KEYTRUDA (Page 5 of 23)
5.2 Infusion-Related Reactions
KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. For severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions, stop infusion and permanently discontinue KEYTRUDA [see Dosage and Administration (2.3)].
5.3 Complications of Allogeneic HSCT
Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT.
Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT.
5.4 Increased Mortality in Patients with Multiple Myeloma when KEYTRUDA is Added to a Thalidomide Analogue and Dexamethasone
In two randomized trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled trials.
5.5 Embryo-Fetal Toxicity
Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Animal models link the PD-1/PD-L1 signaling pathway with maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with KEYTRUDA and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3)].
6 ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling.
- Severe and fatal immune-mediated adverse reactions [see Warnings and Precautions (5.1)].
- Infusion-related reactions [see Warnings and Precautions (5.2)].
6.1 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 randomized, placebo-controlled trial (KEYNOTE-091), which enrolled 580 patients with resected NSCLC, 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 (14.1)]. 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.
Adverse Reaction | KEYTRUDA10 mg/kg every 2 or 3 weeks | Ipilimumab | ||
---|---|---|---|---|
n=555 | 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 |
Other clinically important adverse reactions occurring in ≥10% of patients receiving KEYTRUDA were diarrhea (26%), nausea (21%), and pruritus (17%).
Laboratory Test † | KEYTRUDA10 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 |
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 (14.1)]. 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.
Adverse Reaction | KEYTRUDA2 mg/kg or 10 mg/kg every 3 weeks | Chemotherapy † | ||
---|---|---|---|---|
n=357 | 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 |
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%).
Laboratory Test † | KEYTRUDA2 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 |
Other laboratory abnormalities occurring in ≥20% of patients receiving KEYTRUDA were anemia (44% all Grades; 10% Grades 3-4) and lymphopenia (40% all Grades; 9% Grades 3-4).
Adjuvant Treatment of Resected Stage IIB or IIC Melanoma
Among the 969 patients with Stage IIB or IIC melanoma enrolled in KEYNOTE-716 [see Clinical Studies (14.1)] treated with KEYTRUDA, the median duration of exposure to KEYTRUDA was 9.9 months (range: 0 to 15.4 months). Patients with autoimmune disease or a medical condition that required immunosuppression or mucosal or ocular melanoma were ineligible. Adverse reactions occurring in patients with Stage IIB or IIC melanoma were similar to those occurring in 1011 patients with Stage III melanoma from KEYNOTE-054 or the 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent.
Adjuvant Treatment of Stage III Resected Melanoma
The safety of KEYTRUDA as a single agent was investigated in KEYNOTE-054, a randomized (1:1) double-blind trial in which 1019 patients with completely resected Stage IIIA (>1 mm lymph node metastasis), IIIB or IIIC melanoma received 200 mg of KEYTRUDA by intravenous infusion every 3 weeks (n=509) or placebo (n=502) for up to one year [see Clinical Studies (14.1)]. 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.
Adverse Reaction | KEYTRUDA200 mg every 3 weeksn=509 | Placebon=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 |
Laboratory Test † | KEYTRUDA200 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 |
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 (14.2)]. 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.
Adverse Reaction | KEYTRUDA 200 mg every 3 weeksPemetrexed Platinum Chemotherapyn=405 | PlaceboPemetrexedPlatinum Chemotherapyn=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 |
Laboratory Test * | KEYTRUDA 200 mg every 3 weeksPemetrexed 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 |
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 (14.2)]. 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 (14.2)]. 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.
Adverse Reaction | KEYTRUDA200 mg every 3 weeksn=636 | Chemotherapyn=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 |
Laboratory Test * | KEYTRUDA200 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 |
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 (14.2)]. 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.
Adverse Reaction | KEYTRUDA2 or 10 mg/kg every 3 weeksn=682 | Docetaxel75 mg/m2 every 3 weeksn=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 |
Other clinically important adverse reactions occurring in patients receiving KEYTRUDA were fatigue (25%), diarrhea (14%), asthenia (11%) and pyrexia (11%).
Laboratory Test † | KEYTRUDA2 or 10 mg/kg every 3 weeks | Docetaxel75 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 |
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).
Neoadjuvant and Adjuvant Treatment of Resectable NSCLC
The safety of KEYTRUDA in combination with neoadjuvant platinum-containing chemotherapy followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent after surgery was investigated in KEYNOTE-671, a multicenter, randomized (1:1), double-blind, placebo-controlled trial in patients with previously untreated and resectable Stage II, IIIA, or IIIB (N2) NSCLC by AJCC 8th edition [see Clinical Studies (14.2)]. Patients with active autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible.
The median duration of exposure to KEYTRUDA 200 mg every 3 weeks was 10.9 months (range: 1 day to 18.6 months). The study population characteristics were: median age of 64 years (range: 26 to 83), 45% age 65 or older, 7% age 75 or older; 71% male; 61% White, 31% Asian, 2% Black, 4% race not reported; 9% Hispanic or Latino.
Adverse reactions occurring in patients with resectable NSCLC receiving KEYTRUDA in combination with platinum containing chemotherapy, given as neoadjuvant treatment and continued as single agent adjuvant treatment, were generally similar to those occurring in patients in other clinical trials across tumor types receiving KEYTRUDA in combination with chemotherapy.
Neoadjuvant Phase of KEYNOTE-671
A total of 396 patients received at least 1 dose of KEYTRUDA in combination with platinum-containing chemotherapy as neoadjuvant treatment and 399 patients received at least 1 dose of placebo in combination with platinum-containing chemotherapy as neoadjuvant treatment.
Serious adverse reactions occurred in 34% of patients who received KEYTRUDA in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (≥2%) serious adverse reactions were pneumonia (4.8%), venous thromboembolism (3.3%), and anemia (2%). Fatal adverse reactions occurred in 1.3% of patients, including death due to unknown cause (0.8%), sepsis (0.3%), and immune-mediated lung disease (0.3%).
Permanent discontinuation of any study drug due to an adverse reaction occurred in 18% of patients who received KEYTRUDA in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (≥1%) adverse reactions that led to permanent discontinuation of any study drug were acute kidney injury (1.8%), interstitial lung disease (1.8%), anemia (1.5%), neutropenia (1.5%), and pneumonia (1.3%).
Of the 396 KEYTRUDA-treated patients and 399 placebo-treated patients who received neoadjuvant treatment, 6% (n=25) and 4.3% (n=17), respectively, did not receive surgery due to adverse reactions. The most frequent (≥1%) adverse reactions that led to cancellation of surgery in the KEYTRUDA arm was interstitial lung disease (1%).
Of the 325 KEYTRUDA-treated patients who received surgery, 3.1% (n=10) experienced delay of surgery (surgery more than 8 weeks from last neoadjuvant treatment if patient received less than 4 cycles of neoadjuvant therapy or more than 20 weeks after first dose of neoadjuvant treatment if patient received 4 cycles of neoadjuvant therapy) due to adverse reactions. Of the 317 placebo-treated patients who received surgery, 2.5% (n=8) experienced delay of surgery due to adverse reactions.
Of the 325 KEYTRUDA-treated patients who received surgery, 7% (n=22) did not receive adjuvant treatment due to adverse reactions. Of the 317 placebo-treated patients who received surgery, 3.2% (n=10) did not receive adjuvant treatment due to adverse reactions.
Adjuvant Phase of KEYNOTE-671
A total of 290 patients in the KEYTRUDA arm and 267 patients in the placebo arm received at least 1 dose of adjuvant treatment.
Of the patients who received single agent KEYTRUDA as adjuvant treatment, 14% experienced serious adverse reactions; the most frequent serious adverse reaction was pneumonia (3.4%). One fatal adverse reaction of pulmonary hemorrhage occurred. Permanent discontinuation of adjuvant KEYTRUDA due to an adverse reaction occurred in 12% of patients; the most frequent (≥1%) adverse reactions that led to permanent discontinuation of adjuvant KEYTRUDA were diarrhea (1.7%), interstitial lung disease (1.4%), AST increased (1%), and musculoskeletal pain (1%).
Adjuvant Treatment of Resected NSCLC
The safety of KEYTRUDA as a single agent was investigated in KEYNOTE-091, a multicenter, randomized (1:1), triple-blind, placebo-controlled trial in patients with completely resected Stage IB (T2a ≥4 cm), II, or IIIA NSCLC; adjuvant chemotherapy up to 4 cycles was optional [see Clinical Studies (14.2)]. A total of 1161 patients received KEYTRUDA 200 mg (n=580) or placebo (n=581) every 3 weeks. Patients were ineligible if they had active autoimmune disease, were on chronic immunosuppressive agents, or had a history of interstitial lung disease or pneumonitis.
The median duration of exposure to KEYTRUDA was 11.7 months (range: 1 day to 18.9 months). Sixty-eight percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA for ≥6 months.
The adverse reactions observed in KEYNOTE-091 were generally similar to those occurring in other patients with NSCLC receiving KEYTRUDA as a single agent, with the exception of hypothyroidism (22%), hyperthyroidism (11%), and pneumonitis (7%). Two fatal adverse reactions of myocarditis occurred.
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 (14.3)]. 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.
KEYTRUDA 200 mg every 3 weeks | KEYTRUDA 200 mg every 3 weeks Platinum FU | Cetuximab Platinum FU | ||||
---|---|---|---|---|---|---|
Adverse Reaction | n=300 | n=276 | 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 | ||||||
Pneumonia Þ | 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 neuropathy ß | 1 | 0 | 14 | 1.1 | 7 | 1 |
Musculoskeletal | ||||||
Myalgia à | 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 |
KEYTRUDA 200 mg every 3 weeks | KEYTRUDA 200 mg every 3 weeks Platinum FU | Cetuximab Platinum FU | ||||
---|---|---|---|---|---|---|
Laboratory Test * | All Grades †(%) | Grades 3-4(%) | All Grades †(%) | Grades 3-4(%) | 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 |
Previously treated recurrent or metastatic HNSCC
Among the 192 patients with HNSCC enrolled in KEYNOTE-012 [see Clinical Studies (14.3)] , 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 (5.1)].
Relapsed or Refractory cHL
KEYNOTE-204
The safety of KEYTRUDA was evaluated in KEYNOTE-204 [see Clinical Studies (14.4)]. 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.
Adverse Reaction | KEYTRUDA200 mg every 3 weeksN=148 | Brentuximab Vedotin1.8 mg/kg every 3 weeksN=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 |
Fatigue Þ | 20 | 0 | 22 | 0.7 |
Skin and Subcutaneous Tissue | ||||
Rash ß | 20 | 0 | 19 | 0.7 |
Pruritus | 18 | 0 | 12 | 0 |
Respiratory, Thoracic and Mediastinal | ||||
Cough à | 20 | 0.7 | 14 | 0.7 |
Pneumonitis è | 11 | 5 | 3 | 1.3 |
Dyspnea ð | 11 | 0.7 | 7 | 0.7 |
Endocrine | ||||
Hypothyroidism | 19 | 0 | 3 | 0 |
Nervous System | ||||
Peripheral neuropathy ø | 11 | 0.7 | 43 | 7 |
Headache ý | 11 | 0 | 11 | 0 |
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.
Laboratory Abnormality * | KEYTRUDA200 mg every 3 weeks | Brentuximab Vedotin1.8 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 |
KEYNOTE-087
Among the 210 patients with cHL who received KEYTRUDA in KEYNOTE-087 [see Clinical Studies (14.4)] , 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.
Adverse Reaction | KEYTRUDA200 mg every 3 weeksN=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 | ||
Rash Þ | 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 neuropathy ß | 10 | 0 |
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).
Laboratory Abnormality * | KEYTRUDA200 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 |
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 (14.5)], 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.
Adverse Reaction | KEYTRUDA200 mg every 3 weeksN=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 ß | 11 | 4 |
Nervous System | ||
Headache | 11 | 0 |
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).
Laboratory Abnormality * | KEYTRUDA200 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 |
Urothelial Carcinoma
Cisplatin-ineligible patients with urothelial carcinoma in combination with enfortumab vedotin
The safety of KEYTRUDA in combination with enfortumab vedotin was investigated in KEYNOTE-869 in patients with locally advanced or metastatic urothelial carcinoma and who are not eligible for cisplatin-based chemotherapy [see Clinical Studies (14.6)]. A total of 121 patients received KEYTRUDA 200 mg on Day 1, and enfortumab vedotin 1.25 mg/kg on days 1 and 8 of each 21-day cycle. The median duration of exposure to KEYTRUDA was 6.9 months (range 1 day to 29.6 months).
Fatal adverse reactions occurred in 5% of patients treated with KEYTRUDA in combination with enfortumab vedotin, including sepsis (1.6%), bullous dermatitis (0.8%), myasthenia gravis (0.8%), and pneumonitis (0.8%).
Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA and enfortumab vedotin. Serious adverse reactions in ≥2% of patients receiving KEYTRUDA in combination with enfortumab vedotin were acute kidney injury (7%), urinary tract infection (7%), urosepsis (5%), hematuria (3.3%), pneumonia (3.3%), pneumonitis (3.3%), sepsis (3.3%), anemia (2.5%), diarrhea (2.5%), hypotension (2.5%), myasthenia gravis (2.5%), myositis (2.5%), and urinary retention (2.5%).
Permanent discontinuation of KEYTRUDA occurred in 32% of patients. The most common adverse reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA were pneumonitis (5%), peripheral neuropathy (5%), rash (3.3%), and myasthenia gravis (2.5%).
Dose interruptions of KEYTRUDA occurred in 69% of patients. The most common adverse reactions (≥2%) resulting in interruption of KEYTRUDA were peripheral neuropathy (22%), rash (17%), neutropenia (7%), fatigue (6%), diarrhea (5%), lipase increased (5%), acute kidney injury (3.3%), ALT increased (2.5%), and COVID-19 (2.5%).
Tables 24 and 25 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in combination with enfortumab vedotin in KEYNOTE-869.
Adverse Reaction | KEYTRUDA in combination with EnfortumabVedotinn=121 | |
---|---|---|
All Grades *% | Grade 3-4% | |
| ||
Skin and subcutaneous tissue disorders | ||
Rash † | 71 | 21 |
Alopecia | 52 | 0 |
Pruritus | 40 | 3.3 |
Dry skin | 21 | 0.8 |
Nervous system disorders | ||
Peripheral neuropathy ‡ | 65 | 3.3 |
Dysgeusia | 35 | 0 |
Dizziness | 23 | 0 |
General disorders and administration site conditions | ||
Fatigue | 60 | 11 |
Peripheral edema | 26 | 0 |
Investigations | ||
Weight loss | 48 | 5 |
Gastrointestinal disorders | ||
Diarrhea | 45 | 7 |
Nausea | 36 | 0.8 |
Constipation | 27 | 0 |
Metabolism and nutrition disorders | ||
Decreased appetite | 38 | 0.8 |
Infections and infestations | ||
Urinary tract infection | 30 | 12 |
Eye disorders | ||
Dry eye | 25 | 0 |
Musculoskeletal and connective tissue disorders | ||
Arthralgia | 23 | 1.7 |
Clinically relevant adverse reactions (<20%) include vomiting (19.8%), fever (18%), hypothyroidism (11%), pneumonitis (9%), myositis (3.3%), myasthenia gravis (2.5%), and infusion site extravasation (0.8%).
Laboratory Test * | KEYTRUDA200 mg every 3 weeks andEnfortumab Vedotin | |
---|---|---|
All Grades †% | Grades 3-4% | |
Chemistry | ||
Hyperglycemia | 74 | 13 |
Increased aspartate aminotransferase | 73 | 9 |
Increased creatinine | 69 | 3.3 |
Hyponatremia | 60 | 19 |
Increased alanine aminotransferase | 60 | 7 |
Increased lipase | 59 | 32 |
Hypoalbuminemia | 59 | 4.2 |
Hypophosphatemia | 51 | 15 |
Hypokalemia | 35 | 8 |
Increased potassium | 27 | 1.7 |
Increased calcium | 27 | 4.2 |
Hematology | ||
Anemia | 69 | 15 |
Lymphopenia | 64 | 17 |
Neutropenia | 32 | 12 |
Platinum-Ineligible Patients with Urothelial Carcinoma
The safety of KEYTRUDA was investigated in KEYNOTE-052, a single-arm trial that enrolled 370 patients with locally advanced or metastatic urothelial carcinoma who had one or more comorbidities. Patients with autoimmune disease or medical conditions that required systemic corticosteroids or other immunosuppressive medications were ineligible [see Clinical Studies (14.6)]. 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 26 summarizes adverse reactions in patients on KEYTRUDA in KEYNOTE-052.
Adverse Reaction | KEYTRUDA200 mg every 3 weeksN=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 | ||
Rash Þ | 21 | 0.5 |
Pruritus | 19 | 0.3 |
Edema peripheral ß | 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 |
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 (14.6)]. 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 27 and 28 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-045.
Adverse Reaction | KEYTRUDA200 mg every 3 weeks | Chemotherapy * | ||
---|---|---|---|---|
n=266 | 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 |
Infections | ||||
Urinary tract infection | 15 | 4.9 | 14 | 4.3 |
Metabolism and Nutrition | ||||
Decreased appetite | 21 | 3.8 | 21 | 1.2 |
Respiratory, Thoracic and Mediastinal | ||||
Cough Þ | 15 | 0.4 | 9 | 0 |
Dyspnea ß | 14 | 1.9 | 12 | 1.2 |
Renal and Urinary | ||||
Hematuria à | 12 | 2.3 | 8 | 1.6 |
Laboratory Test * | KEYTRUDA200 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 |
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 29 and 30 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-057.
Adverse Reaction | KEYTRUDA200 mg every 3 weeksN=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 | ||
Cough Þ | 19 | 0 |
Infections | ||
Urinary tract infection | 12 | 2.0 |
Nasopharyngitis | 10 | 0 |
Endocrine | ||
Hypothyroidism | 11 | 0 |
Laboratory Test * | KEYTRUDA200 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 |
Microsatellite Instability-High or Mismatch Repair Deficient Cancer
The safety of KEYTRUDA was investigated in 504 patients with MSI-H or dMMR cancer enrolled in KEYNOTE-158, KEYNOTE-164, and KEYNOTE-051 [see Clinical Studies (14.7)]. The median duration of exposure to KEYTRUDA was 6.2 months (range: 1 day to 53.5 months). Adverse reactions occurring in patients with MSI-H or dMMR cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.
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 (14.8)] 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
First-line Treatment of Locally Advanced Unresectable or Metastatic HER2-Positive Gastric or Gastroesophageal Junction Adenocarcinoma
The safety of KEYTRUDA was evaluated in 433 patients with HER2-positive gastric or GEJ cancer enrolled in KEYNOTE-811, which included 217 patients treated with KEYTRUDA 200 mg, trastuzumab, and CAPOX (n=189) or FP (n=28) every 3 weeks, compared to 216 patients treated with placebo, trastuzumab, and CAPOX (n=187) or FP (n=29) every 3 weeks [see Clinical Studies (14.9)].
The median duration of exposure to KEYTRUDA was 5.8 months (range: 1 day to 17.7 months).
The study population characteristics were: median age of 63 years (range: 19 to 84), 43% age 65 or older; 81% male; 58% White, 35% Asian, and 0.9% Black; 44% ECOG PS of 0 and 56% ECOG PS of 1.
KEYTRUDA and placebo were discontinued due to adverse reactions in 6% of patients in each arm. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 58% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were neutropenia (18%), thrombocytopenia (12%), diarrhea (6%), anemia (3.7%), hypokalemia (3.7%), fatigue/asthenia (3.2%), decreased appetite (3.2%), increased AST (2.8%), increased blood bilirubin (2.8%), pneumonia (2.8%), increased ALT (2.3%), and vomiting (2.3%).
In the KEYTRUDA arm versus placebo, there was a difference of ≥5% incidence between patients treated with KEYTRUDA versus standard of care for diarrhea (53% vs 44%) and nausea (49% vs 44%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms.
There was a difference of ≥5% incidence between patients treated with KEYTRUDA versus standard of care for increased ALT (34% vs 29%) and increased creatinine (20% vs 10%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms.
First-line Treatment of Locally Advanced Unresectable or Metastatic HER2-Negative Gastric or Gastroesophageal Junction Adenocarcinoma
The safety of KEYTRUDA was evaluated in 1572 patients with HER2-negative gastric or GEJ cancer enrolled in KEYNOTE-859, which included 785 patients treated with KEYTRUDA 200 mg and FP (n=106) or CAPOX (n=674) every 3 weeks, compared to 787 patients who received placebo and FP (n=107) or CAPOX (n=679) every 3 weeks [see Clinical Studies (14.9)].
The median duration of exposure to KEYTRUDA was 6.2 months (range: 1 day to 33.7 months).
Serious adverse reactions occurred in 45% of patients receiving KEYTRUDA. Serious adverse reactions in >2% of patients included pneumonia (4.1%), diarrhea (3.9%), hemorrhage (3.9%), and vomiting (2.4%). Fatal adverse reactions occurred in 8% of patients who received KEYTRUDA, including infection (2.3%) and thromboembolism (1.3%).
Permanent discontinuation of KEYTRUDA due to adverse reactions occurred in 15% of patients. Adverse reaction resulting in permanent discontinuation of KEYTRUDA in ≥1% were infections (1.8%) and diarrhea (1.0%).
Dosage interruptions of KEYTRUDA due to an adverse reaction occurred in 65% of patients. Adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were neutropenia (21%), thrombocytopenia (13%), diarrhea (5.5%), fatigue (4.8%), infection (4.8%), anemia (4.5%), increased AST (4.3%), increased ALT (3.8%), increased blood bilirubin (3.3%), white blood cell count decreased (2.2%), nausea (2%), palmar-plantar erythrodysesthesia syndrome (2%), and vomiting (2%).
Tables 31 and 32 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-859.
Adverse Reaction | KEYTRUDA200 mg every 3 weeksand FP or CAPOX n=785 | Placeboand FP or CAPOXn=787 | ||
---|---|---|---|---|
All Grades *(%) | Grades 3-4 (%) | All Grades *(%) | Grades 3-4 (%) | |
| ||||
Nervous System | ||||
Peripheral neuropathy † | 47 | 5 | 48 | 6 |
Gastrointestinal | ||||
Nausea | 46 | 3.7 | 46 | 4.4 |
Diarrhea | 36 | 6 | 32 | 5 |
Vomiting | 34 | 5 | 27 | 5 |
Abdominal Pain ‡ | 26 | 2.8 | 24 | 2.9 |
Constipation | 22 | 0.5 | 21 | 0.8 |
General | ||||
Fatigue § | 40 | 8 | 39 | 9 |
Metabolism and Nutrition | ||||
Decreased appetite | 29 | 3.3 | 29 | 2.5 |
Skin and Subcutaneous Tissue | ||||
Palmar-plantar erythrodysesthesia syndrome | 25 | 3.1 | 22 | 1.8 |
Investigations | ||||
Weight loss | 20 | 2.8 | 19 | 2.7 |
Laboratory Test * | KEYTRUDA200 mg every 3 weeksand FP or CAPOX | Placeboand FP or CAPOX | ||
---|---|---|---|---|
All Grades †% | Grades 3-4% | All Grades †% | Grades 3-4% | |
Hematology | ||||
Anemia | 65 | 15 | 69 | 13 |
Thrombocytopenia | 64 | 12 | 62 | 10 |
Neutropenia | 63 | 25 | 58 | 20 |
Leukopenia | 59 | 7 | 56 | 6 |
Lymphopenia | 57 | 20 | 51 | 16 |
Chemistry | ||||
Increased AST | 57 | 4.7 | 48 | 3.6 |
Hypoalbuminemia | 55 | 4.1 | 52 | 2.9 |
Hyperglycemia | 53 | 6 | 52 | 4.6 |
Hypocalcemia | 49 | 3.6 | 45 | 3.3 |
Increased alkaline phosphatase | 48 | 6 | 41 | 5 |
Hyponatremia | 40 | 13 | 40 | 12 |
Increased ALT | 40 | 4.2 | 29 | 2.9 |
Hypokalemia | 35 | 10 | 27 | 9 |
Bilirubin increased | 32 | 5 | 30 | 5 |
Hypophosphatemia | 30 | 10 | 27 | 8 |
Hypomagnesemia | 29 | 0.3 | 22 | 0.7 |
Increased creatinine | 21 | 3.5 | 18 | 1.7 |
Hyperkalemia | 20 | 3.7 | 18 | 2.9 |
Increased INR | 20 | 1.4 | 22 | 0 |
Esophageal Cancer
First-line Treatment of Locally Advanced Unresectable or Metastatic Esophageal Cancer/Gastroesophageal Junction
The safety of KEYTRUDA, in combination with cisplatin and FU chemotherapy was investigated in KEYNOTE-590, a multicenter, double-blind, randomized (1:1), placebo-controlled trial for the first-line treatment in patients with metastatic or locally advanced esophageal or gastroesophageal junction (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation [see Clinical Studies (14.10)]. A total of 740 patients received either KEYTRUDA 200 mg (n=370) or placebo (n=370) every 3 weeks for up to 35 cycles, both in combination with up to 6 cycles of cisplatin and up to 35 cycles of FU.
The median duration of exposure was 5.7 months (range: 1 day to 26 months) in the KEYTRUDA combination arm and 5.1 months (range: 3 days to 27 months) in the chemotherapy arm.
KEYTRUDA was discontinued for adverse reactions in 15% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 67% of patients. The most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were neutropenia (19%), fatigue/asthenia (8%), decreased white blood cell count (5%), pneumonia (5%), decreased appetite (4.3%), anemia (3.2%), increased blood creatinine (3.2%), stomatitis (3.2%), malaise (3.0%), thrombocytopenia (3%), pneumonitis (2.7%), diarrhea (2.4%), dysphagia (2.2%), and nausea (2.2%).
Tables 33 and 34 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-590.
Adverse Reaction | KEYTRUDA200 mg every 3 weeksCisplatin FUn=370 | PlaceboCisplatinFUn=370 | ||
---|---|---|---|---|
All Grades *(%) | Grades 3-4†(%) | All Grades *(%) | Grades 3-4†(%) | |
Gastrointestinal | ||||
Nausea | 67 | 7 | 63 | 7 |
Constipation | 40 | 0 | 40 | 0 |
Diarrhea | 36 | 4.1 | 33 | 3 |
Vomiting | 34 | 7 | 32 | 5 |
Stomatitis | 27 | 6 | 26 | 3.8 |
General | ||||
Fatigue ‡ | 57 | 12 | 46 | 9 |
Metabolism and Nutrition | ||||
Decreased appetite | 44 | 4.1 | 38 | 5 |
Investigations | ||||
Weight loss | 24 | 3.0 | 24 | 5 |
Laboratory Test * | KEYTRUDA200 mg every 3 weeksCisplatin FU | Chemotherapy(Cisplatin and FU) | ||
---|---|---|---|---|
All Grades †% | Grades 3-4% | All Grades †% | Grades 3-4% | |
Hematology | ||||
Anemia | 83 | 21 | 86 | 24 |
Neutropenia | 74 | 43 | 71 | 41 |
Leukopenia | 72 | 21 | 73 | 17 |
Lymphopenia | 55 | 22 | 53 | 18 |
Thrombocytopenia | 43 | 5 | 46 | 8 |
Chemistry | ||||
Hyperglycemia | 56 | 7 | 55 | 6 |
Hyponatremia | 53 | 19 | 54 | 19 |
Hypoalbuminemia | 52 | 2.8 | 52 | 2.3 |
Increased creatinine | 45 | 2.5 | 42 | 2.5 |
Hypocalcemia | 44 | 3.9 | 38 | 2 |
Hypophosphatemia | 37 | 9 | 31 | 10 |
Hypokalemia | 30 | 12 | 34 | 15 |
Increased alkaline phosphatase | 29 | 1.9 | 29 | 1.7 |
Hyperkalemia | 28 | 3.6 | 27 | 2.6 |
Increased AST | 25 | 4.4 | 22 | 2.8 |
Increased ALT | 23 | 3.6 | 18 | 1.7 |
Previously Treated Recurrent Locally Advanced or Metastatic Esophageal Cancer
Among the 314 patients with esophageal cancer enrolled in KEYNOTE-181 [see Clinical Studies (14.10)] treated with KEYTRUDA, the median duration of exposure to KEYTRUDA was 2.1 months (range: 1 day to 24.4 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with esophageal cancer were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent.
Cervical Cancer
Persistent, Recurrent, or Metastatic Cervical Cancer
The safety of KEYTRUDA in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab, was investigated in KEYNOTE-826, a multicenter, double-blind, randomized (1:1), placebo-controlled trial in patients with persistent, recurrent, or first-line metastatic cervical cancer who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent [see Clinical Studies (14.11)]. A total of 616 patients, regardless of tumor PD-L1 expression, received KEYTRUDA 200 mg and chemotherapy with or without bevacizumab (n=307) every 3 weeks or placebo and chemotherapy with or without bevacizumab (n=309) every 3 weeks.
The median duration of exposure to KEYTRUDA was 9.9 months (range: 1 day to 26 months).
Fatal adverse reactions occurred in 4.6% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab, including 3 cases of hemorrhage, 2 cases of sepsis, 2 cases due to unknown causes, and 1 case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femur fracture with perioperative pulmonary embolus, intestinal perforation, and pelvic infection.
Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab. Serious adverse reactions in ≥3% of patients included febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), acute kidney injury (3.3%), and sepsis (3.3%).
KEYTRUDA was discontinued for adverse reactions in 15% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA (≥1%) was colitis (1%).
Adverse reactions leading to interruption of KEYTRUDA occurred in 66% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were thrombocytopenia (15%), neutropenia (14%), anemia (11%), increased ALT (6%), leukopenia (5%), fatigue/asthenia (4.2%), urinary tract infection (3.6%), increased AST (3.3%), pyrexia (3.3%), diarrhea (2.6%), acute kidney injury (2.6%), increased blood creatinine (2.6%), colitis (2.3%), decreased appetite (2%), and cough (2%).
For patients treated with KEYTRUDA, chemotherapy, and bevacizumab (n=196), the most common (≥20%) adverse reactions were peripheral neuropathy (62%), alopecia (58%), anemia (55%), fatigue/asthenia (53%), nausea (41%), neutropenia (41%), diarrhea (39%), hypertension (35%), thrombocytopenia (35%), constipation (31%), arthralgia (31%), vomiting (30%), urinary tract infection (27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and decreased appetite (21%).
Table 35 and Table 36 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-826.
Adverse Reaction | KEYTRUDA200 mg every 3 weeksand chemotherapy * with or without bevacizumabn=307 | Placeboand chemotherapy * with or without bevacizumabn=309 | ||
---|---|---|---|---|
All Grades †(%) | Grades 3-4(%) | All Grades †(%) | Grades 3-4(%) | |
| ||||
Nervous System | ||||
Peripheral neuropathy ‡ | 58 | 4.2 | 57 | 6 |
Skin and Subcutaneous Tissue | ||||
Alopecia | 56 | 0 | 58 | 0 |
Rash § | 22 | 3.6 | 15 | 0.3 |
General | ||||
Fatigue ¶ | 47 | 7 | 46 | 6 |
Gastrointestinal | ||||
Nausea | 40 | 2 | 44 | 1.6 |
Diarrhea | 36 | 2 | 30 | 2.6 |
Constipation | 28 | 0.3 | 33 | 1 |
Vomiting | 26 | 2.6 | 27 | 1.9 |
Musculoskeletal and Connective Tissue | ||||
Arthralgia | 27 | 0.7 | 26 | 1.3 |
Vascular | ||||
Hypertension | 24 | 9 | 23 | 11 |
Infections | ||||
Urinary tract infection | 24 | 9 | 26 | 8 |
Laboratory Test * | KEYTRUDA200 mg every 3 weeksand chemotherapy † with or without bevacizumabn=307 | Placeboand chemotherapy † with or without bevacizumabn=309 | ||
---|---|---|---|---|
All Grades ‡(%) | Grades 3-4(%) | All Grades ‡(%) | Grades 3-4(%) | |
| ||||
Hematology | ||||
Anemia | 80 | 35 | 77 | 33 |
Leukopenia | 76 | 27 | 69 | 19 |
Neutropenia | 66 | 39 | 58 | 31 |
Lymphopenia | 61 | 33 | 56 | 33 |
Thrombocytopenia | 57 | 19 | 53 | 15 |
Chemistry | ||||
Hyperglycemia | 51 | 4.7 | 46 | 2.3 |
Hypoalbuminemia | 46 | 1.3 | 38 | 5 |
Hyponatremia | 40 | 14 | 38 | 11 |
Increased ALT | 40 | 7 | 38 | 6 |
Increased AST | 40 | 6 | 36 | 3.0 |
Increased alkaline phosphatase | 38 | 3.4 | 40 | 2.3 |
Hypocalcemia | 37 | 4.0 | 31 | 5 |
Increased creatinine | 34 | 5 | 32 | 6 |
Hypokalemia | 29 | 7 | 26 | 7 |
Hyperkalemia | 23 | 3.7 | 27 | 4.7 |
Hypercalcemia | 21 | 1.0 | 20 | 1.3 |
Previously Treated Recurrent or Metastatic Cervical Cancer
Among the 98 patients with cervical cancer enrolled in Cohort E of KEYNOTE-158 [see Clinical Studies (14.11)] , 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 37 and 38 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-158.
Adverse Reaction | KEYTRUDA200 mg every 3 weeksN=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 pain Þ | 22 | 3.1 |
Nausea | 19 | 0 |
Vomiting | 19 | 1.0 |
Constipation | 14 | 0 |
Metabolism and Nutrition | ||
Decreased appetite | 21 | 0 |
Vascular | ||
Hemorrhage ß | 19 | 5 |
Infections | ||
UTI à | 18 | 6 |
Infection (except UTI)è | 16 | 4.1 |
Skin and Subcutaneous Tissue | ||
Rash ð | 17 | 2.0 |
Endocrine | ||
Hypothyroidism | 11 | 0 |
Nervous System | ||
Headache | 11 | 2.0 |
Respiratory, Thoracic and Mediastinal | ||
Dyspnea | 10 | 1.0 |
Laboratory Test * | KEYTRUDA200 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 |
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 (14.12)] , 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%).
BTC
The safety of KEYTRUDA in combination with gemcitabine and cisplatin, was investigated in KEYNOTE-966, a multicenter, double-blind, randomized, placebo-controlled trial in patients with locally advanced unresectable or metastatic BTC who had not received prior systemic therapy in the advanced disease setting [see Clinical Studies (14.13)]. A total of 1063 patients received either KEYTRUDA 200 mg plus gemcitabine and cisplatin chemotherapy (n=529) or placebo plus gemcitabine and cisplatin chemotherapy (n=534) every 3 weeks.
The median duration of exposure to KEYTRUDA was 6 months (range: 1 day to 28 months).
KEYTRUDA was discontinued for adverse reactions in 15% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA (≥1%) was pneumonitis (1.3%).
Adverse reactions leading to the interruption of KEYTRUDA occurred in 55% of patients. The most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were decreased neutrophil count (18%), decreased platelet count (10%), anemia (6%), decreased white blood count (4%), pyrexia (3.8%), fatigue (3.0%), cholangitis (2.8%), increased ALT (2.6%), increased AST (2.5%), and biliary obstruction (2.3%).
In the KEYTRUDA plus chemotherapy versus placebo plus chemotherapy arms, there was a difference of ≥5% incidence in adverse reactions between patients treated with KEYTRUDA versus placebo for pyrexia (26% vs 20%), rash (21% vs 13%), pruritus (15% vs 10%), and hypothyroidism (9% vs. 2.6%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms.
There was a difference of ≥5% incidence in laboratory abnormalities between patients treated with KEYTRUDA plus chemotherapy versus placebo plus chemotherapy for decreased lymphocytes (69% vs 61%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms.
MCC
Among the 105 patients with MCC enrolled in KEYNOTE-017 and KEYNOTE-913 [see Clinical Studies (14.14)] , the median duration of exposure to KEYTRUDA was 6.3 months (range 1 day to 28 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 included increased lipase (17%).
RCC
In combination with axitinib in the first-line treatment of advanced RCC (KEYNOTE-426)
The safety of KEYTRUDA in combination with axitinib was investigated in KEYNOTE-426 [see Clinical Studies (14.15)]. 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 39 and 40 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in at least 20% of patients treated with KEYTRUDA and axitinib in KEYNOTE-426.
Adverse Reaction | KEYTRUDA 200 mg every 3 weeks and Axitinibn=429 | Sunitinibn=425 | ||
---|---|---|---|---|
All Grades *(%) | Grades 3-4(%) | All Grades(%) | Grades 3-4(%) | |
| ||||
Gastrointestinal | ||||
Diarrhea † | 56 | 11 | 45 | 5 |
Nausea | 28 | 0.9 | 32 | 0.9 |
Constipation | 21 | 0 | 15 | 0.2 |
General | ||||
Fatigue/Asthenia | 52 | 5 | 51 | 10 |
Vascular | ||||
Hypertension ‡ | 48 | 24 | 48 | 20 |
Hepatobiliary | ||||
Hepatotoxicity § | 39 | 20 | 25 | 4.9 |
Endocrine | ||||
Hypothyroidism | 35 | 0.2 | 32 | 0.2 |
Metabolism and Nutrition | ||||
Decreased appetite | 30 | 2.8 | 29 | 0.7 |
Skin and Subcutaneous Tissue | ||||
Palmar-plantar erythrodysesthesia syndrome | 28 | 5 | 40 | 3.8 |
Stomatitis/Mucosal inflammation | 27 | 1.6 | 41 | 4 |
Rash ¶ | 25 | 1.4 | 21 | 0.7 |
Respiratory, Thoracic and Mediastinal | ||||
Dysphonia | 25 | 0.2 | 3.3 | 0 |
Cough | 21 | 0.2 | 14 | 0.5 |
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 |
In combination with lenvatinib in the first-line treatment of advanced RCC (KEYNOTE-581)
The safety of KEYTRUDA was evaluated in KEYNOTE-581 [see Clinical Studies (14.15)]. Patients received KEYTRUDA 200 mg intravenously every 3 weeks in combination with lenvatinib 20 mg orally once daily (n=352), or lenvatinib 18 mg orally once daily in combination with everolimus 5 mg orally once daily (n=355), or sunitinib 50 mg orally once daily for 4 weeks then off treatment for 2 weeks (n=340). The median duration of exposure to the combination therapy of KEYTRUDA and lenvatinib was 17 months (range: 0.1 to 39).
Fatal adverse reactions occurred in 4.3% of patients treated with KEYTRUDA in combination with lenvatinib, including cardio-respiratory arrest (0.9%), sepsis (0.9%), and one case (0.3%) each of arrhythmia, autoimmune hepatitis, dyspnea, hypertensive crisis, increased blood creatinine, multiple organ dysfunction syndrome, myasthenic syndrome, myocarditis, nephritis, pneumonitis, ruptured aneurysm, and subarachnoid hemorrhage.
Serious adverse reactions occurred in 51% of patients receiving KEYTRUDA and lenvatinib. Serious adverse reactions in ≥2% of patients were hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%).
Permanent discontinuation of either of KEYTRUDA, lenvatinib or both due to an adverse reaction occurred in 37% of patients receiving KEYTRUDA in combination with lenvatinib; 29% KEYTRUDA only, 26% lenvatinib only, and 13% both. The most common adverse reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA, lenvatinib, or the combination were pneumonitis (3%), myocardial infarction (3%), hepatotoxicity (3%), acute kidney injury (3%), rash (3%), and diarrhea (2%).
Dose interruptions of KEYTRUDA, lenvatinib, or both due to an adverse reaction occurred in 78% of patients receiving KEYTRUDA in combination with lenvatinib. KEYTRUDA was interrupted in 55% of patients and both drugs were interrupted in 39% of patients. The most common adverse reactions (≥3%) resulting in interruption of KEYTRUDA were diarrhea (10%), hepatotoxicity (8%), fatigue (7%), lipase increased (5%), amylase increased (4%), musculoskeletal pain (3%), hypertension (3%), rash (3%), acute kidney injury (3%), and decreased appetite (3%).
Fifteen percent (15%) of patients treated with KEYTRUDA in combination with lenvatinib received an oral prednisone equivalent to ≥40 mg daily for an immune-mediated adverse reaction.
Tables 41 and 42 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in ≥20% of patients treated with KEYTRUDA and lenvatinib in KEYNOTE-581.
Adverse Reaction | KEYTRUDA200 mg every 3 weekswith LenvatinibN=352 | Sunitinib 50 mgN=340 | ||
---|---|---|---|---|
All Grades(%) | Grades 3-4(%) | All Grades(%) | Grades 3-4(%) | |
| ||||
General | ||||
Fatigue * | 63 | 9 | 56 | 8 |
Gastrointestinal | ||||
Diarrhea † | 62 | 10 | 50 | 6 |
Stomatitis ‡ | 43 | 2 | 43 | 2 |
Nausea | 36 | 3 | 33 | 1 |
Abdominal pain § | 27 | 2 | 18 | 1 |
Vomiting | 26 | 3 | 20 | 1 |
Constipation | 25 | 1 | 19 | 0 |
Musculoskeletal and Connective Tissue | ||||
Musculoskeletal disorders ¶ | 58 | 4 | 41 | 3 |
Endocrine | ||||
Hypothyroidism # | 57 | 1 | 32 | 0 |
Vascular | ||||
Hypertension Þ | 56 | 29 | 43 | 20 |
Hemorrhagic events ß | 27 | 5 | 26 | 4 |
Metabolism | ||||
Decreased appetite à | 41 | 4 | 31 | 1 |
Skin and Subcutaneous Tissue | ||||
Rash è | 37 | 5 | 17 | 1 |
Palmar-plantar erythrodysesthesia syndrome ð | 29 | 4 | 38 | 4 |
Investigations | ||||
Weight loss | 30 | 8 | 9 | 0.3 |
Respiratory, Thoracic and Mediastinal | ||||
Dysphonia | 30 | 0 | 4 | 0 |
Renal and Urinary | ||||
Proteinuria ø | 30 | 8 | 13 | 3 |
Acute kidney injury ý | 21 | 5 | 16 | 2 |
Hepatobiliary | ||||
Hepatotoxicity £ | 25 | 9 | 21 | 5 |
Nervous System | ||||
Headache | 23 | 1 | 16 | 1 |
Clinically relevant adverse reactions (<20%) that occurred in patients receiving KEYTRUDA with lenvatinib were myocardial infarction (3%) and angina pectoris (1%).
Laboratory Test * | KEYTRUDA200 mg every 3 weekswith Lenvatinib | Sunitinib 50 mg | ||
---|---|---|---|---|
All Grades %† | Grade 3-4%† | All Grades%† | Grade 3-4%† | |
| ||||
Chemistry | ||||
Hypertriglyceridemia | 80 | 15 | 71 | 15 |
Hypercholesterolemia | 64 | 5 | 43 | 1 |
Increased lipase | 61 | 34 | 59 | 28 |
Increased creatinine | 61 | 5 | 61 | 2 |
Increased amylase | 59 | 17 | 41 | 9 |
Increased AST | 58 | 7 | 57 | 3 |
Hyperglycemia | 55 | 7 | 48 | 3 |
Increased ALT | 52 | 7 | 49 | 4 |
Hyperkalemia | 44 | 9 | 28 | 6 |
Hypoglycemia | 44 | 2 | 27 | 1 |
Hyponatremia | 41 | 12 | 28 | 9 |
Decreased albumin | 34 | 0.3 | 22 | 0 |
Increased alkaline phosphatase | 32 | 4 | 32 | 1 |
Hypocalcemia | 30 | 2 | 22 | 1 |
Hypophosphatemia | 29 | 7 | 50 | 8 |
Hypomagnesemia | 25 | 2 | 15 | 3 |
Increased creatine phosphokinase | 24 | 6 | 36 | 5 |
Hypermagnesemia | 23 | 2 | 22 | 3 |
Hypercalcemia | 21 | 1 | 11 | 1 |
Hematology | ||||
Lymphopenia | 54 | 9 | 66 | 15 |
Thrombocytopenia | 39 | 2 | 73 | 13 |
Anemia | 38 | 3 | 66 | 8 |
Leukopenia | 34 | 1 | 77 | 8 |
Neutropenia | 31 | 4 | 72 | 16 |
Grade 3 and 4 increased ALT or AST was seen in 9% of patients. Grade ≥2 increased ALT or AST was reported in 64 (18%) patients, of whom 20 (31%) received ≥40 mg daily oral prednisone equivalent. Recurrence of Grade ≥2 increased ALT or AST was observed on rechallenge in 10 patients receiving both KEYTRUDA and lenvatinib (n=38) and was not observed on rechallenge with KEYTRUDA alone (n=3).
Adjuvant treatment of RCC
The safety of KEYTRUDA as a single agent was investigated in KEYNOTE-564, a randomized (1:1) double-blind placebo-controlled trial in which 984 patients who had undergone nephrectomy for RCC received 200 mg of KEYTRUDA by intravenous infusion every 3 weeks (n=488) or placebo (n=496) for up to one year [see Clinical Studies (14.15)]. The median duration of exposure to KEYTRUDA was 11.1 months (range: 1 day to 14.3 months). Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible.
Serious adverse reactions occurred in 20% of these patients receiving KEYTRUDA. Serious adverse reactions (≥1%) were acute kidney injury, adrenal insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1% each). Fatal adverse reactions occurred in 0.2% of those treated with KEYTRUDA, including one case of pneumonia.
Discontinuation of KEYTRUDA due to an adverse reaction occurred in 21% of patients; the most common (≥1%) were increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%).
Dose interruptions of KEYTRUDA due to an adverse reaction occurred in 26% of patients; the most common (≥1%) were increased AST (2.3%), arthralgia (1.6%), hypothyroidism (1.6%), diarrhea (1.4%), increased ALT (1.4%), fatigue (1.4%), rash, decreased appetite, and vomiting (1% each). Tables 43 and 44 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-564.
Adverse Reaction | KEYTRUDA200 mg every 3 weeksn=488 | Placebon=496 | ||
---|---|---|---|---|
All Grades †(%) | Grades 3-4(%) | All Grades(%) | Grades 3-4(%) | |
| ||||
Musculoskeletal and Connective Tissue | ||||
Musculoskeletal pain ‡ | 41 | 1.2 | 36 | 0.6 |
General | ||||
Fatigue § | 40 | 1.2 | 31 | 0.2 |
Skin and Subcutaneous Tissue | ||||
Rash ¶ | 30 | 1.4 | 15 | 0.4 |
Pruritus | 23 | 0.2 | 13 | 0 |
Gastrointestinal | ||||
Diarrhea # | 27 | 2.7 | 23 | 0.2 |
Nausea | 16 | 0.4 | 10 | 0 |
Abdominal pain Þ | 11 | 0.4 | 13 | 0.2 |
Endocrine | ||||
Hypothyroidism | 21 | 0.2 | 3.6 | 0 |
Hyperthyroidism | 12 | 0.2 | 0.2 | 0 |
Respiratory, Thoracic and Mediastinal | ||||
Cough ß | 17 | 0 | 12 | 0 |
Nervous System | ||||
Headache à | 15 | 0.2 | 13 | 0 |
Hepatobiliary | ||||
Hepatotoxicity è | 14 | 3.7 | 7 | 0.6 |
Renal and Urinary | ||||
Acute kidney injury ð | 13 | 1.2 | 10 | 0.2 |
Laboratory Test † | KEYTRUDA200 mg every 3 weeks | Placebo | ||
---|---|---|---|---|
All Grades ‡% | Grades 3-4% | All Grades% | Grades 3-4% | |
| ||||
Chemistry | ||||
Increased glucose | 48 | 8 | 45 | 4.5 |
Increased creatinine | 40 | 1.1 | 28 | 0.2 |
Increased INR | 27 | 0.9 | 20 | 0.8 |
Hyponatremia | 21 | 3.3 | 13 | 1.9 |
Increased ALT | 20 | 3.8 | 11 | 0.2 |
Hematology | ||||
Anemia | 28 | 0.5 | 20 | 0.4 |
Endometrial Carcinoma
In Combination with Lenvatinib for the Treatment of Advanced Endometrial Carcinoma That Is pMMR or Not MSI-H.
The safety of KEYTRUDA in combination with lenvatinib was investigated in KEYNOTE-775, a multicenter, open-label, randomized (1:1), active-controlled trial in patients with advanced endometrial carcinoma previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings [see Clinical Studies (14.16)]. Patients with endometrial carcinoma that is pMMR or not MSI-H received KEYTRUDA 200 mg every 3 weeks in combination with lenvatinib 20mg orally once daily (n=342) or received doxorubicin or paclitaxel (n=325).
For patients with pMMR or not MSI-H tumor status, the median duration of study treatment was 7.2 months (range 1 day to 26.8 months) and the median duration of exposure to KEYTRUDA was 6.8 months (range: 1 day to 25.8 months).
Fatal adverse reactions among these patients occurred in 4.7% of those treated with KEYTRUDA and lenvatinib, including 2 cases of pneumonia, and 1 case of the following: acute kidney injury, acute myocardial infarction, colitis, decreased appetite, intestinal perforation, lower gastrointestinal hemorrhage, malignant gastrointestinal obstruction, multiple organ dysfunction syndrome, myelodysplastic syndrome, pulmonary embolism, and right ventricular dysfunction.
Serious adverse reactions occurred in 50% of these patients receiving KEYTRUDA and lenvatinib. Serious adverse reactions (≥3%) were hypertension (4.4%) and urinary tract infections (3.2%).
Discontinuation of KEYTRUDA due to an adverse reaction occurred in 15% of these patients. The most common adverse reaction leading to discontinuation of KEYTRUDA (≥1%) was increased ALT (1.2%).
Dose interruptions of KEYTRUDA due to an adverse reaction occurred in 48% of these patients. The most common adverse reactions leading to interruption of KEYTRUDA (≥3%) were diarrhea (8%), increased ALT (4.4%), increased AST (3.8%), and hypertension (3.5%).
Tables 45 and 46 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in combination with lenvatinib in KEYNOTE-775.
Endometrial Carcinoma (pMMR or not MSI-H) | ||||
---|---|---|---|---|
Adverse Reaction | KEYTRUDA200 mg every 3 weeksand Lenvatinibn=342 | Doxorubicin orPaclitaxeln=325 | ||
All Grades *(%) | Grades 3-4(%) | All Grades *(%) | Grades 3-4(%) | |
| ||||
Endocrine | ||||
Hypothyroidism † | 67 | 0.9 | 0.9 | 0 |
Vascular | ||||
Hypertension ‡ | 67 | 39 | 6 | 2.5 |
Hemorrhagic events § | 25 | 2.6 | 15 | 0.9 |
General | ||||
Fatigue ¶ | 58 | 11 | 54 | 6 |
Gastrointestinal | ||||
Diarrhea # | 55 | 8 | 20 | 2.8 |
Nausea | 49 | 2.9 | 47 | 1.5 |
Vomiting | 37 | 2.3 | 21 | 2.2 |
Stomatitis Þ | 35 | 2.6 | 26 | 1.2 |
Abdominal pain ß | 34 | 2.6 | 21 | 1.2 |
Constipation | 27 | 0 | 25 | 0.6 |
Musculoskeletal and Connective Tissue | ||||
Musculoskeletal disorders à | 53 | 5 | 27 | 0.6 |
Metabolism | ||||
Decreased appetite è | 44 | 7 | 21 | 0 |
Investigations | ||||
Weight loss | 34 | 10 | 6 | 0.3 |
Renal and Urinary | ||||
Proteinuria ð | 29 | 6 | 3.4 | 0.3 |
Infections | ||||
Urinary tract infection ø | 31 | 5 | 13 | 1.2 |
Nervous System | ||||
Headache | 26 | 0.6 | 9 | 0.3 |
Respiratory, Thoracic and Mediastinal | ||||
Dysphonia | 22 | 0 | 0.6 | 0 |
Skin and Subcutaneous Tissue | ||||
Palmar-plantar erythrodysesthesia ý | 23 | 2.9 | 0.9 | 0 |
Rash £ | 20 | 2.3 | 4.9 | 0 |
Endometrial Carcinoma (pMMR or not MSI-H) | ||||
---|---|---|---|---|
Laboratory Test † | KEYTRUDA200 mg every 3 weeksand Lenvatinib | Doxorubicin orPaclitaxel | ||
All Grades ‡% | Grades 3-4% | All Grades ‡% | Grades 3-4% | |
| ||||
Chemistry | ||||
Hypertriglyceridemia | 70 | 6 | 45 | 1.7 |
Hypoalbuminemia | 60 | 2.7 | 42 | 1.6 |
Increased aspartate aminotransferase | 58 | 9 | 23 | 1.6 |
Hyperglycemia | 58 | 8 | 45 | 4.4 |
Hypomagnesemia | 53 | 6 | 32 | 3.8 |
Increased alanine aminotransferase | 55 | 9 | 21 | 1.2 |
Hypercholesteremia | 53 | 3.2 | 23 | 0.7 |
Hyponatremia | 46 | 15 | 28 | 7 |
Increased alkaline phosphatase | 43 | 4.7 | 18 | 0.9 |
Hypocalcemia | 40 | 4.7 | 21 | 1.9 |
Increased lipase | 36 | 14 | 13 | 3.9 |
Increased creatinine | 35 | 4.7 | 18 | 1.9 |
Hypokalemia | 34 | 10 | 24 | 5 |
Hypophosphatemia | 26 | 8 | 17 | 3.2 |
Increased amylase | 25 | 7 | 8 | 1 |
Hyperkalemia | 23 | 2.4 | 12 | 1.2 |
Increased creatine kinase | 19 | 3.7 | 7 | 0 |
Increased bilirubin | 18 | 3.6 | 6 | 1.6 |
Hematology | ||||
Lymphopenia | 50 | 16 | 65 | 20 |
Thrombocytopenia | 50 | 8 | 30 | 4.7 |
Anemia | 49 | 8 | 84 | 14 |
Leukopenia | 43 | 3.5 | 83 | 43 |
Neutropenia | 31 | 6 | 76 | 58 |
As a Single Agent for the Treatment of Advanced MSI-H or dMMR Endometrial Carcinoma
Among the 90 patients with MSI-H or dMMR endometrial carcinoma enrolled in KEYNOTE-158 [see Clinical Studies (14.16)] treated with KEYTRUDA as a single agent, the median duration of exposure to KEYTRUDA was 8.3 months (range: 1 day to 26.9 months). Adverse reactions occurring in patients with endometrial carcinoma were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent.
TMB-H Cancer
The safety of KEYTRUDA was investigated in 105 patients with TMB-H cancer enrolled in KEYNOTE-158 [see Clinical Studies (14.17)]. The median duration of exposure to KEYTRUDA was 4.9 months (range: 0.03 to 35.2 months). Adverse reactions occurring in patients with TMB-H cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.
cSCC
Among the 159 patients with advanced cSCC (recurrent or metastatic or locally advanced disease) enrolled in KEYNOTE-629 [see Clinical Studies (14.18)] , the median duration of exposure to KEYTRUDA was 6.9 months (range 1 day to 28.9 months). Patients with autoimmune disease or a medical condition that required systemic corticosteroids or other immunosuppressive medications were ineligible. Adverse reactions occurring in patients with recurrent or metastatic cSCC or locally advanced cSCC were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence included lymphopenia (10%) and decreased sodium (10%).
TNBC
Neoadjuvant and Adjuvant Treatment of High-Risk Early-Stage TNBC
The safety of KEYTRUDA in combination with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent was investigated in KEYNOTE-522, a randomized (2:1), multicenter, double-blind, placebo-controlled trial in patients with newly diagnosed, previously untreated, high-risk early-stage TNBC.
A total of 778 patients on the KEYTRUDA arm received at least 1 dose of KEYTRUDA in combination with neoadjuvant chemotherapy followed by KEYTRUDA as adjuvant treatment after surgery, compared to 389 patients who received at least 1 dose of placebo in combination with neoadjuvant chemotherapy followed by placebo as adjuvant treatment after surgery [see Clinical Studies (14.19)].
The median duration of exposure to KEYTRUDA 200 mg every 3 weeks was 13.3 months (range: 1 day to 21.9 months).
Fatal adverse reactions occurred in 0.9% of patients receiving KEYTRUDA, including 1 each of adrenal crisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, and sepsis in association with multiple organ dysfunction syndrome and myocardial infarction.
Serious adverse reactions occurred in 44% of patients receiving KEYTRUDA. Serious adverse reactions in ≥2% of patients who received KEYTRUDA included febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%).
KEYTRUDA was discontinued for adverse reactions in 20% of patients. The most common adverse reactions (≥1%) resulting in permanent discontinuation of KEYTRUDA were increased ALT (2.7%), increased AST (1.5%), and rash (1%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 57% of patients. The most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were neutropenia (26%), thrombocytopenia (6%), increased ALT (6%), increased AST (3.7%), anemia (3.5%), rash (3.2%), febrile neutropenia (2.8%), leukopenia (2.8%), upper respiratory tract infection (2.6%), pyrexia (2.2%), and fatigue (2.1%).
Tables 47 and 48 summarize the adverse reactions and laboratory abnormalities, respectively, in patients treated with KEYTRUDA in KEYNOTE-522.
Adverse Reaction | KEYTRUDA200 mg every 3 weekswith chemotherapy */KEYTRUDAn=778 | Placebowith chemotherapy */Placebon=389 | ||
---|---|---|---|---|
All Grades †(%) | Grades 3-4(%) | All Grades †(%) | Grades 3-4(%) | |
| ||||
General | ||||
Fatigue ‡ | 70 | 8 | 66 | 3.9 |
Pyrexia | 28 | 1.3 | 19 | 0.3 |
Gastrointestinal | ||||
Nausea | 67 | 3.7 | 66 | 1.8 |
Constipation | 42 | 0 | 39 | 0.3 |
Diarrhea | 41 | 3.2 | 34 | 1.8 |
Stomatitis § | 34 | 2.7 | 29 | 1 |
Vomiting | 31 | 2.7 | 28 | 1.5 |
Abdominal pain ¶ | 24 | 0.5 | 23 | 0.8 |
Skin and Subcutaneous Tissue | ||||
Alopecia | 61 | 0 | 58 | 0 |
Rash # | 52 | 5 | 41 | 0.5 |
Nervous System | ||||
Peripheral neuropathy Þ | 41 | 3.3 | 42 | 2.3 |
Headache | 30 | 0.5 | 29 | 1 |
Musculoskeletal and Connective Tissue | ||||
Arthralgia | 29 | 0.5 | 31 | 0.3 |
Myalgia | 20 | 0.5 | 19 | 0 |
Respiratory, Thoracic and Mediastinal | ||||
Cough ß | 26 | 0.1 | 24 | 0 |
Metabolism and Nutrition | ||||
Decreased appetite | 23 | 0.9 | 17 | 0.3 |
Psychiatric | ||||
Insomnia | 21 | 0.5 | 19 | 0 |
Laboratory Test * | KEYTRUDA200 mg every 3 weekswith chemotherapy †/KEYTRUDA | Placebowith chemotherapy †/Placebo | ||
---|---|---|---|---|
All Grades ‡% | Grades 3-4% | All Grades ‡% | Grades 3-4% | |
| ||||
Hematology | ||||
Anemia | 97 | 22 | 96 | 19 |
Leukopenia | 93 | 41 | 91 | 32 |
Neutropenia | 88 | 62 | 89 | 62 |
Lymphopenia | 80 | 28 | 74 | 22 |
Thrombocytopenia | 58 | 11 | 57 | 9 |
Chemistry | ||||
Increased ALT | 71 | 9 | 69 | 4.6 |
Increased AST | 66 | 6 | 58 | 1.8 |
Hyperglycemia | 65 | 5 | 62 | 2.8 |
Increased alkaline phosphatase | 41 | 1 | 37 | 0.8 |
Hyponatremia | 38 | 9 | 28 | 6 |
Hypoalbuminemia | 36 | 1.2 | 30 | 1.5 |
Hypocalcemia | 32 | 3.2 | 29 | 4.4 |
Hypokalemia | 32 | 6 | 24 | 2.8 |
Hypophosphatemia | 23 | 6 | 18 | 4.5 |
Hypercalcemia | 21 | 3 | 24 | 3.4 |
Locally Recurrent Unresectable or Metastatic TNBC
The safety of KEYTRUDA in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin was investigated in KEYNOTE-355, a multicenter, double-blind, randomized (2:1), placebo-controlled trial in patients with locally recurrent unresectable or metastatic TNBC who had not been previously treated with chemotherapy in the metastatic setting [see Clinical Studies (14.19)]. 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 49 and 50 summarize the adverse reactions and laboratory abnormalities in patients on KEYTRUDA in KEYNOTE-355.
Adverse Reaction | KEYTRUDA200 mg every 3 weekswith chemotherapyn=596 | Placebo every 3 weekswith chemotherapyn=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 |
Laboratory Test * | KEYTRUDA 200 mg every 3 weekswith chemotherapy | Placebo every 3 weekswith 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 |
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