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Keytruda

Last reviewed on RxList: 4/9/2021
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.

SLIDESHOW

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Keytruda Consumer Information

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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)

QUESTION

Self-examination is important in the detection of skin cancer. See Answer
Keytruda Professional Information

SIDE EFFECTS

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

  • Immune-mediated pneumonitis [see WARNINGS AND PRECAUTIONS].
  • Immune-mediated colitis [see WARNINGS AND PRECAUTIONS].
  • Immune-mediated hepatitis (KEYTRUDA) and hepatotoxicity (KEYTRUDA in combination with axitinib) [see WARNINGS AND PRECAUTIONS].
  • Immune-mediated endocrinopathies [see WARNINGS AND PRECAUTIONS].
  • Immune-mediated nephritis and renal dysfunction [see WARNINGS AND PRECAUTIONS].
  • Immune-mediated skin adverse reactions [see WARNINGS AND PRECAUTIONS].
  • Other 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 two randomized, open-label, active-controlled clinical trials (KEYNOTE-042 and KEYNOTE-024), which enrolled 790 patients with NSCLC; in a non-randomized, open-label, multi-cohort trial (KEYNOTE-012), a non-randomized, open-label, single-cohort trial (KEYNOTE-055), and two randomized, open-label, active-controlled trials (KEYNOTE-040 and KEYNOTE-048 single agent arms), which enrolled 909 patients with HNSCC; in two non-randomized, open-label trials (KEYNOTE-013 and KEYNOTE-087), which enrolled 241 patients with cHL; in combination with chemotherapy in a randomized, active-controlled trial (KEYNOTE-189), which enrolled 405 patients with nonsquamous NSCLC; in a randomized, open-label, active-controlled trial (KEYNOTE-048 combination arm), which enrolled 276 patients with HNSCC; in combination with axitinib in a randomized, active-controlled trial (KEYNOTE 426), which enrolled 429 patients with RCC; and in post-marketing use. Across all trials, KEYTRUDA was administered at 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.

The data described in this section were obtained in eleven randomized, controlled trials (KEYNOTE-002, KEYNOTE-006, KEYNOTE-010, KEYNOTE-042, KEYNOTE-045, KEYNOTE-177, KEYNOTE-048, KEYNOTE-189, KEYNOTE-407, KEYNOTE-181, and KEYNOTE-426) and twelve non-randomized, open-label trials (KEYNOTE-028, KEYNOTE-012, KEYNOTE-087, KEYNOTE-170, KEYNOTE-052, KEYNOTE-057, KEYNOTE-059, KEYNOTE-158, KEYNOTE-224, KEYNOTE-017, KEYNOTE-146, and KEYNOTE-629). The data described in this section also included a single randomized, double-blind, placebo-controlled trial (KEYNOTE-054) in which KEYTRUDA was administered for the adjuvant treatment of 509 patients with melanoma with involvement of lymph node(s) following complete surgical resection. In these trials, KEYTRUDA was administered at 2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every 2 or 3 weeks.

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 3 and 4 summarize selected adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-006.

Table 3: Selected* Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-006

Adverse Reaction KEYTRUDA 10 mg/kg every 2 or 3 weeks
n=555
Ipilimumab
n=256
All Grades† (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
General
Fatigue 28 0.9 28 3.1
Skin and Subcutaneous Tissue
Rash‡ 24 0.2 23 1.2
Vitiligo§ 13 0 2 0
Musculoskeletal and Connective Tissue
Arthralgia 18 0.4 10 1.2
Back pain 12 0.9 7 0.8
Respiratory, Thoracic and Mediastinal
Cough 17 0 7 0.4
Dyspnea 11 0.9 7 0.8
Metabolism and Nutrition
Decreased appetite 16 0.5 14 0.8
Nervous System
Headache 14 0.2 14 0.8
* Adverse reactions occurring at same or higher incidence than in the ipilimumab arm
† Graded per NCI CTCAE v4.0
‡ Includes rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo - papular, 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 4: 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 on-study laboratory measurement available: KEYTRUDA (520 to 546 patients) and ipilimumab (237 to 247 patients); hypertriglyceridemia: KEYTRUDA n=429 and ipilimumab n=183; hypercholesterolemia: KEYTRUDA n=484 and ipilimumab n=205.
‡ Graded per NCI CTCAE v4.0

Other laboratory abnormalities occurring in ≥20% of patients receiving KEYTRUDA were increased hypoalbuminemia (27% all Grades; 2.4% Grades 3-4), increased ALT (23% all Grades; 3.1% Grades 3­4), 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 5 and 6 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-002.

Table 5: 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 6: 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 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 7 and 8 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-054.

Table 7: 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 8: 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 9 and 10 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE­ 189.

Table 9: 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 10: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients in KEYNOTE-189

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

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

The safety of KEYTRUDA in combination with carboplatin and investigator's choice of either paclitaxel 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). Forty-eight percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA 200 mg for ≥6 months.

The study population characteristics were: median age of 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 11 and 12 summarize the adverse reactions and laboratory abnormalities, respectively, in patients treated with KEYTRUDA in KEYNOTE-042.

Table 11: 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 12: Laboratory Abnormalities Worsened from Baseline in ≥20% of Patients in KEYNOTE-042

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

Previously Treated NSCLC

The safety of KEYTRUDA was investigated in KEYNOTE-010, a multicenter, open-label, randomized (1:1:1), active-controlled trial, in patients with advanced NSCLC who had documented disease progression following treatment with platinum-based chemotherapy and, if positive for EGFR or ALK genetic aberrations, appropriate therapy for these aberrations [see Clinical Studies]. A total of 991 patients received KEYTRUDA 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 13 and 14 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-010.

Table 13: 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 14: 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 on-study laboratory measurement available: KEYTRUDA (range: 631 to 638 patients) and docetaxel (range: 274 to 277 patients).
‡ Graded per NCI CTCAE v4.0

Other laboratory abnormalities occurring in ≥20% of patients receiving KEYTRUDA were hyperglycemia (44% all Grades; 4.1% Grades 3-4), anemia (37% all Grades; 3.8% 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).

SCLC

Among the 131 patients with previously treated SCLC who received KEYTRUDA in KEYNOTE-158 Cohort G (n=107) and KEYNOTE-028 Cohort C1 (n=24) [see Clinical Studies], the median duration of exposure to KEYTRUDA was 2 months (range: 1 day to 2.25 years). Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with SCLC were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

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

Table 15: 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
ÞIncludes 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 Includes back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia

Table 16: 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].

cHL

Among the 210 patients with cHL enrolled in KEYNOTE-087 [see Clinical Studies], the median duration of exposure to KEYTRUDA was 8.4 months (range: 1 day to 15.2 months). KEYTRUDA was discontinued due to adverse reactions in 5% of patients, and treatment was interrupted due to adverse reactions in 26%. Fifteen percent (15%) of patients had an adverse reaction requiring systemic corticosteroid therapy. Serious adverse reactions occurred in 16% of patients. The most frequent serious adverse reactions (≥1%) included pneumonia, pneumonitis, pyrexia, dyspnea, graft versus host disease and herpes zoster. Two patients died from causes other than disease progression; one from GVHD after subsequent allogeneic HSCT and one from septic shock. Tables 17 and 18 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-087.

Table 17: Adverse Reactions in ≥10% of Patients with cHL 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, seborrhoeic dermatitis, dermatitis psoriasiform
β Includes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy

Other clinically important adverse reactions that occurred in less than 10% of patients on KEYNOTE-087 included infusion reactions (9%), hyperthyroidism (3%), pneumonitis (3%), uveitis and myositis (1% each), and myelitis and myocarditis (0.5% each).

Table 18: Selected Laboratory Abnormalities Worsened from Baseline Occurring in ≥15% of cHL Patients Receiving KEYTRUDA in KEYNOTE-087

Laboratory Test* 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 treated in KEYNOTE-170 [see Clinical Studies], the median duration of exposure to KEYTRUDA was 3.5 months (range: 1 day to 22.8 months).

KEYTRUDA was discontinued due to adverse reactions in 8% of patients, and treatment was interrupted due to adverse reactions in 15%. Twenty-five percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Serious adverse reactions occurred in 26% of patients, and 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. Tables 19 and 20 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-170.

Table 19: Adverse Reactions in ≥10% of Patients with PMBCL 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
Arrhythmia β 11 4
Nervous System
Headache 11 0
* Graded per NCI CTCAE v4.0
† Includes arthralgia, back pain, myalgia, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, bone pain, neck pain, non-cardiac chest pain
‡ Includes nasopharyngitis, pharyngitis, rhinorrhea, rhinitis, sinusitis, upper respiratory tract infection
§ Includes fatigue, asthenia
¶ Includes allergic cough, cough, productive cough
# Includes diarrhea, gastroenteritis
Þ Includes abdominal pain, abdominal pain upper
β Includes atrial fibrillation, sinus tachycardia, supraventricular tachycardia, tachycardia

Other clinically important adverse reactions that occurred in less than 10% of patients in KEYNOTE-170 included hypothyroidism (8%), hyperthyroidism and pericarditis (4% each), and thyroiditis, pericardial effusion, pneumonitis, arthritis and acute kidney injury (2% each).

Table 20: Laboratory Abnormalities Worsened from Baseline Occurring in≥15% of PMBCL Patients Receiving KEYTRUDA in KEYNOTE-170

Laboratory Test* 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

Cisplatin 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 were not eligible for cisplatin-containing chemotherapy. Patients with autoimmune disease or medical conditions that required systemic corticosteroids or other immunosuppressive medications were ineligible [see Clinical Studies]. Patients received KEYTRUDA 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 21 summarizes adverse reactions in patients on KEYTRUDA in KEYNOTE-052.

Table 21: 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 22 and 23 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-045.

Table 22: 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
Hematuriaa 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
aIncludes blood urine present, hematuria, chromaturia

Table 23: 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 24 and 25 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-057.

Table 24: 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
Rash1 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 25: 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

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

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

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 26 and 27 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-158.

Table 26: 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 pain1 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
UTI! 18 6
Infection (except UTI)e 16 4.1
Skin and Subcutaneous Tissue
Rashð 17 2.0
Endocrine
Hypothyroidism 11 0
Nervous System
Headache 11 2.0
Respiratory, Thoracic and Mediastinal
Dyspnea 10 1.0
* Graded per NCI CTCAE v4.0
† Includes asthenia, fatigue, lethargy, malaise
‡ Includes breast pain, cancer pain, dysesthesia, dysuria, ear pain, gingival pain, groin pain, lymph node pain, oropharyngeal pain, pain, pain of skin, pelvic pain, radicular pain, stoma site pain, toothache
§ Includes edema peripheral, peripheral swelling
¶ Includes arthralgia, back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, myositis, neck pain, non-cardiac chest pain, pain in extremity
# Includes colitis, diarrhea, gastroenteritis
Þ Includes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper
β Includes epistaxis, hematuria, hemoptysis, metrorrhagia, rectal hemorrhage, uterine hemorrhage, vaginal hemorrhage
a Includes bacterial pyelonephritis, pyelonephritis acute, urinary tract infection, urinary tract infection bacterial, urinary tract infection pseudomonal, urosepsis
e Includes cellulitis, clostridium difficile infection, device-related infection, empyema, erysipelas, herpes virus infection, infected neoplasm, infection, influenza, lower respiratory tract congestion, lung infection, oral candidiasis, oral fungal infection, osteomyelitis, pseudomonas infection, respiratory tract infection, tooth abscess, upper respiratory tract infection, uterine abscess, vulvovaginal candidiasis
ðIncludes dermatitis, drug eruption, eczema, erythema, palmar-plantar erythrodysesthesia syndrome, rash, rash generalized, rash maculo-papular

Table 27: 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

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 28 and 29 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 28: 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 erythrodysaesthesia syndrome 28 5 40 3.8
Stomatitis/Mucosal inflammation 27 1.6 41 4
Rash¶ 25 1.4 21 0.7
Respiratory, Thoracic and Mediastinal
Dysphonia 25 0.2 3.3 0
Cough 21 0.2 14 0.5
* Graded per NCI CTCAE v4.03
† Includes diarrhea, colitis, enterocolitis, gastroenteritis, enteritis, enterocolitis hemorrhagic
‡ Includes hypertension, blood pressure increased, hypertensive crisis, labile hypertension
§ Includes ALT increased, AST increased, autoimmune hepatitis, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic function abnormal, hepatitis, hepatitis fulminant, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, liver function test increased, liver injury, transaminases increased
¶ Includes rash, butterfly rash, dermatitis, dermatitis acneform, dermatitis atopic, dermatitis bullous, dermatitis contact, exfoliative rash, genital rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, seborrhoeric dermatitis, skin discoloration, skin exfoliation, perineal rash

Table 29: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA with Axitinib in KEYNOTE-426

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

Endometrial Carcinoma

The safety of KEYTRUDA in combination with lenvatinib (20 mg orally once daily) was investigated in KEYNOTE-146, a single-arm, multicenter, open-label trial in 94 patients with endometrial carcinoma whose tumors had progressed following one line of systemic therapy and were not MSI-H or dMMR [see Clinical Studies]. The median duration of study treatment was 7 months (range: 0.03 to 37.8 months). The median duration of exposure to KEYTRUDA was 6 months (range: 0.03 to 23.8 months). KEYTRUDA was continued for a maximum of 24 months; however, treatment with lenvatinib could be continued beyond 24 months.

Fatal adverse reactions occurred in 3% of patients receiving KEYTRUDA and lenvatinib, including gastrointestinal perforation, reversible posterior leukoencephalopathy syndrome (RPLS) with intraventricular hemorrhage, and intracranial hemorrhage.

Serious adverse reactions occurred in 52% of patients receiving KEYTRUDA and lenvatinib. Serious adverse reactions in ≥3% of patients were hypertension (9%), abdominal pain (6%), musculoskeletal pain (5%), hemorrhage (4%), fatigue (4%), nausea (4%), confusional state (4%), pleural effusion (4%), adrenal insufficiency (3%), colitis (3%), dyspnea (3%), and pyrexia (3%).

KEYTRUDA was discontinued for adverse reactions (Grade 1-4) in 19% of patients, regardless of action taken with lenvatinib. The most common adverse reactions (≥ 2%) leading to discontinuation of KEYTRUDA were adrenal insufficiency (2%), colitis (2%), pancreatitis (2%), and muscular weakness (2%).

Adverse reactions leading to interruption of KEYTRUDA occurred in 49% of patients; the most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were: fatigue (14%), diarrhea (6%), decreased appetite (6%), rash (5%), renal impairment (4%), vomiting (4%), increased lipase (4%), decreased weight (4%), nausea (3%), increased blood alkaline phosphatase (3%), skin ulcer (3%), adrenal insufficiency (2%), increased amylase (2%), hypocalcemia (2%), hypomagnesemia (2%), hyponatremia (2%), peripheral edema (2%), musculoskeletal pain (2%), pancreatitis (2%), and syncope (2%).

Tables 30 and 31 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in combination with lenvatinib.

Table 30: Adverse Reactions Occurring in ≥20% of Patients with Endometrial Carcinoma in KEYNOTE-146

Adverse Reaction KEYTRUDA 200 mg every 3 weeks with Lenvatinib
N=94
All Grades (%) Grades 3-4 (%)
General
Fatigue* 65 17
Musculoskeletal and Connective Tissue
Musculoskeletal pain† 65 3
Vascular
Hypertension‡ 65 38
Hemorrhagic events§ 28 4
Gastrointestinal
Diarrhea¶ 64 4
Nausea 48 5
Stomatitis# 43 0
Vomiting 39 0
Abdominal painÞ 33 6
Constipation 32 0
Metabolism
Decreased appetiteβ 52 0
Hypomagnesemia 27 3
Endocrine
Hypothyroidisma 51 1
Investigations
Decreased weight 36 3
Nervous System
Headache 33 1
Infections
Urinary tract infectione 31 4
Respiratory, Thoracic and Mediastinal
Dysphonia 29 0
Dyspneað 24 2
Cough 21 0
Skin and Subcutaneous Tissue
Palmar-plantar 26 3
erythrodysesthesia syndrome
Rashø 21 3
* Includes asthenia, fatigue, and malaise
† Includes arthralgia, arthritis, back pain, breast pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity
‡ Includes essential hypertension, hypertension, and hypertensive encephalopathy
§ Includes catheter site bruise, contusion, epistaxis, gastrointestinal hemorrhage, hematemesis, hematuria, hemorrhage intracranial, injection site hemorrhage, intraventricular hemorrhage, large intestinal hemorrhage, metrorrhagia, mouth hemorrhage, uterine hemorrhage, and vaginal hemorrhage
¶ Includes diarrhea, gastroenteritis, gastrointestinal viral infection, and viral diarrhea
# Includes glossitis, mouth ulceration, oral discomfort, oral mucosal blistering, oropharyngeal pain, and stomatitis
Þ Includes abdominal discomfort, abdominal pain, lower abdominal pain, and upper abdominal pain
ß Includes decreased appetite and early satiety
a Includes increased blood thyroid stimulating hormone and hypothyroidism
e Includes cystitis and urinary tract infection
ð Includes dyspnea and exertional dyspnea
øIncludes rash, rash generalized, rash macular, and rash maculo-papular

Table 31: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% (All Grades) or ≥3% (Grades 3-4) of Patients with Endometrial Carcinoma in KEYNOTE-146

Laboratory Test* KEYTRUDA 200 mg every 3 weeks with Lenvatinib
All Grades %† Grade 3-4 %†
Chemistry
Increased creatinine 80 7
Hypertriglyceridemia 58 4
Hyperglycemia 53 1
Hypercholesteremia 49 6
Hypoalbuminemia 48 0
Hypomagnesemia 47 2
Increased aspartate aminotransferase 43 4
Hyponatremia 42 13
Increased lipase 42 18
Increased alanine aminotransferase 35 3
Increased alkaline phosphatase 32 1
Hypokalemia 27 5
Increased amylase 19 6
Hypocalcemia 14 3
Hypermagnesemia 4 3
Hematology
Thrombocytopenia 48 0
Leukopenia 38 2
Lymphopenia 36 7
Anemia 35 1
Increased INR 21 3
Neutropenia 12 3
* With at least 1 grade increase from baseline
† Laboratory abnormality percentage is based on the number of patients who had both baseline and at least one post-baseline laboratory measurement for each parameter (range: 71 to 92 patients).

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 105 patients with cSCC enrolled in KEYNOTE-629 [see Clinical Studies], the median duration of exposure to KEYTRUDA was 5.8 months (range 1 day to 16.1 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 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 (11%).

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.

DRUG INTERACTIONS

No Information provided

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, single-cohort 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, active-controlled trial (KEYNOTE-048 combination arm), which enrolled 276 patients with HNSCC; in combination with axitinib in a randomized, active-controlled trial (KEYNOTE 426), which enrolled 429 patients with RCC; and in post-marketing use. Across all trials, KEYTRUDA was administered at 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
* Adverse reactions occurring at same or higher incidence than in the ipilimumab arm
† Graded per NCI CTCAE v4.0
‡ Includes rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo- papular, 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 on-study laboratory measurement available: KEYTRUDA (520 to 546 patients) and ipilimumab (237 to 247 patients); hypertriglyceridemia: KEYTRUDA n=429 and ipilimumab n=183; hypercholesterolemia: KEYTRUDA n=484 and ipilimumab n=205.
‡ Graded per NCI CTCAE v4.0

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

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

The safety of KEYTRUDA in combination with carboplatin and investigator's choice of either paclitaxel 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). Forty-eight percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA 200 mg for ≥6 months.

The study population characteristics were: median age of 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 on-study laboratory measurement available: KEYTRUDA (range: 598 to 610 patients) and chemotherapy (range: 588 to 597 patients); increased prothrombin INR: KEYTRUDA n=203 and chemotherapy n=173.
† Graded per NCI CTCAE v4.03

Previously Treated NSCLC

The safety of KEYTRUDA was investigated in KEYNOTE-010, a multicenter, open-label, randomized (1:1:1), active-controlled trial, in patients with advanced NSCLC who had documented disease progression following treatment with platinum-based chemotherapy and, if positive for EGFR or ALK genetic aberrations, appropriate therapy for these aberrations [see Clinical Studies]. A total of 991 patients received KEYTRUDA 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 Docetaxel
2 or 10 mg/kg every 3 weeks 75 mg/m² every 3 weeks
All Grades‡% Grades 3-4% All Grades‡% Grades 3-4%
Chemistry
Hyponatremia 32 8 27 2.9
Increased alkaline phosphatase 28 3.0 16 0.7
Increased AST 26 1.6 12 0.7
Increased ALT 22 2.7 9 0.4
* Laboratory abnormalities occurring at same or higher incidence than in docetaxel arm.
† Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 631 to 638 patients) and docetaxel (range: 274 to 277 patients).
‡ Graded per NCI CTCAE v4.0

Other laboratory abnormalities occurring in ≥20% of patients receiving KEYTRUDA were hyperglycemia (44% all Grades; 4.1% Grades 3-4), anemia (37% all Grades; 3.8% 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).

SCLC

Among the 131 patients with previously treated SCLC who received KEYTRUDA in KEYNOTE-158 Cohort G (n=107) and KEYNOTE-028 Cohort C1 (n=24) [see Clinical Studies], the median duration of exposure to KEYTRUDA was 2 months (range: 1 day to 2.25 years). Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with SCLC were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

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 7 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
a Includes back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia

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

Laboratory Test* KEYTRUDA 200 mg every 3 weeks KEYTRUDA 200 mg every 3 weeks Platinum FU Cetuximab Platinum FU
All Grades†(%) Grades 34 (%) All Grades† (%) Grades 34 (%) All Grades† (%) Grades 3-4 (%)
Hematology
Lymphopenia 54 25 69 35 74 45
Anemia 52 7 89 28 78 19
Thrombocytopenia 12 3.8 73 18 76 18
Neutropenia 7 1.4 67 35 71 42
Chemistry
Hyperglycemia 47 3.8 55 6 66 4.7
Hyponatremia 46 17 56 20 59 20
Hypoalbuminemia 44 3.2 47 4.0 49 1.1
Increased AST 28 3.1 24 2.0 37 3.6
Increased ALT 25 2.1 22 1.6 38 1.8
Increased alkaline phosphatase 25 2.1 27 1.2 33 1.1
Hypercalcemia 22 4.6 16 4.3 13 2.6
Hypocalcemia 22 1.1 32 4 58 7
Hyperkalemia 21 2.8 27 4.3 29 4.3
Hypophosphatemia 20 5 35 12 48 19
Hypokalemia 19 5 34 12 47 15
Increased creatinine 18 1.1 36 2.3 27 2.2
Hypomagnesemia 16 0.4 42 1.7 76 6
* Each test incidence is based on the number of patients who had both baseline and at least one on-study 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 adverse reactions in ≥1% included pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three patients (2%) died from causes other than disease progression: two from complications after allogeneic HSCT and one from unknown cause.

Permanent discontinuation of KEYTRUDA due to an adverse reaction 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
Dyspneað 11 0.7 7 0.7
Endocrine
Hypothyroidism 19 0 3 0
Nervous System
Peripheral neuropathyø 11 0.7 43 7
Headachey 11 0 11 0
* Graded per NCI CTCAE v4.0
† Adverse reactions in BV arm were Grade 3 only.
‡ Includes acute sinusitis, nasopharyngitis, pharyngitis, pharyngotonsillitis, rhinitis, sinusitis, sinusitis bacterial, tonsillitis, upper 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
Þ Includes fatigue, asthenia
β Includes dermatitis acneiform, dermatitis atopic, dermatitis allergic, dermatitis contact, dermatitis exfoliative, dermatitis psoriasiform, eczema, rash, rash erythematous, rash follicular, rash maculo-papular, rash papular, rash pruritic, toxic skin eruption
a Includes cough, productive cough
ð Includes pneumonitis, interstitial lung disease
ð Includes dyspnea, dyspnea exertional, wheezing
ø Includes dysaesthesia, hypoaesthesia, neuropathy peripheral, paraesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, polyneuropathy
y 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, seborrhoeic 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 fromBaseline 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 painÞ 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

Cisplatin 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 were not eligible for cisplatin-containing chemotherapy. Patients with autoimmune disease or medical conditions that required systemic corticosteroids or other immunosuppressive medications were ineligible [see Clinical Studies ]. Patients received KEYTRUDA 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 a 12 2.3 8 1.6
* Chemotherapy: paclitaxel, docetaxel, or vinflunine
† Graded per NCI CTCAE v4.0
‡ Includes asthenia, fatigue, malaise, lethargy
§ Includes back pain, myalgia, bone pain, musculoskeletal pain, pain in extremity, musculoskeletal 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
a Includes blood urine present, hematuria, chromaturia

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

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

BCG-unresponsive High-risk NMIBC

The safety of KEYTRUDA was investigated in KEYNOTE-057, a multicenter, open-label, single-arm trial that enrolled 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

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

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

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 29 and 30 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-158.

Table 29: 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
UTIa 18 6
Infection (except UTI)e 16 4.1
Skin and Subcutaneous Tissue
Rashð 17 2.0
Endocrine
Hypothyroidism 11 0
Nervous System
Headache 11 2.0
Respiratory, Thoracic and Mediastinal
Dyspnea 10 1.0
* Graded per NCI CTCAE v4.0
† Includes asthenia, fatigue, lethargy, malaise
‡ Includes breast pain, cancer pain, dysesthesia, dysuria, ear pain, gingival pain, groin pain, lymph node pain, oropharyngeal pain, pain, pain of skin, pelvic pain, radicular pain, stoma site pain, toothache
§ Includes edema peripheral, peripheral swelling
¶ Includes arthralgia, back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, myositis, neck pain, non-cardiac chest pain, pain in extremity
# Includes colitis, diarrhea, gastroenteritis
Þ Includes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper
β Includes epistaxis, hematuria, hemoptysis, metrorrhagia, rectal hemorrhage, uterine hemorrhage, vaginal hemorrhage
a Includes bacterial pyelonephritis, pyelonephritis acute, urinary tract infection, urinary tract infection bacterial, urinary tract infection pseudomonal, urosepsis
e Includes cellulitis, clostridium difficile infection, device-related infection, empyema, erysipelas, herpes virus infection, infected neoplasm, infection, influenza, lower respiratory tract congestion, lung infection, oral candidiasis, oral fungal infection, osteomyelitis, pseudomonas infection, respiratory tract infection, tooth abscess, upper respiratory tract infection, uterine abscess, vulvovaginal candidiasis
ðIncludes dermatitis, drug eruption, eczema, erythema, palmar-plantar erythrodysesthesia syndrome, rash, rash generalized, rash maculo-papular

Table 30: 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

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 31 and 32 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 31: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA with Axitinib in KEYNOTE-426

Adverse Reaction KEYTRUDA200 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 erythrodysaesthesia syndrome 28 5 40 3.8
Stomatitis/Mucosal inflammation 27 1.6 41 4
Rash¶ 25 1.4 21 0.7
Respiratory, Thoracic and Mediastinal
Dysphonia 25 0.2 3.3 0
Cough 21 0.2 14 0.5
* Graded per NCI CTCAE v4.03
† Includes diarrhea, colitis, enterocolitis, gastroenteritis, enteritis, enterocolitis hemorrhagic
‡ Includes hypertension, blood pressure increased, hypertensive crisis, labile hypertension
§ Includes ALT increased, AST increased, autoimmune hepatitis, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic function abnormal, hepatitis, hepatitis fulminant, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, liver function test increased, liver injury, transaminases increased
¶ Includes rash, butterfly rash, dermatitis, dermatitis acneform, dermatitis atopic, dermatitis bullous, dermatitis contact, exfoliative rash, genital rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, seborrhoeric dermatitis, skin discoloration, skin exfoliation, perineal rash

Table 32: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA with Axitinib in KEYNOTE-426

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

Endometrial Carcinoma

The safety of KEYTRUDA in combination with lenvatinib (20 mg orally once daily) was investigated in KEYNOTE-146, a single-arm, multicenter, open-label trial in 94 patients with endometrial carcinoma whose tumors had progressed following one line of systemic therapy and were not MSI-H or dMMR [see Clinical Studies]. The median duration of study treatment was 7 months (range: 0.03 to 37.8 months). The median duration of exposure to KEYTRUDA was 6 months (range: 0.03 to 23.8 months). KEYTRUDA was continued for a maximum of 24 months; however, treatment with lenvatinib could be continued beyond 24 months.

Fatal adverse reactions occurred in 3% of patients receiving KEYTRUDA and lenvatinib, including gastrointestinal perforation, reversible posterior leukoencephalopathy syndrome (RPLS) with intraventricular hemorrhage, and intracranial hemorrhage.

Serious adverse reactions occurred in 52% of patients receiving KEYTRUDA and lenvatinib. Serious adverse reactions in ≥3% of patients were hypertension (9%), abdominal pain (6%), musculoskeletal pain (5%), hemorrhage (4%), fatigue (4%), nausea (4%), confusional state (4%), pleural effusion (4%), adrenal insufficiency (3%), colitis (3%), dyspnea (3%), and pyrexia (3%).

KEYTRUDA was discontinued for adverse reactions (Grade 1-4) in 19% of patients, regardless of action taken with lenvatinib. The most common adverse reactions (≥ 2%) leading to discontinuation of KEYTRUDA were adrenal insufficiency (2%), colitis (2%), pancreatitis (2%), and muscular weakness (2%).

Adverse reactions leading to interruption of KEYTRUDA occurred in 49% of patients; the most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were: fatigue (14%), diarrhea (6%), decreased appetite (6%), rash (5%), renal impairment (4%), vomiting (4%), increased lipase (4%), decreased weight (4%), nausea (3%), increased blood alkaline phosphatase (3%), skin ulcer (3%), adrenal insufficiency (2%), increased amylase (2%), hypocalcemia (2%), hypomagnesemia (2%), hyponatremia (2%), peripheral edema (2%), musculoskeletal pain (2%), pancreatitis (2%), and syncope (2%).

Tables 33 and 34 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in combination with lenvatinib.

Table 33: Adverse Reactions Occurring in ≥20% of Patients with Endometrial Carcinoma in KEYNOTE-146

Adverse Reaction KEYTRUDA 200 mg every 3 weeks with Lenvatinib
N=94
All Grades (%) Grades 3-4 (%)
General
Fatigue* 65 17
Musculoskeletal and Connective Tissue
Musculoskeletal pain† 65 3
Vascular
Hypertension‡ 65 38
Hemorrhagic events§ 28 4
Gastrointestinal
Diarrhea¶ 64 4
Nausea 48 5
Stomatitis# 43 0
Vomiting 39 0
Abdominal painÞ 33 6
Constipation 32 0
Metabolism
Decreased appetiteβ 52 0
Hypomagnesemia 27 3
Endocrine
Hypothyroidisma 51 1
Investigations
Decreased weight 36 3
Nervous System
Headache 33 1
Infections
Urinary tract infectione 31 4
Respiratory, Thoracic and Mediastinal
Dysphonia 29 0
Dyspneað 24 2
Cough 21 0
Skin and Subcutaneous Tissue
Palmar-plantar erythrodysesthesia syndrome 26 3
Rashø 21 3
* Includes asthenia, fatigue, and malaise
† Includes arthralgia, arthritis, back pain, breast pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity
‡ Includes essential hypertension, hypertension, and hypertensive encephalopathy
§ Includes catheter site bruise, contusion, epistaxis, gastrointestinal hemorrhage, hematemesis, hematuria, hemorrhage intracranial, injection site hemorrhage, intraventricular hemorrhage, large intestinal hemorrhage, metrorrhagia, mouth hemorrhage, uterine hemorrhage, and vaginal hemorrhage
¶ Includes diarrhea, gastroenteritis, gastrointestinal viral infection, and viral diarrhea
# Includes glossitis, mouth ulceration, oral discomfort, oral mucosal blistering, oropharyngeal pain, and stomatitis
Þ Includes abdominal discomfort, abdominal pain, lower abdominal pain, and upper abdominal painβ Includes decreased appetite and early satiety à Includes increased blood thyroid stimulating hormone and hypothyroidism
e Includes cystitis and urinary tract infection
o Includes dyspnea and exertional dyspnea ø Includes rash, rash generalized, rash macular, and rash maculo-papular

Table 34: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% (All Grades) or ≥3% (Grades 3-4) of Patients with Endometrial Carcinoma in KEYNOTE-146

Laboratory Test* KEYTRUDA 200 mg every 3 weeks with Lenvatinib
All Grades %† Grade 3-4 %†
Chemistry
Increased creatinine 80 7
Hypertriglyceridemia 58 4
Hyperglycemia 53 1
Hypercholesteremia 49 6
Hypoalbuminemia 48 0
Hypomagnesemia 47 2
Increased aspartate aminotransferase 43 4
Hyponatremia 42 13
Increased lipase 42 18
Increased alanine aminotransferase 35 3
Increased alkaline phosphatase 32 1
Hypokalemia 27 5
Increased amylase 19 6
Hypocalcemia 14 3
Hypermagnesemia 4 3
Hematology
Thrombocytopenia 48 0
Leukopenia 38 2
Lymphopenia 36 7
Anemia 35 1
Increased INR 21 3
Neutropenia 12 3
* With at least 1 grade increase from baseline
† Laboratory abnormality percentage is based on the number of patients who had both baseline and at least one post-baseline laboratory measurement for each parameter (range: 71 to 92 patients).

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 105 patients with cSCC enrolled in KEYNOTE-629 [see Clinical Studies], the median duration of exposure to KEYTRUDA was 5.8 months (range 1 day to 16.1 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 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 (11%).

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 35 and 36 summarize the adverse reactions and laboratory abnormalities in patients on KEYTRUDA in KEYNOTE-355.

Table 35: Adverse Reactions Occurring in ≥20% of PatientsReceiving KEYTRUDA with Chemotherapy in KEYNOTE-355

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

Table 36: 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.

DRUG INTERACTIONS

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