Response Rate‡
ORR (95% CI) 44% (35.8, 52.0) 33% (25.8, 41.1)
Complete response rate 11% 4%
Partial response rate 33% 29%
Duration of Response‡,§
Median in months (range) NR (2.3+, 41.4+) 10.6 (2.8, 37.5+)
% with duration ≥12 months¶ 75% 37%
% with duration ≥24 months¶ 43% 18%
* Based on Cox regression model
† Two-sided p-value based on log-rank test (compared to a significance level of 0.0234)
‡ Based on confirmed response by BICR review § Based on n=67 patients with a response in the KEYTRUDA arm and n=51 patients with a response in the chemotherapy arm
¶ Based on observed duration of response
+ Denotes ongoing response
NR = not reached

Figure 13: Kaplan-Meier Curve for PFS in KEYNOTE-177

Kaplan-Meier Curve for PFS in KEYNOTE-177 - Illustration

Gastric Cancer

First-line Treatment Of Locally Advanced Unresectable Or Metastatic HER2-Positive Gastric Or Gastroesophageal Junction (GEJ) Adenocarcinoma

The efficacy of KEYTRUDA in combination with trastuzumab plus fluoropyrimidine and platinum chemotherapy was investigated in KEYNOTE-811 (NCT03615326), a multicenter, randomized, double-blind, placebo-controlled trial that was designed to enroll 692 patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma who had not previously received systemic therapy for metastatic disease. Patients with an autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by PD-L1 expression (CPS ≥1 or CPS <1), chemotherapy regimen (5-FU plus cisplatin [FP] or capecitabine plus oxaliplatin [CAPOX]), and geographic region (Europe/Israel/North America/Australia, Asia, or Rest of the World). Patients were randomized (1:1) to one of the following treatment arms.

  • KEYTRUDA 200 mg, trastuzumab 8 mg/kg on first infusion and 6 mg/kg in subsequent cycles, followed by investigator’s choice of combination chemotherapy of cisplatin 80 mg/m² for up to 6 cycles and 5-FU 800 mg/m²/day for 5 days (FP) or oxaliplatin 130 mg/m² up to 6-8 cycles and capecitabine 1000 mg/m² bid for 14 days (CAPOX). KEYTRUDA was administered prior to trastuzumab and chemotherapy on Day 1 of each cycle.
  • Placebo, trastuzumab 8 mg/kg on first infusion and 6 mg/kg in subsequent cycles, followed by investigator’s choice of combination chemotherapy of cisplatin 80 mg/m² for up to 6 cycles and 5-FU 800 mg/m²/day for 5 days (FP) or oxaliplatin 130 mg/m² up to 6-8 cycles and capecitabine 1000 mg/m² bid for 14 days (CAPOX).

All study medications, except oral capecitabine, were administered as an intravenous infusion for every 3 week cycle. Treatment with KEYTRUDA continued until RECIST v1.1-defined progression of disease as determined by BICR, unacceptable toxicity, or a maximum of 24 months. In an interim efficacy analysis, major outcome measures assessed were ORR and DoR by BICR using RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

At the time of the interim analysis, ORR and DoR were assessed in the first 264 patients randomized. Among the 264 patients, the population characteristics were: median age of 62 years (range: 19 to 84), 41% age 65 or older; 82% male; 63% White, 31% Asian, and 0.8% Black; 47% ECOG PS of 0 and 53% ECOG PS of 1. Ninety-seven percent of patients had metastatic disease (stage IV) and 3% had locally advanced unresectable disease. Eighty-seven percent had tumors that expressed PD-L1 with a CPS ≥1. Ninety-one percent (n=240) had tumors that were not MSI-H, 1% (n=2) had tumors that were MSI-H, and in 8% (n=22) the status was not known. Eighty-seven percent of patients received CAPOX.

A statistically significant improvement in ORR was demonstrated in patients randomized to KEYTRUDA in combination with trastuzumab and chemotherapy compared with placebo in combination with trastuzumab and chemotherapy. Efficacy results are summarized in Table 60.

Table 60: Efficacy Results for KEYNOTE-811

Endpoint KEYTRUDA 200 mg every 3 weeks Trastuzumab Fluoropyrimidine and Platinum Chemotherapy n=133 Placebo Trastuzumab Fluoropyrimidine and Platinum Chemotherapy
n=131
Objective Response Rate
ORR* (95% CI) 74% (66, 82) 52% (43, 61)
Complete response rate 11% 3.1%
Partial response rate 63% 49%
p-Value† <0.0001
Duration of Response n=99 n=68
Median in months (range) 10.6 (1.1+, 16.5+) 9.5 (1.4+, 15.4+)
% with duration ≥6 months 65% 53%
* Response: Best objective response as confirmed complete response or partial response
† p-Value based on stratified Miettinen and Nurminen method (compared to an alpha boundary of 0.002)

Previously Treated Gastric Or Gastroesophageal Junction (GEJ) Adenocarcinoma

The efficacy of KEYTRUDA was investigated in KEYNOTE-059 (NCT02335411), a multicenter, non-randomized, open-label multi-cohort trial that enrolled 259 patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma who progressed on at least 2 prior systemic treatments for advanced disease. Previous treatment must have included a fluoropyrimidine and platinum doublet. HER2/neu positive patients must have previously received treatment with approved HER2/neu-targeted therapy. Patients with active autoimmune disease or a medical condition that required immunosuppression or with clinical evidence of ascites by physical exam were ineligible. Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Assessment of tumor status was performed every 6 to 9 weeks. The major efficacy outcome measures were ORR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR, and DoR.

Among the 259 patients, 55% (n = 143) had tumors that expressed PD-L1 with a CPS ≥1 and microsatellite stable (MSS) tumor status or undetermined MSI or MMR status. PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx kit. The baseline characteristics of these 143 patients were: median age of 64 years, 47% age 65 or older; 77% male; 82% White and 11% Asian; and 43% ECOG PS of 0 and 57% ECOG PS of 1. Eighty-five percent had M1 disease and 7% had M0 disease. Fifty-one percent had two and 49% had three or more prior lines of therapy in the recurrent or metastatic setting.

For the 143 patients, the ORR was 13.3% (95% CI: 8.2, 20.0); 1.4% had a complete response and 11.9% had a partial response. Among the 19 responding patients, the DoR ranged from 2.8+ to 19.4+ months, with 11 patients (58%) having responses of 6 months or longer and 5 patients (26%) having responses of 12 months or longer.

Among the 259 patients enrolled in KEYNOTE-059, 7 (3%) had tumors that were determined to be MSI-H. An objective response was observed in 4 patients, including 1 complete response. The DoR ranged from 5.3+ to 14.1+ months.

Esophageal Cancer

First-line Treatment Of Locally Advanced Unresectable Or Metastatic Esophageal/Gastroesophageal Junction Cancer

KEYNOTE-590

The efficacy of KEYTRUDA was investigated in KEYNOTE-590 (NCT03189719), a multicenter, randomized, placebo-controlled trial that enrolled 749 patients with metastatic or locally advanced esophageal or gastroesophageal junction (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation. PD-L1 status was centrally determined in tumor specimens in all patients using the PD-L1 IHC 22C3 pharmDx kit. Patients with active autoimmune disease, a medical condition that required immunosuppression, or who received prior systemic therapy in the locally advanced or metastatic setting were ineligible. Randomization was stratified by tumor histology (squamous cell carcinoma vs. adenocarcinoma), geographic region (Asia vs. ex-Asia), and ECOG performance status (0 vs. 1).

Patients were randomized (1:1) to one of the following treatment arms; all study medications were administered via intravenous infusion:

  • KEYTRUDA 200 mg on Day 1 of each three-week cycle in combination with cisplatin 80 mg/m² IV on Day 1 of each three-week cycle for up to six cycles and FU 800 mg/m² IV per day on Day 1 to Day 5 of each three-week cycle, or per local standard for FU administration, for up to 24 months.
  • Placebo on Day 1 of each three-week cycle in combination with cisplatin 80 mg/m² IV on Day 1 of each three-week cycle for up to six cycles and FU 800 mg/m² IV per day on Day 1 to Day 5 of each three-week cycle, or per local standard for FU administration, for up to 24 months.

Treatment with KEYTRUDA or chemotherapy continued until unacceptable toxicity or disease progression. Patients could be treated with KEYTRUDA for up to 24 months in the absence of disease progression. The major efficacy outcome measures were OS and PFS as assessed by the investigator according to RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ). The study pre-specified analyses of OS and PFS based on squamous cell histology, CPS ≥10, and in all patients. Additional efficacy outcome measures were ORR and DoR, according to modified RECIST v1.1, as assessed by the investigator.

The study population characteristics were: median age of 63 years (range: 27 to 94), 43% age 65 or older; 83% male; 37% White, 53% Asian, and 1% Black; 40% had an ECOG PS of 0 and 60% had an ECOG PS of 1. Ninety-one percent had M1 disease and 9% had M0 disease. Seventy-three percent had a tumor histology of squamous cell carcinoma, and 27% had adenocarcinoma.

The trial demonstrated a statistically significant improvement in OS and PFS for patients randomized to KEYTRUDA in combination with chemotherapy, compared to chemotherapy.

Table 61 and Figure 14 summarize the efficacy results for KEYNOTE-590 in all patients.

Table 61: Efficacy Results in Patients with Locally Advanced Unresectable or Metastatic Esophageal Cancer in KEYNOTE-590

Endpoint KEYTRUDA 200 mg every 3 weeks Cisplatin FU
n=373
Placebo Cisplatin FU
n=376
OS
Number (%) of events 262 (70) 309 (82)
Median in months 12.4 9.8
(95% CI) (10.5, 14.0) (8.8, 10.8)
Hazard ratio* (95% CI) 0.73 (0.62, 0.86)
p-Value† <0.0001
PFS
Number of events (%) 297 (80) 333 (89)
Median in months 6.3 5.8
(95% CI) (6.2, 6.9) (5.0, 6.0)
Hazard ratio* (95% CI) 0.65 (0.55, 0.76)
p-Value† <0.0001
Objective Response Rate
ORR, %‡ 45 29
(95% CI) (40, 50) (25, 34)
Number (%) of complete responses 24 (6) 9 (2.4)
Number (%) of partial responses 144 (39) 101 (27)
p-Value§ <0.0001
Duration of Response
Median in months 8.3 6.0
(range) (1.2+, 31.0+) (1.5+, 25.0+)
* Based on the stratified Cox proportional hazard model
† Based on a stratified log-rank test
‡ Confirmed complete response or partial response
§ Based on the stratified Miettinen and Nurminen method

Figure 14: Kaplan-Meier Curve for Overall Survival in KEYNOTE-590

Kaplan-Meier Curve for Overall Survival in
KEYNOTE-590 - Illustration

In a pre-specified formal test of OS in patients with PD-L1 CPS ≥ 10 (n=383), the median was 13.5 months (95% CI: 11.1, 15.6) for the KEYTRUDA arm and 9.4 months (95% CI: 8.0, 10.7) for the placebo arm, with a HR of 0.62 (95% CI: 0.49, 0.78; p-Value < 0.0001). In an exploratory analysis, in patients with PD-L1 CPS < 10 (n=347), the median OS was 10.5 months (95% CI: 9.7, 13.5) for the KEYTRUDA arm and 10.6 months (95% CI: 8.8, 12.0) for the placebo arm, with a HR of 0.86 (95% CI: 0.68, 1.10).

Previously Treated Recurrent Locally Advanced Or Metastatic Esophageal Cancer

KEYNOTE-181

The efficacy of KEYTRUDA was investigated in KEYNOTE-181 (NCT02564263), a multicenter, randomized, open-label, active-controlled trial that enrolled 628 patients with recurrent locally advanced or metastatic esophageal cancer who progressed on or after one prior line of systemic treatment for advanced disease. Patients with HER2/neu positive esophageal cancer were required to have received treatment with approved HER2/neu targeted therapy. All patients were required to have tumor specimens for PD-L1 testing at a central laboratory; PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx kit. Patients with a history of non-infectious pneumonitis that required steroids or current pneumonitis, active autoimmune disease, or a medical condition that required immunosuppression were ineligible.

Patients were randomized (1:1) to receive either KEYTRUDA 200 mg every 3 weeks or investigator’s choice of any of the following chemotherapy regimens, all given intravenously: paclitaxel 80-100 mg/m² on Days 1, 8, and 15 of every 4-week cycle, docetaxel 75 mg/m² every 3 weeks, or irinotecan 180 mg/m² every 2 weeks. Randomization was stratified by tumor histology (esophageal squamous cell carcinoma [ESCC] vs. esophageal adenocarcinoma [EAC]/Siewert type I EAC of the gastroesophageal junction [GEJ]), and geographic region (Asia vs. ex-Asia). Treatment with KEYTRUDA or chemotherapy continued until unacceptable toxicity or disease progression. Patients randomized to KEYTRUDA were permitted to continue beyond the first RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined disease progression if clinically stable until the first radiographic evidence of disease progression was confirmed at least 4 weeks later with repeat imaging. Patients treated with KEYTRUDA without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every 9 weeks. The major efficacy outcome measure was OS evaluated in the following co-primary populations: patients with ESCC, patients with tumors expressing PD-L1 CPS ≥10, and all randomized patients. Additional efficacy outcome measures were PFS, ORR, and DoR, according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR.

A total of 628 patients were enrolled and randomized to KEYTRUDA (n=314) or investigator’s treatment of choice (n=314). Of these 628 patients, 167 (27%) had ESCC that expressed PD-L1 with a CPS ≥10. Of these 167 patients, 85 patients were randomized to KEYTRUDA and 82 patients to investigator’s treatment of choice [paclitaxel (n=50), docetaxel (n=19), or irinotecan (n=13)]. The baseline characteristics of these 167 patients were: median age of 65 years (range: 33 to 80), 51% age 65 or older; 84% male; 32% White and 68% Asian; 38% had an ECOG PS of 0 and 62% had an ECOG PS of 1. Ninety percent had M1 disease and 10% had M0 disease. Prior to enrollment, 99% of patients had received platinum-based treatment and 84% had also received treatment with a fluoropyrimidine. Thirty-three percent of patients received prior treatment with a taxane.

The observed OS hazard ratio was 0.77 (95% CI: 0.63, 0.96) in patients with ESCC, 0.70 (95% CI: 0.52, 0.94) in patients with tumors expressing PD-L1 CPS ≥10, and 0.89 (95% CI: 0.75, 1.05) in all randomized patients. On further examination in patients whose ESCC tumors expressed PD-L1 (CPS ≥10), an improvement in OS was observed among patients randomized to KEYTRUDA as compared with chemotherapy. Table 62 and Figure 15 summarize the key efficacy measures for KEYNOTE-181 for patients with ESCC CPS ≥10.

Table 62: Efficacy Results in Patients with Recurrent or Metastatic ESCC (CPS ≥10) in KEYNOTE-181

Endpoint KEYTRUDA 200 mg every 3 weeks
n=85
Chemotherapy
n=82
OS
Number (%) of patients with event 68 (80%) 72 (88%)
Median in months (95% CI) 10.3 (7.0, 13.5) 6.7 (4.8, 8.6)
Hazard ratio* (95% CI) 0.64 (0.46, 0.90)
PFS
Number (%) of patients with event 76 (89%) 76 (93%)
Median in months (95% CI) 3.2 (2.1, 4.4) 2.3 (2.1, 3.4)
Hazard ratio* (95% CI) 0.66 (0.48, 0.92)
Objective Response Rate
ORR (95% CI) 22 (14, 33) 7 (3, 15)
Number (%) of complete responses 4 (5) 1 (1)
Number (%) of partial responses 15 (18) 5 (6)
Median duration of response in months (range) 9.3 (2.1+, 18.8+) 7.7 (4.3, 16.8+)
* Based on the Cox regression model stratified by geographic region (Asia vs. ex-Asia)

Figure 15: Kaplan-Meier Curve for Overall Survival in KEYNOTE-181 (ESCC CPS ≥10)

Kaplan-Meier
Curve for Overall Survival in KEYNOTE-181 (ESCC CPS =10) - Illustration

KEYNOTE-180

The efficacy of KEYTRUDA was investigated in KEYNOTE-180 (NCT02559687), a multicenter, non-randomized, open-label trial that enrolled 121 patients with locally advanced or metastatic esophageal cancer who progressed on or after at least 2 prior systemic treatments for advanced disease. With the exception of the number of prior lines of treatment, the eligibility criteria were similar to and the dosage regimen identical to KEYNOTE-181.

The major efficacy outcome measures were ORR and DoR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR.

Among the 121 patients enrolled, 29% (n=35) had ESCC that expressed PD-L1 CPS ≥10. The baseline characteristics of these 35 patients were: median age of 65 years (range: 47 to 81), 51% age 65 or older; 71% male; 26% White and 69% Asian; 40% had an ECOG PS of 0 and 60% had an ECOG PS of 1. One hundred percent had M1 disease.

The ORR in the 35 patients with ESCC expressing PD-L1 was 20% (95% CI: 8, 37). Among the 7 responding patients, the DoR ranged from 4.2 to 25.1+ months, with 5 patients (71%) having responses of 6 months or longer and 3 patients (57%) having responses of 12 months or longer.

Cervical Cancer

The efficacy of KEYTRUDA was investigated in 98 patients with recurrent or metastatic cervical cancer enrolled in a single cohort (Cohort E) in KEYNOTE-158 (NCT02628067), a multicenter, non-randomized, open-label, multi-cohort trial. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression. Patients with initial radiographic disease progression could receive additional doses of treatment during confirmation of progression unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Patients without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every 9 weeks for the first 12 months, and every 12 weeks thereafter. The major efficacy outcome measures were ORR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR, and DoR.

Among the 98 patients in Cohort E, 77 (79%) had tumors that expressed PD-L1 with a CPS ≥ 1 and received at least one line of chemotherapy in the metastatic setting. PD-L1 status was determined using the IHC 22C3 pharmDx kit. The baseline characteristics of these 77 patients were: median age of 45 years (range: 27 to 75); 81% White, 14% Asian, and 3% Black; 32% ECOG PS of 0 and 68% ECOG PS of 1; 92% had squamous cell carcinoma, 6% adenocarcinoma, and 1% adenosquamous histology; 95% had M1 disease and 5% had recurrent disease; and 35% had one and 65% had two or more prior lines of therapy in the recurrent or metastatic setting.

No responses were observed in patients whose tumors did not have PD-L1 expression (CPS <1). Efficacy results are summarized in Table 63 for patients with PD-L1 expression (CPS ≥1).

Table 63: Efficacy Results in Patients with Recurrent or Metastatic Cervical Cancer (CPS ≥1) in KEYNOTE-158

Endpoint KEYTRUDA 200 mg every 3 weeks
n=77*
Objective Response Rate
ORR (95% CI) 14.3% (7.4, 24.1)
Complete response rate 2.6%
Partial response rate 11.7%
Duration of Response
Median in months (range) NR (4.1, 18.6+)†
% with duration ≥6 months 91%
* Median follow-up time of 11.7 months (range 0.6 to 22.7 months)
† Based on patients (n=11) with a response by independent review
+ Denotes ongoing response NR = not reached

Hepatocellular Carcinoma

The efficacy of KEYTRUDA was investigated in KEYNOTE-224 (NCT02702414), a single-arm, multicenter trial in 104 patients with HCC who had disease progression on or after sorafenib or were intolerant to sorafenib; had measurable disease; and Child-Pugh class A liver impairment. Patients with active autoimmune disease, greater than one etiology of hepatitis, a medical condition that required immunosuppression, or clinical evidence of ascites by physical exam were ineligible for the trial. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity, investigator-assessed confirmed disease progression (based on repeat scan at least 4 weeks from the initial scan showing progression), or completion of 24 months of KEYTRUDA. Assessment of tumor status was performed every 9 weeks. The major efficacy outcome measures were ORR and DoR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR.

The study population characteristics were: median age of 68 years, 67% age 65 or older; 83% male; 81% White and 14% Asian; and 61% ECOG PS of 0 and 39% ECOG PS of 1. Child-Pugh class and score were A5 for 72%, A6 for 22%, B7 for 5%, and B8 for 1% of patients. Twenty-one percent of the patients were HBV seropositive and 25% HCV seropositive. There were 9 patients (9%) who were seropositive for both HBV and HCV. For these 9 patients, all of the HBV cases and three of the HCV cases were inactive. Sixty-four percent (64%) of patients had extrahepatic disease, 17% had vascular invasion, and 9% had both. Thirty-eight percent (38%) of patients had alpha-fetoprotein (AFP) levels ≥400 mcg/L. All patients received prior sorafenib; of whom 20% were unable to tolerate sorafenib. No patient received more than one prior systemic therapy (sorafenib).

Efficacy results are summarized in Table 64.

Table 64: Efficacy Results in KEYNOTE-224

Endpoint KEYTRUDA 200 mg every 3 weeks
n=104
BICR-Assessed Objective Response Rate (RECIST v1.1)
ORR (95% CI)* 17% (11, 26)
Complete response rate 1%
Partial response rate 16%
BICR-Assessed Duration of Response
% with duration ≥6 months 89%
% with duration ≥12 months 56%
* Based on patients (n=18) with a confirmed response by independent review

Merkel Cell Carcinoma

The efficacy of KEYTRUDA was investigated in KEYNOTE-017 (NCT02267603), a multicenter, non-randomized, open-label trial that enrolled 50 patients with recurrent locally advanced or metastatic MCC who had not received prior systemic therapy for their advanced disease. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible.

Patients received KEYTRUDA 2 mg/kg every 3 weeks until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Assessment of tumor status was performed at 13 weeks followed by every 9 weeks for the first year and every 12 weeks thereafter. The major efficacy outcome measures were ORR and DoR as assessed by BICR per RECIST v1.1.

The study population characteristics were: median age of 71 years (range: 46 to 91), 80% age 65 or older; 68% male; 90% White; and 48% ECOG PS of 0 and 52% ECOG PS of 1. Fourteen percent had stage IIIB disease and 86% had stage IV. Eighty-four percent of patients had prior surgery and 70% had prior radiation therapy.

Efficacy results are summarized in Table 65.

Table 65: Efficacy Results in KEYNOTE-017

Endpoint KEYTRUDA 2 mg/kg every 3 weeks
n=50
Objective Response Rate
ORR (95% CI) 56% (41, 70)
Complete response rate (95% CI) 24% (13, 38)
Partial response rate (95% CI) 32% (20, 47)
Duration of Response
Range in months* 5.9, 34.5+
Patients with duration ≥6 months, n (%) 27 (96%)
Patients with duration ≥12 months, n (%) 15 (54%)
* The median duration of response was not reached.
+ Denotes ongoing response

Renal Cell Carcinoma

The efficacy of KEYTRUDA in combination with axitinib was investigated in KEYNOTE-426 (NCT02853331), a randomized, multicenter, open-label trial conducted in 861 patients who had not received systemic therapy for advanced RCC. Patients were enrolled regardless of PD-L1 tumor expression status. Patients with active autoimmune disease requiring systemic immunosuppression within the last 2 years were ineligible. Randomization was stratified by International Metastatic RCC Database Consortium (IMDC) risk categories (favorable versus intermediate versus poor) and geographic region (North America versus Western Europe versus “Rest of the World”).

Patients were randomized (1:1) to one of the following treatment arms:

  • KEYTRUDA 200 mg intravenously every 3 weeks up to 24 months in combination with axitinib 5 mg orally, twice daily. Patients who tolerated axitinib 5 mg twice daily for 2 consecutive cycles (6 weeks) could increase to 7 mg and then subsequently to 10 mg twice daily. Axitinib could be interrupted or reduced to 3 mg twice daily and subsequently to 2 mg twice daily to manage toxicity.
  • Sunitinib 50 mg orally, once daily for 4 weeks and then off treatment for 2 weeks.

Treatment with KEYTRUDA and axitinib continued until RECIST v1.1-defined progression of disease or unacceptable toxicity. Administration of KEYTRUDA and axitinib was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed at baseline, after randomization at Week 12, then every 6 weeks thereafter until Week 54, and then every 12 weeks thereafter.

The study population characteristics were: median age of 62 years (range: 26 to 90); 38% age 65 or older; 73% male; 79% White and 16% Asian; 19% and 80% of patients had a baseline KPS of 70 to 80 and 90 to 100, respectively; and patient distribution by IMDC risk categories was 31% favorable, 56% intermediate and 13% poor.

The main efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures included ORR, as assessed by BICR. A statistically significant improvement in OS was demonstrated at the pre-specified interim analysis in patients randomized to KEYTRUDA in combination with axitinib compared with sunitinib. The trial also demonstrated statistically significant improvements in PFS and ORR. Table 66 and Figure 16 summarize the efficacy results for KEYNOTE-426. The median follow-up time was 12.8 months (range 0.1 to 22.0 months). Consistent results were observed across pre-specified subgroups, IMDC risk categories and PD-L1 tumor expression status.

Table 66: Efficacy Results in KEYNOTE-426

Endpoint KEYTRUDA 200 mg every 3 weeks and Axitinib
n=432
Sunitinib
n=429
OS
Number of patients with event (%) 59 (14%) 97 (23%)
Median in months (95% CI) NR (NR, NR) NR (NR, NR)
Hazard ratio* (95% CI) 0.53 (0.38, 0.74)
p-Value† <0.0001‡
12-month OS rate 90% (86, 92) 78% (74, 82)
PFS
Number of patients with event (%) 183 (42%) 213 (50%)
Median in months (95% CI) 15.1 (12.6, 17.7) 11.0 (8.7, 12.5)
Hazard ratio* (95% CI) 0.69 (0.56, 0.84)
p-Value† 0.0001§
Objective Response Rate
ORR1 (95% CI) 59% (54, 64) 36% (31, 40)
Complete response rate 6% 2%
Partial response rate 53% 34%
p-Value# <0.0001
* Based on the stratified Cox proportional hazard model
† Based on stratified log-rank test
‡ p-Value (one-sided) is compared with the allocated alpha of 0.0001 for this interim analysis (with 39% of the planned number of events for final analysis).
§ p-Value (one-sided) is compared with the allocated alpha of 0.0013 for this interim analysis (with 81% of the planned number of events for final analysis).
¶ Response: Best objective response as confirmed complete response or partial response
# Based on Miettinen and Nurminen method stratified by IMDC risk group and geographic region
NR = not reached

Figure 16: Kaplan-Meier Curve for Overall Survival in KEYNOTE-426

 Kaplan-Meier
Curve for Overall Survival in KEYNOTE-426 - Illustration

Endometrial Carcinoma

The efficacy of KEYTRUDA in combination with lenvatinib was investigated in KEYNOTE-146 (NCT02501096), a single-arm, multicenter, open-label, multi-cohort trial that enrolled 108 patients with metastatic endometrial carcinoma that had progressed following at least one prior systemic therapy in any setting. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients were treated with KEYTRUDA 200 mg intravenously every 3 weeks in combination with lenvatinib 20 mg orally once daily until unacceptable toxicity or disease progression as determined by the investigator. The major efficacy outcome measures were ORR and DoR as assessed by BICR using RECIST 1.1.

Administration of KEYTRUDA and lenvatinib was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. KEYTRUDA dosing was continued for a maximum of 24 months; however, treatment with lenvatinib could be continued beyond 24 months. Assessment of tumor status was performed at baseline and then every 6 weeks until week 24, followed by every 9 weeks thereafter.

Among the 108 patients, 87% (n=94) had tumors that were not MSI-H or dMMR, 10% (n=11) had tumors that were MSI-H or dMMR, and in 3% (n=3) the status was not known. Tumor MSI status was determined using a polymerase chain reaction (PCR) test. Tumor MMR status was determined using an IHC test. The baseline characteristics of the 94 patients with tumors that were not MSI-H or dMMR were: median age of 66 years, 62% age 65 or older; 86% White, 6% Black, 4% Asian, and 3% other races; and ECOG PS of 0 (52%) or 1 (48%). All 94 of these patients received prior systemic therapy for endometrial carcinoma: 51% had one, 38% had two, and 11% had three or more prior systemic therapies.

Efficacy results are summarized in Table 67.

Table 67: Efficacy Results in KEYNOTE-146

Endpoint KEYTRUDA 200 mg every 3 weeks with lenvatinib
n=94*
Objective Response Rate
ORR (95% CI) 38.3% (29, 49)
Complete response rate 10.6%
Partial response rate 27.7%
Response duration
Median in months (range) NR (1.2+, 33.1+)†
% with duration ≥6 months 69%
* Median follow-up time of 18.7 months
† Based on patients (n=36) with a response by independent review
+ Denotes ongoing response NR = not reached

Tumor Mutational Burden-High Cancer

The efficacy of KEYTRUDA was investigated in a prospectively-planned retrospective analysis of 10 cohorts (A through J) of patients with various previously treated unresectable or metastatic solid tumors with high tumor mutation burden (TMB-H) who were enrolled in a multicenter, non-randomized, open-label trial, KEYNOTE-158 (NCT02628067). The trial excluded patients who previously received an anti-PD-1 or other immune-modulating monoclonal antibody, or who had an autoimmune disease, or a medical condition that required immunosuppression. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression. Assessment of tumor status was performed every 9 weeks for the first 12 months and every 12 weeks thereafter.

The statistical analysis plan pre-specified ≥10 and ≥13 mutations per megabase using the FoundationOne CDx assay as cutpoints to assess TMB. Testing of TMB was blinded with respect to clinical outcomes. The major efficacy outcome measures were ORR and DoR in patients who received at least one dose of KEYTRUDA as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

In KEYNOTE-158, 1050 patients were included in the efficacy analysis population. TMB was analyzed in the subset of 790 patients with sufficient tissue for testing based on protocol-specified testing requirements. Of the 790 patients, 102 (13%) had tumors identified as TMB-H, defined as TMB ≥10 mutations per megabase. Among the 102 patients with TMB-H advanced solid tumors, the study population characteristics were: median age of 61 years (range: 27 to 80), 34% age 65 or older; 34% male; 81% White; and 41% ECOG PS of 0 and 58% ECOG PS of 1. Fifty-six percent of patients had at least two prior lines of therapy.

Efficacy results are summarized in Tables 68 and 69.

Table 68: Efficacy Results for Patients with TMB-H Cancer in KEYNOTE-158

Endpoint KEYTRUDA 200 mg every 3 weeks
TMB ≥10 mut/Mb
n=102*
TMB ≥13 mut/Mb
n=70
Objective Response Rate
ORR (95% CI) 29% (21, 39) 37% (26, 50)
Complete response rate 4% 3%
Partial response rate 25% 34%
Duration of Response n=30 n=26
Median in months (range)† NR (2.2+, 34.8+) NR (2.2+, 34.8+)
% with duration ≥12 months 57% 58%
% with duration ≥24 months 50% 50%
* Median follow-up time of 11.1 months
† From product-limit (Kaplan-Meier) method for censored data
+ Denotes ongoing response NR = not reached

Table 69: Response by Tumor Type (TMB ≥10 mut/Mb)

N Objective Response Rate n (%) 95% CI Duration of Response range (months)
Overall* 102 30 (29%) (21%, 39%) (2.2+, 34.8+)
Small cell lung cancer 34 10 (29%) (15%, 47%) (4.1, 32.5+)
Cervical cancer 16 5 (31%) (11%, 59%) (3.7+, 34.8+)
Endometrial cancer 15 7 (47%) (21%, 73%) (8.4+, 33.9+)
Anal cancer 14 1 (7%) (0.2%, 34%) 18.8+
Vulvar cancer 12 2 (17%) (2%, 48%) (8.8, 11.0)
Neuroendocrine cancer 5 2 (40%) (5%, 85%) (2.2+, 32.6+)
Salivary cancer 3 PR, SD, PD 31.3+
Thyroid cancer 2 CR, CR (8.2, 33.2+)
Mesothelioma cancer 1 PD
* No TMB-H patients were identified in the cholangiocarcinoma cohort
CR = complete response
PR = partial response
SD = stable disease
PD = progressive disease

In an exploratory analysis in 32 patients enrolled in KEYNOTE-158 whose cancer had TMB ≥10 mut/Mb and <13 mut/Mb, the ORR was 13% (95% CI: 4%, 29%), including two complete responses and two partial responses.

Cutaneous Squamous Cell Carcinoma

The efficacy of KEYTRUDA was investigated in patients with recurrent or metastatic cSCC enrolled in KEYNOTE-629 (NCT03284424), a multicenter, multi-cohort, non-randomized, open-label trial. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression.

Patients received KEYTRUDA 200 mg intravenously every 3 weeks until documented disease progression, unacceptable toxicity, or a maximum of 24 months. Patients with initial radiographic disease progression could receive additional doses of KEYTRUDA during confirmation of progression unless disease progression was symptomatic, rapidly progressive, required urgent intervention, or occurred with a decline in performance status.

Assessment of tumor status was performed every 6 weeks during the first year, and every 9 weeks during the second year. The major efficacy outcome measures were ORR and DoR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

Among the 105 patients treated, the study population characteristics were: median age of 72 years (range: 29 to 95), 71% age 65 or older; 76% male; 71% White, 25% race unknown; 34% ECOG PS of 0 and 66% ECOG PS of 1. Forty-five percent of patients had locally recurrent only cSCC, 24% had metastatic only cSCC, and 31% had both locally recurrent and metastatic cSCC. Eighty-seven percent received one or more prior lines of therapy; 74% received prior radiation therapy.

Efficacy results are summarized in Table 70.

Table 70: Efficacy Results in KEYNOTE-629

Endpoint KEYTRUDA
n=105
Objective Response Rate
ORR (95% CI) 34% (25, 44)
Complete response rate 4%
Partial response rate 31%
Duration of Response* n=36
Median in months (range) NR (2.7, 13.1+)†
% with duration ≥6 months 69%
* Median follow-up time of 9.5 months
† Based on patients (n=36) with a confirmed response by independent review
+ Denotes ongoing response

Triple-Negative Breast Cancer

The efficacy of KEYTRUDA in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin was investigated in KEYNOTE-355 (NCT02819518), a multicenter, double-blind, randomized, placebo-controlled trial conducted in 847 patients with locally recurrent unresectable or metastatic TNBC, regardless of tumor PD-L1 expression, who had not been previously treated with chemotherapy in the metastatic setting. Patients with active autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by chemotherapy treatment (paclitaxel or paclitaxel protein-bound vs. gemcitabine and carboplatin), tumor PD-L1 expression (CPS ≥1 vs. CPS <1) according to the PD-L1 IHC 22C3 pharmDx kit, and prior treatment with the same class of chemotherapy in the neoadjuvant setting (yes vs. no).

Patients were randomized (2:1) to one of the following treatment arms; all study medications were administered via intravenous infusion:

  • KEYTRUDA 200 mg on Day 1 every 3 weeks in combination with paclitaxel protein-bound 100 mg/m² on Days 1, 8 and 15 every 28 days, paclitaxel 90 mg/m² on Days 1, 8, and 15 every 28 days, or gemcitabine 1000 mg/m² and carboplatin AUC 2 mg/mL/min on Days 1 and 8 every 21 days.
  • Placebo on Day 1 every 3 weeks in combination with paclitaxel protein-bound 100 mg/m² on Days 1, 8 and 15 every 28 days, paclitaxel 90 mg/m² on Days 1, 8, and 15 every 28 days, or gemcitabine 1000 mg/m² and carboplatin AUC 2 mg/mL/min on Days 1 and 8 every 21 days.

Assessment of tumor status was performed at Weeks 8, 16, and 24, then every 9 weeks for the first year, and every 12 weeks thereafter. The main efficacy outcome measure was PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ tested in the subgroup of patients with CPS ≥10. Additional efficacy outcome measures were OS as well as ORR and DoR as assessed by BICR.

The study population characteristics for patients were: median age of 53 years (range: 22 to 85), 21% age 65 or older; 100% female; 68% White, 21% Asian, and 4% Black; 60% ECOG PS of 0 and 40% ECOG PS of 1; and 68% were post-menopausal status. Seventy-five percent of patients had tumor PD-L1 expression CPS ≥1 and 38% had tumor PD-L1 expression CPS ≥10.

Table 71 and Figure 17 summarize the efficacy results for KEYNOTE-355.

Table 71: Efficacy Results in KEYNOTE-355 (CPS ≥10)

Endpoint KEYTRUDA 200 mg every 3 weeks with chemotherapy
n=220
Placebo every 3 weeks with chemotherapy
n=103
PFS
Number of patients with event (%) 136 (62%) 79 (77%)
Median in months (95% CI) 9.7 (7.6, 11.3) 5.6 (5.3, 7.5)
Hazard ratio* (95% CI) 0.65 (0.49, 0.86)
p-Value† 0.0012
ORR
Objective confirmed response rate (95% CI) 53% (46, 60) 40% (30, 50)
Complete response rate 17% 13%
Partial response rate 36% 27%
DoR
Median in months (95% CI) 19.3 (9.9, 29.8) 7.3 (5.3, 15.8)
* Based on stratified Cox regression model
† One-sided p-Value based on stratified log-rank test

Figure 17: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-355 (CPS ≥10)

Kaplan-Meier
Curve for Progression-Free Survival in KEYNOTE-355 (CPS =10) - Illustration

Adult Indications: Additional Dosing Regimen Of 400 mg Every 6 Weeks

The efficacy and safety of KEYTRUDA using a dosage of 400 mg every 6 weeks for all approved adult indications was primarily based on the modeling of dose/exposure efficacy and safety relationships and observed pharmacokinetic data in patients with melanoma [see CLINICAL PHARMACOLOGY].

Medication Guide

PATIENT INFORMATION

KEYTRUDA®
(key-true-duh)
(pembrolizumab) injection

What is the most important information I should know about KEYTRUDA?

KEYTRUDA is a medicine that may treat certain cancers by working with your immune system. KEYTRUDA can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or life-threatening and can lead to death. You can have more than oneof these problems at the same time. These problems may happen anytime during treatment or even after your treatment has ended.

Call or see your healthcare provider right away if you develop any new or worsening signs or symptoms, including:

Lung problems

  • cough
  • shortness of breath
  • chest pain

Intestinal problems

  • diarrhea (loose stools) or more frequent bowel movements than usual
  • stools that are black, tarry, sticky, or have blood or mucus
  • severe stomach-area (abdomen) pain or tenderness

Liver problems

  • yellowing of your skin or the whites of your eyes
  • dark urine (tea colored)
  • severe nausea or vomiting
  • bleeding or bruising more easily than normal
  • pain on the right side of your stomach area (abdomen)

Hormone gland problems

  • headaches that will not go away or unusual headaches
  • urinating more often than usual
  • eye sensitivity to light
  • hair loss
  • eye problems
  • feeling cold
  • rapid heartbeat
  • constipation
  • increased sweating
  • your voice gets deeper
  • extreme tiredness
  • dizziness or fainting
  • weight gain or weight loss
  • feeling more hungry or thirsty than usual
  • changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness

Kidney problems

  • decrease in your amount of urine
  • swelling of your ankles
  • blood in your urine
  • loss of appetite

Skin problems

  • rash
  • painful sores or ulcers in your mouth or in your nose, throat, or genital area
  • itching
  • fever or flu-like symptoms
  • skin blistering or peeling
  • swollen lymph nodes

Problems can also happen in other organs and tissues. These are not all of the signs and symptoms ofimmune system problems that can happen with KEYTRUDA. Call or see your healthcare provider right away forany new or worsening signs or symptoms, which may include

  • chest pain, irregular heartbeat, shortness of breath, swelling of ankles
  • confusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems, tingling or numbness of the arms or legs
  • double vision, blurry vision, sensitivity to light, eye pain, changes in eyesight
  • persistent or severe muscle pain or weakness, muscle cramps
  • low red blood cells, bruising

Infusion reactions that can sometimes be severe or life-threatening. Signs and symptoms of infusion reactions may include:

  • chills or shaking
  • dizziness
  • itching or rash
  • feeling like passing out
  • flushing
  • fever
  • shortness of breath or wheezing
  • back pain

Rejection of a transplanted organ. Your healthcare provider should tell you what signs and symptoms you should report and monitor you, depending on the type of organ transplant that you have had.

Complications, including graft-versus-host-disease (GVHD), in people who have received a bone marrow (stemcell) transplant that uses donor stem cells (allogeneic). These complications can be serious and can lead to death.These complications may happen if you underwent transplantation either before or after being treated with KEYTRUDA.Your healthcare provider will monitor you for these complications.

Getting medical treatment right away may help keep these problems from becoming more serious. Your healthcare provider will check you for these problems during treatment with KEYTRUDA. Your healthcare providermay treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may also need to delayor completely stop treatment with KEYTRUDA if you have severe side effects.

What is KEYTRUDA?

KEYTRUDA is a prescription medicine used to treat:

  • a kind of skin cancer called melanoma. KEYTRUDA may be used:
    • when your melanoma has spread or cannot be removed by surgery (advanced melanoma), or
    • to help prevent melanoma from coming back after it and lymph nodes that contain cancer have been removed by surgery.
  • a kind of lung cancer called non-small cell lung cancer (NSCLC).
    • KEYTRUDA may be used with the chemotherapy medicines pemetrexed and a platinum as your first treatment when your lung cancer:
      • has spread (advanced NSCLC), and
      • is a type called “nonsquamous”, and
      • your tumor does not have an abnormal “EGFR” or “ALK” gene.
    • KEYTRUDA may be used with the chemotherapy medicines carboplatin and either paclitaxel or paclitaxel protein-bound as your first treatment when your lung cancer:
      • has spread (advanced NSCLC), and
      • is a type called “squamous”.
    • KEYTRUDA may be used alone as your first treatment when your lung cancer:
      • has not spread outside your chest (stage III) and you cannot have surgery or chemotherapy with radiation or
      • your NSCLC has spread to other areas of your body (advanced NSCLC), and
      • your tumor tests positive for “PD-L1”, and
      • does not have an abnormal “EGFR” or “ALK” gene.
    • KEYTRUDA may also be used alone when:
      • you have received chemotherapy that contains platinum to treat your advanced NSCLC, and it did not work or it is no longer working, and
      • your tumor tests positive for “PD-L1”, and
      • if your tumor has an abnormal “EGFR” or “ALK” gene, you have also received an EGFR or ALK inhibitor medicine and it did not work or is no longer working.
  • a kind of cancer called head and neck squamous cell cancer (HNSCC).
    • KEYTRUDA may be used with the chemotherapy medicines fluorouracil and a platinum as your first treatment when your head and neck cancer has spread or returned and cannot be removed by surgery.
    • KEYTRUDA may be used alone as your first treatment when your head and neck cancer:
      • has spread or returned and cannot be removed by surgery, and
      • your tumor tests positive for “PD-L1”.
  • KEYTRUDA may be used alone when your head and neck cancer:
    • has spread or returned, and
    • you have received chemotherapy that contains platinum and it did not work or is no longer working.
  • a kind of cancer called classical Hodgkin lymphoma (cHL):
    •  in adults when:
      • your cHL has returned or
      • you have tried a treatment and it did not work, or
    • in children when:
      • you have tried a treatment and it did not work or
      • your cHL has returned after you received 2 or more types of treatment.
  • a kind of cancer called primary mediastinal B-cell lymphoma (PMBCL) in adults and children when:
    • you have tried a treatment and it did not work or
    • your PMBCL has returned after you received 2 or more types of treatment.
  • a kind of bladder and urinary tract cancer called urothelial carcinoma.
    • KEYTRUDA may be used when your cancerhas not spread to nearby tissue in the bladder, but is at high-riskfor spreading (high-risk non-muscle-invasive bladder cancer [NMIBC]) when:
      • your tumor is a type called “carcinoma in situ” (CIS), and
      • you have tried treatment withBacillus Calmette-Guerin(BCG) and it did not work, and
      • you are not able to or have decided not to have surgery to remove your bladder.
  • KEYTRUDA may be used when your bladder or urinary tract cancer:
    • has spread or cannot be removed by surgery (advanced urothelial cancer) and,
    • you are not able to receive chemotherapy that contains a medicine called cisplatin, and your tumor tests positive for “PD-L1”, or
    • you are not able to receive a medicine called cisplatin or carboplatin, or
    • you have received chemotherapy that contains platinum, and it did not work or is no longer working.
  • a kind of cancer that is shown by a laboratory test to be a microsatellite instability-high (MSI-H) or a mismatch repair deficient (dMMR) solid tumor. KEYTRUDA may be used in adults and children to treat:
    • cancer that has spread or cannot be removed by surgery (advanced cancer), and
    • has progressed following treatment, and you have no satisfactory treatment options.

It is not known if KEYTRUDA is safe and effective in children with MSI-H cancers of the brain or spinal cord (central nervous system cancers).

  • a kind of cancer called colon or rectal cancer. KEYTRUDA may be used when your cancer:
    • has spread or cannot be removed by surgery (advanced colon or rectal cancer), and
    • has been shown by a laboratory test to be microsatellite instability-high (MSI-H) or mismatch repair deficient(dMMR).
  • a kind of stomach cancer called gastric or gastroesophageal junction (GEJ) adenocarcinoma.
    • KEYTRUDA may beused with the medicine trastuzumabwithfluoropyrimidine and platinumchemotherapy asyour first treatment when your stomach cancer:
      • is HER2-positive, and
      • has spread or cannot be removed by surgery (advanced gastric cancer).
    • KEYTRUDA may be used alone when your stomach cancer:
      • tests positive for “PD-L1”, and
      • has returned or spread (advanced gastric cancer), and
      • you have received 2 or more types of chemotherapy,including fluoropyrimidine and chemotherapy thatcontains platinum, and it did not work or is no longer working, and
      • if your tumoris HER2-positive, you also received a HER2-targeted medicine and it did not work or is no longer working.
  • a kind of cancer called esophagealor certain gastroesophageal junction (GEJ) carcinomasthat cannot be cured by surgery or a combination of chemotherapy and radiation therapy.
    • KEYTRUDA may be used with platinum-and fluoropyrimidine-based chemotherapy medicines.
    • KEYTRUDA may be used alone when:
      • you have received one or more types of treatment, and it did not work or it is no longer working, and
      • your tumor is a type called “squamous”, and
      • your tumor tests positive for “PD-L1”.
  • a kind of cancer called cervical cancer that tests positive for “PD-L1.” KEYTRUDA may be used when your cervical cancer:
    • has returned, or has spread or cannot be removed by surgery (advanced cervical cancer), and
    • you have received chemotherapy, and it did not work or is no longer working.
  • a kind of liver cancer called hepatocellular carcinoma, after you have received the medicine sorafenib.
  • a kind of skin cancer called Merkel cell carcinoma (MCC) in adults and children. KEYTRUDA may be used to treat your skin cancer when it has spread or returned.
  • a kind of kidney cancer called renal cell carcinoma (RCC).
    • KEYTRUDA may be used with the medicine axitinib as your first treatment when your kidney cancer has spread or cannot be removed by surgery (advanced RCC).
    • KEYTRUDA may be used with the medicine lenvatinib as your first treatment when your kidney cancer hasspread or cannot be removed bysurgery (advanced RCC).
  • a kind of uterine cancer called endometrial carcinoma. KEYTRUDA may be used with the medicine lenvatinib:
    • when a laboratory test shows that yourtumorisnot microsatellite instability-high (MSI-H) or mismatch repairdeficient (dMMR), and
    • you have received anti-cancer treatment, and it is no longer working, and
    • your cancer cannot be cured by surgery or radiation (advanced endometrial carcinoma).
  • a kind of cancer that is shown by a test to be tumor mutational burden-high (TMB-H). KEYTRUDA may be used in adults and children to treat:
    • solid tumorsthat have spread or cannot be removed by surgery (advanced cancer), and
      • you have received anti-cancer treatment, and it did not work or is no longer working, and
      • you have no satisfactory treatment options.It is not known if KEYTRUDA is safe and effective in children with TMB-H cancers of the brain or spinal cord (central nervous system cancers).
  • a kind of skin cancer called cutaneous squamous cell carcinoma (cSCC). KEYTRUDA may be used when your skin cancer:
    • has returned or spread, and
    • cannot be cured by surgery or radiation.
  • a kind of cancer called triple-negative breast cancer (TNBC).
    • KEYTRUD A may be used with chemotherapy medicines as treatment before surgery and then continued alone after surgery when you:
      • have early-stage breast cancer, and
      • are at high risk of your breast cancer coming back.
    • KEYTRUDA may be used with chemotherapy medicines when your breast cancer:
      • has returned and cannot be removed by surgery or has spread, and
      • tests positive for “PD-L1”.

Before receiving KEYTRUDA, tell your healthcare provider about all of your medical conditions, including if you:

  • have immune system problems such as Crohn’s disease, ulcerative colitis, or lupus
  • have received an organ transplant
  • have received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic)
  • have received radiation treatment to your chest area
  • have a condition that affects your nervous system, such as myasthenia gravis or Guillain-Barré syndrome
  • are pregnant or plan to become pregnant. KEYTRUDA can harm your unborn baby.

Females who are able to become pregnant:

    • Your healthcare provider will give you a pregnancy test before you start treatment with KEYTRUDA.
    • You should use an effective method of birth control during and for at least 4 months after the final dose ofKEYTRUDA. Talk to your healthcare provider about birth control methods that you can use during this time.
    • Tell your healthcare provider right away if you think you may be pregnant or if you become pregnantduring treatment with KEYTRUDA.
  • are breastfeeding or plan to breastfeed. It is not known if KEYTRUDA passes into your breast milk. Do not breastfeed during treatment with KEYTRUDA and for 4 months after your final dose of KEYTRUDA.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

How will I receive KEYTRUDA?

  • Your healthcare provider will give you KEYTRUDA into your vein through an intravenous (IV) line over 30 minutes.
  • In adults, KEYTRUDA is usually given every 3 weeks or 6 weeks depending on the dose of KEYTRUDA that you are receiving.
  • In children, KEYTRUDA is usually given every 3 weeks.
  • Your healthcare provider will decide how many treatments you need.
  • Your healthcare provider will do blood tests to check you for side effects.
  • If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.

What are the possible side effects of KEYTRUDA?

KEYTRUDA can cause serious side effects. See “What is the most important information I should know aboutKEYTRUDA?”

Common side effects of KEYTRUDA when used alone include: feeling tired, pain, including pain in muscles, bones or joints and stomach-area (abdominal) pain, decreased appetite, itching, diarrhea, nausea, rash, fever, cough,shortness of breath, and constipation.

Side effects of KEYTRUDA when used alone that are more common in children than in adults include: fever, vomiting, upper respiratory tract infection, headache, and low levels of white blood cells and red blood cells (anemia).

Common side effects of KEYTRUDA when given with certain chemotherapy medicines include: feeling tired or weak, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, trouble breathing, fever, hair loss,inflammation of the nerves that may cause pain, weakness, and paralysis in the arms and legs, swelling of the lining of the mouth, nose, eyes, throat, intestines, or vagina, mouth sores, headache, weight loss, stomach-area (abdominal)pain, joint and muscle pain, and trouble sleeping.

Common side effects of KEYTRUDA when given with axitinib include: diarrhea, feeling tired or weak, high blood pressure, liver problems, low levels of thyroid hormone, decreased appetite, blisters or rash on the palms of your hands and soles of your feet, nausea, mouth sores or swelling of the lining of the mouth, nose, eyes, throat, intestines, or vagina, hoarseness, rash, cough, and constipation.

Common side effects of KEYTRUDA when given with lenvatinib include: low levels of thyroid hormone, high blood pressure, feeling tired, diarrhea, joint and muscle pain, nausea, decreased appetite,vomiting, mouth sores,weight loss, stomach-area (abdominal) pain, urinary tract infection,protein in your urine, constipation, headache,bleeding, blisters or rash on the palms of your handsand soles of your feet, hoarseness,rash, liver problems,and kidney problems.

These are not all the possible side effects of KEYTRUDA.

Call yourhealthcare providerfor medical advice about side effects.You may report side effects to FDA at 1-800-FDA1088.

General information about the safe and effective use of KEYTRUDA

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about KEYTRUDA that is written for health professionals.

What are the ingredients in KEYTRUDA?

Active ingredient: pembrolizumab

Inactive ingredients: KEYTRUDA injection: L-histidine, polysorbate 80, sucrose, and Water for Injection.

This Medication Guide has been approved by theU.S. Food andDrug Administration. Revised: August 2021

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Report Problems to the Food and Drug Administration

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.

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