On September 10, 2017 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported updated results from the phase 3 KEYNOTE-045 trial evaluating KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, in patients with locally advanced or metastatic urothelial carcinoma (a type of bladder cancer) with disease progression on or after platinum-containing chemotherapy (post-platinum failure) (Press release, Merck & Co, SEP 10, 2017, View Source [SID1234520454]). Updated data show that with median follow-up of 22.5 months, KEYTRUDA continues to demonstrate an overall survival (OS) benefit over investigator’s choice of paclitaxel, docetaxel or vinflunine as a second-line therapy, post-platinum failure, regardless of PD-L1 expression (HR, 0.70 [95% CI, 0.57-0.86], p=0.0003). Findings are being presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2017 Congress in Madrid, Spain, on Sunday, Sept. 10 (poster from 2:45 – 4:15 p.m. CEST; discussion: 3:15 – 3:45 p.m. CEST) (Location: Cordoba Auditorium) (Abstract #LBA37_PR).

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"These data at ESMO (Free ESMO Whitepaper) provide further insights and greater understanding in using KEYTRUDA in select second-line advanced urothelial carcinoma treatment settings, and importantly, demonstrate an overall survival advantage with KEYTRUDA compared to standard chemotherapy agents vinflunine, docetaxel and paclitaxel, which are common in clinical practice for the treatment of this disease," said professor Ronald de Wit, M.D., Ph.D., group leader experimental systemic therapy of urogenital cancers, Erasmus MC Cancer Institute. "For previously treated patients, post-platinum failure, these findings are also encouraging as they show an overall survival benefit regardless of PD-L1 status or choice of commonly used chemotherapy."

"With nearly two years follow-up, these updated phase 3 data continue to show an overall survival benefit with KEYTRUDA in patients with advanced urothelial carcinoma whose cancer has progressed after receiving previous treatment for their disease," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "We are pleased that, with the approval in the U.S. and recent approval of KEYTRUDA in the EU, more patients now have an important treatment option available to them."

Currently, Merck also has the largest immuno-oncology clinical development program in bladder cancer, with 29 trials underway involving KEYTRUDA (pembrolizumab) as monotherapy and in combination, including four registration-enabling studies.

Data in Second-Line Post-Platinum Failure Patients, KEYNOTE-045

KEYNOTE-045 is an open-label, randomized phase 3 trial of KEYTRUDA compared to investigator’s choice of chemotherapy (paclitaxel, docetaxel or vinflunine) in patients with locally advanced or metastatic urothelial cancer with disease progression on or after platinum-containing chemotherapy. The trial was prematurely stopped after a pre-planned interim analysis demonstrated significantly longer OS with KEYTRUDA compared to chemotherapy (median follow-up, 14.1 months). Efficacy was assessed in the overall study population (n=542), as well as in patients with PD-L1 expression – defined as a combined positive score of 10 or more (CPS ≥10) (KEYTRUDA arm: n=74/270; chemotherapy arm; n=90/272) (additional details on the trial design are provided below).

Data presented at ESMO (Free ESMO Whitepaper) (Abstract #LBA37_PR) include four months of additional follow-up (data cut-off, May 19, 2017; median follow up, 22.5 months) and continue to show a superior OS advantage with KEYTRUDA compared to chemotherapy in the second-line setting, regardless of PD-L1 expression. In the overall study population, data show a 30 percent reduction in the risk of death with KEYTRUDA (HR, 0.70 [95% CI, 0.57-0.86], p=0.0003), the median OS was 10.3 months with KEYTRUDA (95% CI, 8.0-12.3) and 7.4 months with chemotherapy (95% CI, 6.3-8.3), and the 18-month OS rate was 33.2 percent with KEYTRUDA compared to 19.7 percent with chemotherapy. Analysis of OS based on PD-L1 expression show a 42 percent reduction in the risk of death with KEYTRUDA (HR, 0.58 [95% CI, 0.39-0.86], p=0.0029) in patients whose tumors expressed PD-L1 (CPS ≥10), the median OS was 8.0 months with KEYTRUDA (95% CI, 5.0-12.3) and 5.2 months with chemotherapy (95% CI, 4.2-7.5), and the 18-month OS rate was 30.0 percent with KEYTRUDA compared to 16.9 percent with chemotherapy.

As previously reported, there was no significant difference in progression-free-survival (PFS) between treatment arms in the overall study population (HR, 0.96 [95% CI, 0.79-1.16], p=0.32). The median PFS was 2.1 months with KEYTRUDA (95% CI, 2.0-2.2) and 3.3 months with chemotherapy (95% CI, 2.4-3.5); the 18-month PFS rate was 15.3 percent with KEYTRUDA (pembrolizumab) compared to 4.8 percent with chemotherapy. In patients whose tumors expressed PD-L1 (CPS ≥10), the median PFS was 2.1 months with KEYTRUDA (95% CI, 1.9-2.1) and 3.2 months with chemotherapy (95% CI, 2.2-3.5); the 18-month PFS rate was 16.3 percent with KEYTRUDA compared to 5.3 percent with chemotherapy (HR, 0.93 [95% CI, 0.65-1.33], p=0.32).

Analyses of the secondary endpoints showed nearly double the overall response rate (ORR) with KEYTRUDA compared to chemotherapy in the overall study population, with an ORR of 21.1 percent in the KEYTRUDA arm (complete response rate (CR) of 7.8 percent and a partial response rate (PR) of 13.3 percent) and 11.0 percent in the chemotherapy arm (CR of 2.9 percent and a PR of 8.1 percent). The median time to response was 2.1 months in both treatment arms; 57.9 percent of responses in the KEYTRUDA arm were ongoing at the time of analysis compared to 20.0 percent in the chemotherapy arm. Median duration of response in patients with partial or complete responses had not yet been reached in the KEYTRUDA arm at the time of analysis (range: 1.6+ to 24.6+) with 67.0 percent of responses ongoing at 12 months (calculated per Kaplan-Meier curve); in the chemotherapy arm, the median duration of response was 4.4 months (range: 1.4+ to 24.0+) with 35.0 percent of responses ongoing at 12 months (calculated per Kaplan-Meier curve).

In patients whose tumors expressed PD-L1, the ORR was 20.3 percent in the KEYTRUDA arm (CR of 6.8 percent and a PR of 13.5 percent) and 6.7 percent in the chemotherapy arm (CR of 2.2 percent and a PR of 4.4 percent). The median time to response was 2.0 months in the KEYTRUDA arm and 2.1 months in the chemotherapy arm; 73.3 percent of responses in the KEYTRUDA arm were ongoing at the time of analysis compared to 33.3 percent in the chemotherapy arm. The median duration of response in patients with partial or complete responses had not yet been reached in the KEYTRUDA arm at the time of analysis (range: 1.6+ to 23.5+) with 77.0 percent of responses ongoing at 12 months (calculated per Kaplan-Meier curve); in the chemotherapy arm, the median duration of response was 4.4 months (range: 1.5+ to 20.8+) with 40.0 percent of responses ongoing at 12 months (calculated per Kaplan-Meier curve).

A second abstract including a subgroup analysis from KEYNOTE-045 (Abstract #851PD) was also accepted as a poster at ESMO (Free ESMO Whitepaper) and provides greater insight into the OS advantage with KEYTRUDA compared to the individual chemotherapy agents. The retrospective analysis showed a 27 percent reduction in the risk of death versus paclitaxel (HR, 0.73 [95% CI, 0.55-0.96]), a 21 percent reduction in the risk of death versus docetaxel (HR, 0.79 [95% CI, 0.59-1.07]), and a 35 percent reduction in the risk of death versus vinflunine (HR, 0.65 [95% CI, 0.49-0.87]). No statistically significant difference in PFS was seen between KEYTRUDA and each chemotherapy agent. Analyses of the secondary endpoints showed an ORR of 11.9 percent, 6.0 percent, and 17.2 percent with paclitaxel, docetaxel, and vinflunine, respectively, compared to 21.1 percent in the KEYTRUDA (pembrolizumab) arm.

The safety profile of KEYTRUDA was consistent with that observed in previously reported studies. Treatment-related adverse events (TRAEs) of any grade occurred in 62.0 percent in the KEYTRUDA arm and 90.6 percent in the chemotherapy arm. Grade 3 or higher TRAEs occurred in 16.5 percent and 50.2 percent of KEYTRUDA and chemotherapy patients, respectively. Immune-mediated adverse events occurred in 19.5 percent of patients in the KEYTRUDA arm and 7.5 percent in the chemotherapy arm. The discontinuation rate due to treatment-related adverse events was 7.1 percent of patients in the KEYTRUDA arm and 12.5 percent of patients in the chemotherapy arm. Deaths due to treatment-related adverse events occurred in four patients treated with KEYTRUDA, one patient treated with paclitaxel, and three patients treated with vinflunine.

About KEYNOTE-045

In KEYNOTE-045, patients were randomized to receive either KEYTRUDA 200 mg every three weeks (n=270) or investigator’s choice of any of the following chemotherapy regimens, all given intravenously, every three weeks (n=272): paclitaxel 175 mg/m2, docetaxel 75 mg/m2, or vinflunine 320 mg/m2. The dual primary endpoints were OS and PFS, as assessed by blinded independent central review (BICR) per RECIST (Response Evaluation Criteria in Solid Tumors) v1.1; key secondary endpoints included ORR, as assessed by BICR per RECIST 1.1, duration of response and safety. Efficacy was assessed in all patients, as well as in patients with PD-L1 expression.

About KEYTRUDA (pembrolizumab) Injection 100mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Studies of KEYTRUDA – from the largest immuno-oncology program in the industry with more than 550 trials – include a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand factors that predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including the exploration of several different biomarkers across a broad range of tumors.

KEYTRUDA (pembrolizumab) Indications and Dosing

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [tumor proportion score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

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

KEYTRUDA, in combination with pemetrexed and carboplatin, is indicated for the first-line treatment of patients with metastatic nonsquamous NSCLC. This indication is approved under accelerated approval based on tumor response rate and progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA should be administered prior to chemotherapy when given on the same day. See also the Prescribing Information for pemetrexed and carboplatin.

Head and Neck Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Classical Hodgkin Lymphoma

KEYTRUDA (pembrolizumab) is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after three or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In adults with cHL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with cHL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA is also indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

In locally advanced or metastatic urothelial carcinoma, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA (pembrolizumab) in pediatric patients with MSI-H central nervous system cancers have not been established.

In adult patients with MSI-H cancer, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with MSI-H cancer, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%) pneumonitis, and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%) hepatitis. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%) hypophysitis. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

KEYTRUDA (pembrolizumab) can cause thyroid disorders, including hyperthyroidism, hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.8%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 237 (8.5%) of 2799 patients receiving KEYTRUDA, including Grade 2 (6.2%) and 3 (0.1%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in patients with HNSCC, occurring in 28 (15%) of 192 patients with HNSCC, including Grade 3 (0.5%) hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.3%) thyroiditis. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.

KEYTRUDA can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 9 (0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs and symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

KEYTRUDA can cause other clinically important immune-mediated adverse reactions. These immune-mediated reactions may occur in any organ system. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA (pembrolizumab) for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.

Solid organ transplant rejection has been reported in postmarketing use of KEYTRUDA. Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment with KEYTRUDA vs the risk of possible organ rejection in these patients.

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for signs and symptoms of infusion-related reactions, including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after being treated with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after treatment with KEYTRUDA on any trial, 6 patients (26%) developed graft-versus-host-disease (GVHD), one of which was fatal, and 2 patients (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning, one of which was fatal. Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor–blocking antibody before transplantation. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT. Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly.

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to discontinuation 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 (pembrolizumab) occurred in 21% of patients; the most common (≥1%) was diarrhea (2.5%). The most common adverse reactions with KEYTRUDA vs ipilimumab were fatigue (28% vs 28%), diarrhea (26% with KEYTRUDA), rash (24% vs 23%), and nausea (21% with KEYTRUDA). Corresponding incidence rates are listed for ipilimumab only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.

KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC. The most common adverse event 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%). The most common adverse reactions (occurring in at least 20% of patients and at a higher incidence than with docetaxel) were decreased appetite (25% vs 23%), dyspnea (23% vs 20%), and nausea (20% vs 18%).

When KEYTRUDA was administered in combination with carboplatin and pemetrexed (carbo/pem), KEYTRUDA was discontinued in 10% of 59 patients. The most common adverse reaction resulting in discontinuation of KEYTRUDA (≥2%) was acute kidney injury (3.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 39% of patients; the most common (≥2%) were fatigue (8%), neutrophil count decreased (8%), anemia (5%), dyspnea (3.4%), and pneumonitis (3.4%).The most common adverse reactions (≥20%) with KEYTRUDA compared to carbo/pem alone were fatigue (71% vs 50%), nausea (68% vs 56%), constipation (51% vs 37%), rash (42% vs 21%), vomiting (39% vs 27%), dyspnea (39% vs 21%), diarrhea (37% vs 23%), decreased appetite (31% vs 23%), headache (31% vs 16%), cough (24% vs 18%), dizziness (24% vs 16%), insomnia (24% vs 15%), pruritus (24% vs 4.8%), peripheral edema (22% vs 18%), dysgeusia (20% vs 11%), alopecia (20% vs 3.2%), upper respiratory tract infection (20% vs 3.2%), and arthralgia (15% vs 24%). This study was not designed to demonstrate a statistically significant difference in adverse reaction rates for KEYTRUDA as compared to carbo/pem alone for any specified adverse reaction.

KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. 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 most common adverse reactions (reported in at least 20% of patients) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC, with the exception of increased incidences of facial edema (10% all Grades; 2.1% Grades 3 or 4) and new or worsening hypothyroidism.

KEYTRUDA (pembrolizumab) was discontinued due to adverse reactions in 5% of 210 patients with cHL, and treatment was interrupted due to adverse reactions in 26% of patients. Fifteen percent (15%) of patients had an adverse reaction requiring systemic corticosteroid therapy. Serious adverse reactions occurred in 16% of patients. The most frequent serious adverse reactions (≥1%) included pneumonia, pneumonitis, pyrexia, dyspnea, 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. The most common adverse reactions (occurring in ≥20% of patients) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reactions (in≥20% of patients) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%). 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 3 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 (≥2%) of which were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis.

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. 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%). The most common adverse reactions (20%) in patients who received KEYTRUDA vs those who received chemotherapy were fatigue (38% vs 56%), musculoskeletal pain (32% vs 27%), pruritus (23% vs 6%), decreased appetite (21% vs 21%), nausea (21% vs 29%), and rash (20% vs 13%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients, the most frequent (≥2%) of which were urinary tract infection, pneumonia, anemia, and pneumonitis.

There is limited experience in pediatric patients. Efficacy for pediatric patients was extrapolated from the results in the adult cHL population. In a study of 40 pediatric patients with advanced melanoma, PD-L1–positive advanced, relapsed, or refractory solid tumors or lymphoma, patients were treated with KEYTRUDA (pembrolizumab) for a median of 43 days (range 1-414 days), with 24 patients (60%) receiving treatment for 42 days or more. The safety profile in pediatric patients was similar to that seen in adults treated with KEYTRUDA. Toxicities that occurred at a higher rate (≥15% difference) in these patients when compared to adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), hypertransaminasemia (28%), and hyponatremia (18%).

It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.