Keytruda Side Effects Center

Last updated on RxList: 6/3/2022
Keytruda Side Effects Center

What Is Keytruda?

Keytruda (pembrolizumab) is a monoclonal antibody used to treat patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.

What Are Side Effects of Keytruda?

Common side effects of Keytruda include:

Dosage for Keytruda

The recommended dose of Keytruda is 2 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.

What Drugs, Substances, or Supplements Interact with Keytruda?

Keytruda may interact with other drugs. Tell your doctor all medications and supplements you use.

Keytruda During Pregnancy and Breastfeeding

Keytruda is not recommended for use during pregnancy; it may harm a fetus. It is unknown if this drug passes into breast milk. Consult your doctor before breastfeeding.

Additional Information

Our Keytruda (pembrolizumab) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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Keytruda Consumer Information

Get emergency medical help if you have signs of an allergic reaction (hives, difficult breathing, swelling in your face or throat) or a severe skin reaction (fever, sore throat, burning eyes, skin pain, red or purple skin rash with blistering and peeling).

Some side effects may occur during the injection. Tell your caregiver if you feel dizzy, light-headed, itchy, hot, sweaty, chilled, or have back pain or trouble breathing.

Pembrolizumab strengthens your immune system to help your body fight against cancer cells. This may cause the immune system to attack normal healthy tissues or organs. When this happens, you may develop serious or life-threatening medical problems.

Call your doctor at once if you have:

  • new or worsening cough, chest pain, shortness of breath;
  • pale skin, easy bruising or bleeding;
  • sores in your mouth, throat, or nose, or on your genital area;
  • severe headache, confusion, eye pain, vision problems (your eyes may be more sensitive to light);
  • numbness, tingling, burning pain, redness, rash, or blisters on your hands or feet;
  • fever, swollen glands, neck stiffness;
  • diarrhea or increased stools, severe stomach pain, bloody or tarry stools;
  • kidney problems--swelling in your ankles, blood in your urine, little or no urination;
  • liver problems--loss of appetite, right-sided stomach pain, vomiting, dark urine, jaundice (yellowing of the skin or eyes);
  • transplant rejection--mouth sores, stomach pain, feeling sick or uneasy, rash, pain or swelling near your transplanted organ; or
  • signs of a hormonal disorder--frequent or unusual headaches, dizziness, feeling very tired, mood or behavior changes, hoarse or deepened voice, increased hunger or thirst, increased urination, constipation, hair loss, sweating, feeling cold, weight gain, or weight loss.

Your cancer treatments may be delayed or permanently discontinued if you have certain side effects.

Common side effects (some are more likely with combination chemotherapy) may include:

  • nausea, vomiting, stomach pain, loss of appetite, diarrhea, constipation;
  • low sodium levels, abnormal liver or thyroid function tests;
  • fever, feeling weak or tired;
  • cough, hoarse voice, feeling short of breath;
  • itching, rash, hair loss;
  • increased blood pressure;
  • pain in your muscles, bones, or joints; or
  • soreness in or around your mouth, nose, eyes, throat, or vagina.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the entire detailed patient monograph for Keytruda (Pembrolizumab for Injection)

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Keytruda Professional Information

SIDE EFFECTS

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

  • Severe and fatal immune-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 655 patients with melanoma and 550 patients with NSCLC. In addition to the 2799 patients, certain subsections in the WARNINGS AND PRECAUTIONS describe adverse reactions observed with exposure to KEYTRUDA as a single agent in a non-randomized, open-label, multi-cohort trial (KEYNOTE-012), a non-randomized, open-label, singlecohort trial (KEYNOTE-055), and two randomized, open-label, active-controlled trials (KEYNOTE-040 and KEYNOTE-048 single agent arms), which enrolled 909 patients with HNSCC; in two 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, activecontrolled 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 doses of 2 mg/kg intravenously every 3 weeks, 10 mg/kg intravenously every 2 weeks, 10 mg/kg intravenously every 3 weeks, or 200 mg intravenously every 3 weeks. Among the 2799 patients, 41% were exposed for 6 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 10 mg/kg every 2 weeks (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 10 mg/kg every 2 or 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 62 years (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 2 week and every 3 week schedule, 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
† Graded per NCI CTCAE v4.0
‡ Includes rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, and exfoliative rash.
§ Includes skin hypopigmentation

Other clinically important adverse reactions occurring in ≥10% of patients receiving KEYTRUDA were diarrhea (26%), nausea (21%), and pruritus (17%).

Table 5: Selected* Laboratory Abnormalities Worsened from Baseline Occurringin ≥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 onstudy 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 KEYTRUDA were increased hypoalbuminemia (27% all Grades; 2.4% Grades 3-4), increased ALT (23% all Grades; 3.1% Grades 3- 4), and increased alkaline phosphatase (21% all Grades, 2% Grades 3-4).

Ipilimumab-Refractory Melanoma

The safety of KEYTRUDA in patients 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 Grade 4 toxicity or Grade 3 toxicity requiring corticosteroid treatment (greater than 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 lung disease; or an active infection requiring therapy, including HIV or hepatitis B or C, were ineligible.

The median duration of exposure to KEYTRUDA 2 mg/kg every 3 weeks was 3.7 months (range: 1 day to 16.6 months) and to KEYTRUDA 10 mg/kg every 3 weeks was 4.8 months (range: 1 day to 16.8 months). 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 62 years (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 general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 14% of patients; 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% all Grades; 10% Grades 3-4) and lymphopenia (40% all Grades; 9% Grades 3-4).

Adjuvant Treatment Of Resected Stage IIB Or IIC Melanoma

Among the 969 patients with stage IIB or IIC melanoma enrolled in KEYNOTE-716 [see Clinical Studies] treated with KEYTRUDA, the median duration of exposure to KEYTRUDA was 9.9 months (range: 0 to 15.4 months). Patients with autoimmune disease or a medical condition that required immunosuppression or mucosal or ocular melanoma were ineligible. Adverse reactions occurring in patients with stage IIB or IIC melanoma were similar to those occurring in 1011 patients with stage III melanoma from KEYNOTE-054 or the 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent.

Adjuvant Treatment Of Stage III 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 200 mg of KEYTRUDA by intravenous infusion every 3 weeks (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 ocular melanoma were ineligible. Seventy-six percent of patients received KEYTRUDA for 6 months or longer.

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).

Two patients treated with KEYTRUDA died from causes other than disease progression; causes of death were drug reaction with eosinophilia and systemic symptoms and autoimmune myositis with respiratory failure. Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. Adverse reactions leading to permanent discontinuation occurred in 14% of patients receiving KEYTRUDA; the most common (≥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%). Tables 8 and 9 summarize 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 in patients 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 3 weeks for 4 cycles 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 200 mg every 3 weeks was 7.2 months (range: 1 day 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 64 years (range: 34 to 84), 49% age 65 or older; 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%). Tables 10 and 11 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-189.

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 Placebo
200 mg every 3 weeks Pemetrexed Platinum Chemotherapy 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 onstudy 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 or paclitaxel protein-bound was 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 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 was 7 months (range: 1 day to 12 months). Sixty-one percent of patients in 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 65 years (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 trial in 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 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 was 5.6 months (range: 1 day to 27.3 months). Fortyeight percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA 200 mg for ≥6 months.

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. Eighty-seven percent had metastatic disease (stage IV), 13% had stage III disease (2% stage IIIA and 11% 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 12 and 13 summarize 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 onstudy 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 2 mg/kg (n=339) or 10 mg/kg (n=343) every 3 weeks or docetaxel (n=309) at 75 mg/m² every 3 weeks. Patients with autoimmune disease, medical conditions that required systemic corticosteroids or other immunosuppressive medication, 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 2 mg/kg every 3 weeks was 3.5 months (range: 1 day to 22.4 months) and to KEYTRUDA 10 mg/kg every 3 weeks was 3.5 months (range 1 day to 20.8 months). The data described below reflect exposure to KEYTRUDA 2 mg/kg in 31% of patients exposed to KEYTRUDA for ≥6 months. In the KEYTRUDA 10 mg/kg arm, 34% of patients were exposed to KEYTRUDA for ≥6 months.

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; 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 KEYTRUDA occurred 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 14 and 15 summarize 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% of NSCLC Patients Receiving KEYTRUDA in KEYNOTE-010

Laboratory Test† KEYTRUDA 2 or 10 mg/kg every 3 weeks Docetaxel 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 onstudy 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% Grades 3-4), 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% Grades 3-4).

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 or metastatic HNSCC [see Clinical Studies]. Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. A total of 576 patients received KEYTRUDA 200 mg every 3 weeks 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 3.5 months (range: 1 day to 24.2 months) in the KEYTRUDA single agent arm and was 5.8 months (range: 3 days to 24.2 months) 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 agent arm. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were sepsis (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 patients in 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 16 and 17 summarize 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 8 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, dermatitis exfoliative, 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
à 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 laboratory measurement available: KEYTRUDA/chemotherapy (range: 235 to 266 patients), KEYTRUDA (range: 241 to 288 patients), cetuximab/chemotherapy (range: 249 to 282 patients).
† Graded per NCI CTCAE v4.0

Previously Treated Recurrent Or Metastatic HNSCC

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

The study population characteristics were: median age of 60 years (range: 20 to 84), 35% age 65 or older; 83% male; and 77% 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 most common 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 2799 patients 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 200 mg intravenously every 3 weeks (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 times ULN, and ECOG performance status of 0 or 1. The trial excluded patients with active non-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 was 10 months (range: 1 day to 2.2 years), with 68% receiving at least 6 months of treatment and 48% receiving at least 1 year of treatment.

Serious adverse reactions occurred in 30% of patients who received KEYTRUDA. Serious adversereactions 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 occurred in 14% of patients; 7% of patients 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
Dyspnea ð 11 0.7 7 0.7
Endocrine
Hypothyroidism 19 0 3 0
Nervous System
Peripheral neuropathyø 11 0.7 43 7
Headacheý 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 respiratory tract infection, viral upper respiratory tract infection
§ Includes arthralgia, back pain, bone pain, musculoskeletal discomfort, musculoskeletal chest pain, 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
ÞIncludes 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
à Includes cough, productive cough
è 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
ý Includes headache, migraine, tension headache

Clinically relevant adverse reactions in <10% of patients who 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 mg every 3 weeks Brentuximab Vedotin 1.8 mg/kg 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
Hematology
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 148 patients) 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 210 patients 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. Tables 20 and 21 summarize 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 53 patients 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. Serious adverse 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. Tables 22 and 23 summarize adverse reactions and laboratory abnormalities, respectively, in KEYNOTE-170.

Table 22: Adverse Reactions (≥10%) in Patients with PMBCL who Received KEYTRUDA in KEYNOTE-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 pain Þ 13 0
Nausea 11 0
Cardiac
Arrhythmiaβ 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 relevant adverse 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 at least 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

Platinum Ineligible Patients With Urothelial Carcinoma

The safety of KEYTRUDA was investigated in KEYNOTE-052, a single-arm trial that enrolled 370 patients with locally advanced or metastatic urothelial carcinoma who had one or more comorbidities. Patients with autoimmune disease or medical conditions that required systemic corticosteroids or other immunosuppressive medications were ineligible [see Clinical Studies]. Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity or either radiographic or clinical disease progression.

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

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, joint pain, 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, and 5% of patients required at least one steroid dose ≥40 mg oral prednisone 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, flank pain, 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 or other immunosuppressive medications were ineligible.

The median duration of exposure was 3.5 months (range: 1 day to 20 months) in patients who received KEYTRUDA and 1.5 months (range: 1 day to 14 months) 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% of patients; 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 25 and 26 summarize 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 à 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 chest pain, 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
à 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 148 patients with high-risk non-muscle invasive bladder cancer (NMIBC), 96 of whom had BCG-unresponsive carcinoma in situ (CIS) with or without papillary tumors. Patients received KEYTRUDA 200 mg every 3 weeks 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 4.3 months (range: 1 day to 25.6 months).

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% of patients; 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 in KEYNOTE-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
* 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: 124 to 147 patients)
† Graded per NCI CTCAE v4.03

Microsatellite Instability-High Or Mismatch Repair Deficient Colorectal Cancer

Among the 153 patients 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: 1 day to 30.6 months). 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

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

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

The study population characteristics were: median age of 63 years (range: 19 to 84), 43% age 65 or older; 81% male; 58% White, 35% Asian, and 0.9% Black; 44% ECOG PS of 0 and 56% ECOG PS of 1.

KEYTRUDA and placebo were discontinued due to adverse reactions in 6% of patients in 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 most common 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 KEYTRUDA arm versus placebo, there was a difference of ≥5% incidence between patients treated 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 of care for increased ALT (34% vs 29%), and increased creatinine (20% vs 10%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms.

Esophageal Cancer

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

The safety of KEYTRUDA, in combination with cisplatin and FU chemotherapy was investigated in KEYNOTE-590, a multicenter, double-blind, randomized (1:1), placebo-controlled trial for the first-line treatment in 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 [see Clinical Studies]. A total of 740 patients received either KEYTRUDA 200 mg (n=370) or placebo (n=370) every 3 weeks for up to 35 cycles, both in 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 KEYTRUDA combination arm and 5.1 months (range: 3 days to 27 months) 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 of KEYTRUDA 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 onstudy laboratory measurement available: KEYTRUDA/cisplatin/FU (range: 345 to 365 patients) and placebo/cisplatin/FU (range: 330 to 358 patients)
† Graded per NCI CTCAE v4.03

Previously Treated Recurrent Locally Advanced Or Metastatic Esophageal Cancer

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

Cervical Cancer

Persistent, Recurrent, Or Metastatic Cervical Cancer

The safety of KEYTRUDA in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab, was investigated in KEYNOTE-826, a multicenter, double-blind, randomized (1:1), placebo-controlled trial in patients with persistent, recurrent, or first-line metastatic cervical cancer who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent [see Clinical Studies]. A total of 616 patients, regardless of tumor PD-L1 expression, received KEYTRUDA 200 mg and chemotherapy with or without bevacizumab (n=307) every 3 weeks or placebo and chemotherapy with or without bevacizumab (n=309) every 3 weeks.

The median duration of exposure to KEYTRUDA was 9.9 months (range: 1 day to 26 months).

Fatal adverse reactions occurred in 4.6% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab, including 3 cases of hemorrhage, 2 cases of sepsis, 2 cases due to unknown causes, and 1 case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femur fracture with perioperative pulmonary embolus, intestinal perforation, and pelvic infection.

Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab. Serious adverse reactions in ≥3% of patients included febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), acute kidney injury (3.3%), and sepsis (3.3%).

KEYTRUDA was discontinued for adverse reactions in 15% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA (≥1%) was colitis (1%).

Adverse reactions leading to interruption of KEYTRUDA occurred in 66% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were thrombocytopenia (15%), neutropenia (14%), anemia (11%), increased ALT (6%), leukopenia (5%), fatigue/asthenia (4.2%), urinary tract infection (3.6%), increased AST (3.3%), pyrexia (3.3%), diarrhea (2.6%), acute kidney injury (2.6%), increased blood creatinine (2.6%), colitis (2.3%), decreased appetite (2%), and cough (2%).

For patients treated with KEYTRUDA, chemotherapy, and bevacizumab (n=196), the most common (≥20%) adverse reactions were peripheral neuropathy (62%), alopecia (58%), anemia (55%), fatigue/asthenia (53%), nausea (41%), neutropenia (41%), diarrhea (39%), hypertension (35%), thrombocytopenia (35%), constipation (31%), arthralgia (31%), vomiting (30%), urinary tract infection (27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and decreased appetite (21%). Table 31 and Table 32 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-826.

Table 31: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-826

Adverse Reaction KEYTRUDA 200 mg every 3 weeks and chemotherapy* with or without bevacizumab
n=307
Placebo and chemotherapy* with or without bevacizumab
n=309
All Grades† (%) Grades 3-4 (%) All Grades† (%) Grades 3-4 (%)
Nervous System
Peripheral neuropathy‡ 58 4.2 57 6
Skin and Subcutaneous Tissue
Alopecia 56 0 58 0
Rash§ 22 3.6 15 0.3
General
Fatigue¶ 47 7 46 6
Gastrointestinal
Nausea 40 2 44 1.6
Diarrhea 36 2 30 2.6
Constipation 28 0.3 33 1
Vomiting 26 2.6 27 1.9
Musculoskeletal and Connective Tissue
Arthralgia 27 0.7 26 1.3
Vascular
Hypertension 24 9 23 11
Infections
Urinary tract infection 24 9 26 8
* Chemotherapy (paclitaxel and cisplatin or paclitaxel and carboplatin)
† Graded per NCI CTCAE v4.0
‡ Includes neuropathy peripheral, peripheral sensory neuropathy, peripheral motor neuropathy, peripheral sensorimotor neuropathy, paresthesia
§ Includes rash, rash maculo-papular, rash erythematous, rash macular, rash papular, rash pruritic, rash pustular
¶ Includes fatigue, asthenia

Table 32: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-826

Laboratory Test* KEYTRUDA Placebo
200 mg every 3 weeks and chemotherapy†, with or without bevacizumab
n=307
and chemotherapy† with or without bevacizumab
n=309
All Grades‡ (%) Grades 3-4 (%) All Grades‡ (%) Grades 3-4 (%)
Hematology
Anemia 80 35 77 33
Leukopenia 76 27 69 19
Neutropenia 66 39 58 31
Lymphopenia 61 33 56 33
Thrombocytopenia 57 19 53 15
Chemistry
Hyperglycemia 51 4.7 46 2.3
Hypoalbuminemia 46 1.3 38 5
Hyponatremia 40 14 38 11
Increased ALT 40 7 38 6
Increased AST 40 6 36 3.0
Increased alkaline phosphatase 38 3.4 40 2.3
Hypocalcemia 37 4.0 31 5
Increased creatinine 34 5 32 6
Hypokalemia 29 7 26 7
Hyperkalemia 23 3.7 27 4.7
Hypercalcemia 21 1.0 20 1.3
* Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA plus chemotherapy (range: 297 to 301 patients) and placebo plus chemotherapy (range: 299 to 302 patients)
† Chemotherapy (paclitaxel and cisplatin or paclitaxel and carboplatin)
‡ Graded per NCI CTCAE v4.0

Previously Treated Recurrent Or Metastatic Cervical Cancer

Among the 98 patients 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%). Tables 33 and 34 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-158.

Table 33: 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)è 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
à Includes bacterial pyelonephritis, pyelonephritis acute, urinary tract infection, urinary tract infection bacterial, urinary tract infection pseudomonal, urosepsis
è 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 34: 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
* 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: 76 to 79 patients)
† Graded per NCI CTCAE v4.0

Other laboratory abnormalities occurring in ≥10% of patients receiving KEYTRUDA were hypophosphatemia (19% all Grades; 6% Grades 3-4), increased INR (19% all Grades; 0% Grades 3-4), hypercalcemia (14% all Grades; 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% Grades 3-4), 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 104 patients with HCC who received KEYTRUDA in KEYNOTE-224 [see Clinical Studies], the median duration of exposure to KEYTRUDA was 4.2 months (range: 1 day to 1.5 years). Adverse reactions occurring in patients with HCC were generally similar to those in 2799 patients with melanoma or NSCLC treated 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 50 patients with MCC enrolled in KEYNOTE-017 [see Clinical Studies], the median duration of exposure to KEYTRUDA was 6.6 months (range 1 day to 23.6 months). 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 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. Laboratory abnormalities (Grades 3-4) that occurred 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 systemic corticosteroids 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 200 mg intravenously every 3 weeks and axitinib 5 mg orally twice daily, or sunitinib 50 mg once daily for 4 weeks and then off treatment for 2 weeks. The median duration of exposure to the combination therapy of KEYTRUDA and axitinib was 10.4 months (range: 1 day to 21.2 months).

The study population characteristics were: median age of 62 years (range: 30 to 89), 40% age 65 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 cell myeloma, 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% of patients receiving 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 of KEYTRUDA infusions due to infusion-related reactions, occurred in 76% of patients receiving KEYTRUDA in combination with axitinib. 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 of axitinib 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 equivalent to ≥40 mg daily for an immune-mediated adverse reaction.

Tables 35 and 36 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in at least 20% of patients treated with KEYTRUDA and axitinib in KEYNOTE-426.

Table 35: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA with Axitinib in KEYNOTE-426

Adverse Reaction KEYTRUDA 200 mg every 3 weeks and 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, druginduced 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 36: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA with Axitinib in KEYNOTE-426

Laboratory Test* 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. Serious adverse reactions in ≥2% of patients were 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. The most 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 of 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 37 and 38 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in ≥20% of patients treated with KEYTRUDA and lenvatinib in KEYNOTE-581.

Table 37: 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 disorders¶ 58 4 41 3
Endocrine
Hypothyroidism# 57 1 32 0
Vascular
HypertensionÞ 56 29 43 20
Hemorrhagic eventsβ 27 5 26 4
Metabolism
Decreased appetiteà 41 4 31 1
Skin and Subcutaneous Tissue
Rashè 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 injuryý 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, oropharyngeal 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
à Includes decreased appetite, early satiety
è 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
ý 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 KEYTRUDA with lenvatinib were myocardial infarction (3%) and angina pectoris (1%).

Table 38: 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 postbaseline laboratory measurement for each parameter: KEYTRUDA with lenvatinib (range: 343 to 349 patients) and sunitinib (range: 329 to 335 patients).

Grade 3 and 4 increased ALT or AST was seen in 9% of patients. Grade ≥2 increased ALT or AST was reported in 64 (18%) patients, of whom 20 (31%) received ≥40 mg daily oral prednisone equivalent. Recurrence of Grade ≥2 increased ALT or AST was observed on rechallenge in 10 patients receiving both KEYTRUDA and lenvatinib (n=38) and was not observed on rechallenge with KEYTRUDA alone (n=3).

Adjuvant treatment Of RCC

The safety of KEYTRUDA as a single agent was investigated in KEYNOTE-564, a randomized (1:1) double-blind placebo-controlled trial in which 984 patients who had undergone nephrectomy for RCC received 200 mg of KEYTRUDA by intravenous infusion every 3 weeks (n=488) or placebo (n=496) for up to one year [see Clinical Studies]. The median duration of exposure to KEYTRUDA was 11.1 months (range: 1 day to 14.3 months). Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible.

Serious adverse reactions occurred in 20% of these patients receiving KEYTRUDA. Serious adverse reactions (≥1%) were acute kidney injury, adrenal insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1% each). Fatal adverse reactions occurred in 0.2% of those treated with KEYTRUDA, including one case of pneumonia.

Discontinuation of KEYTRUDA due to an adverse reaction occurred in 21% of patients; the most common (≥1%) were increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%).

Dose interruptions of KEYTRUDA due to an adverse reaction occurred in 26% of patients; the most common (≥1%) were increased AST (2.3%), arthralgia (1.6%), hypothyroidism (1.6%), diarrhea (1.4%), increased ALT (1.4%), fatigue (1.4%), rash, decreased appetite, and vomiting (1% each). Tables 39 and 40 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-564.

Table 39: Selected* Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-564

Adverse Reaction KEYTRUDA 200 mg every 3 weeks n=488 Placebo n=496
All Grades† (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
Musculoskeletal and Connective Tissue
Musculoskeletal pain‡ 41 1.2 36 0.6
General
Fatigue§ 40 1.2 31 0.2
Skin and Subcutaneous Tissue
Rash¶ 30 1.4 15 0.4
Pruritus 23 0.2 13 0
Gastrointestinal
Diarrhea# 27 2.7 23 0.2
Nausea 16 0.4 10 0
Abdominal painÞ 11 0.4 13 0.2
Endocrine
Hypothyroidism 21 0.2 3.6 0
Hyperthyroidism 12 0.2 0.2 0
Respiratory, Thoracic and Mediastinal
Coughβ 17 0 12 0
Nervous System
Headacheà 15 0.2 13 0
Hepatobiliary
Hepatotoxicityè 14 3.7 7 0.6
Renal and Urinary
Acute kidney injuryð 13 1.2 10 0.2
* Adverse reactions occurring at same or higher incidence than in placebo arm
† Graded per NCI CTCAE v4.0
‡ Includes arthralgia, back pain, myalgia, arthritis, pain in extremity, neck pain, musculoskeletal pain, musculoskeletal stiffness, spinal pain, musculoskeletal chest pain, bone pain, musculoskeletal discomfort
§ Includes asthenia, fatigue
¶ Includes rash, rash maculo-papular, rash papular, skin exfoliation, lichen planus, rash erythematous, eczema, rash macular, dermatitis acneiform, dermatitis, rash pruritic, stevens-johnson syndrome, eczema asteatotic, palmar-plantar erythrodysaesthesia syndrome
# Includes diarrhoea, colitis, enterocolitis, frequent bowel movements, enteritis
Þ Includes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal discomfort, gastrointestinal pain
β Includes upper-airway cough syndrome, productive cough, cough
à Includes tension headache, headache, sinus headache, migraine with aura
è Includes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic function abnormal, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, liver function test increased, transaminases increased, gamma-glutamyltransferase increased, bilirubin conjugated increased
ð Includes acute kidney injury, blood creatinine increased, renal failure, renal impairment, oliguria, glomerular filtration rate decreased, nephropathy toxic

Table 40: Selected* Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-564

Laboratory Test* KEYTRUDA 200 mg every 3 weeks Placebo
All Grades‡ % Grades 3-4 % All Grades % Grades 3-4 %
Chemistry
Increased glucose 48 8 45 4.5
Increased creatinine 40 1.1 28 0.2
Increased INR 27 0.9 20 0.8
Hyponatremia 21 3.3 13 1.9
Increased ALT 20 3.8 11 0.2
Hematology
Anemia 28 0.5 20 0.4
* 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: 440 to 449 patients) and placebo (range: 461 to 469 patients); increased INR: KEYTRUDA n=228 and placebo n=254.
‡ Graded per NCI CTCAE v4.03

Endometrial Carcinoma

In Combination with Lenvatinib for the Treatment of Advanced Endometrial Carcinoma That is Not MSI-H or dMMR

The safety of KEYTRUDA in combination with lenvatinib was investigated in KEYNOTE-775, a multicenter, open-label, randomized (1:1), active-controlled trial in patients with advanced endometrial carcinoma previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings [see Clinical Studies]. Patients with endometrial carcinoma that is not MSI-H or dMMR received 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 these patients. The most common adverse reaction leading to discontinuation of KEYTRUDA (≥1%) was increased ALT (1.2%).

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

Tables 41 and 42 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in combination with lenvatinib in KEYNOTE-775.

Table 41: 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 0.9 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 disordersà 53 5 27 0.6
Metabolism
Decreased appetiteè 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 erythrodysesthesiaý 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
à 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
è Includes decreased appetite, early satiety
ð Includes proteinuria, protein urine present, hemoglobinuria
ø Includes urinary tract infection, cystitis, pyelonephritis
ý 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 42: 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 postbaseline 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

As a Single Agent for the Treatment of Advanced MSI-H or dMMR Endometrial Carcinoma

Among the 90 patients with MSI-H or dMMR endometrial carcinoma enrolled in KEYNOTE-158 [see Clinical Studies (14.15)] treated with KEYTRUDA as a single agent, the median duration of exposure to KEYTRUDA was 8.3 months (range: 1 day to 26.9 months). Adverse reactions occurring in patients with endometrial carcinoma were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent.

TMB-H Cancer

The safety of KEYTRUDA was investigated in 105 patients with TMB-H cancer enrolled in KEYNOTE-158 [see Clinical Studies]. The median duration of exposure to KEYTRUDA was 4.9 months (range: 0.03 to 35.2 months). 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 the 159 patients with advanced cSCC (recurrent or metastatic or locally advanced disease) enrolled in KEYNOTE-629 [see Clinical Studies], the median duration of exposure to KEYTRUDA was 6.9 months (range 1 day to 28.9 months). 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 2799 patients 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 with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) followed by surgery and continued adjuvant treatment with KEYTRUDA as 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 778 patients 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 chemotherapy followed by placebo as adjuvant treatment after surgery [see Clinical Studies].

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

Fatal adverse reactions occurred in 0.9% of patients receiving KEYTRUDA, including 1 each of adrenal crisis, 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 KEYTRUDA occurred 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 43 and 44 summarize the adverse reactions and laboratory abnormalities, respectively, in patients treated with KEYTRUDA in KEYNOTE-522.

Table 43: 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 and cyclophosphamide
† Graded per NCI CTCAE v4.0
‡ Includes asthenia, fatigue
§ Includes aphthous ulcer, cheilitis, lip pain, lip ulceration, mouth ulceration, mucosal inflammation, oral mucosal eruption, oral pain, stomatitis, tongue blistering, tongue ulceration
¶ Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness
# Includes dermatitis, 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, peripheral sensory neuropathy
β Includes cough, productive cough, upper-airway cough syndrome

Table 44: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients 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: 759 to 777 patients) and placebo in combination with chemotherapy followed by placebo (range: 378 to 389 patients).
† 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 of KEYTRUDA 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 not been previously treated with chemotherapy in the metastatic setting [see Clinical Studies]. A total of 596 patients (including 34 patients from a safety run-in) received KEYTRUDA 200 mg every 3 weeks in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin.

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

Fatal adverse reactions occurred in 2.5% of patients receiving KEYTRUDA in combination with chemotherapy, including cardio-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 permanent discontinuation of KEYTRUDA (≥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 of KEYTRUDA (≥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 45 and 46 summarize the adverse reactions and laboratory abnormalities in patients on KEYTRUDA in KEYNOTE-355.

Table 45: Adverse Reactions Occurring in ≥20% of Patients Receiving 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 46: 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 antibody formation 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, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to pembrolizumab in the studies described below with the incidences of antibodies in 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 2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every 2 or 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 no evidence 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 always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hepatobiliary: sclerosing cholangitis

DRUG INTERACTIONS

No Information provided

Read the entire FDA prescribing information for Keytruda (Pembrolizumab for Injection)

© Keytruda Patient Information is supplied by Cerner Multum, Inc. and Keytruda Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

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