On November 12, 2016 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported results from the pivotal KEYNOTE-045 study investigating the use of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, in patients with advanced bladder (urothelial) cancer previously treated with platinum-containing chemotherapy (Press release, Merck & Co, NOV 12, 2016, View Source [SID1234516529]). As previously announced, KEYTRUDA was superior to investigator-choice chemotherapy for the primary endpoint of overall survival (OS) in this phase 3 study, and was stopped early. Specifically, there was a 27 percent reduction in the risk of death in patients treated with KEYTRUDA compared to chemotherapy (OS, HR = 0.73, p-value: 0.0022). Data presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 31st Annual Meeting are the first publicly presented findings from this study.

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"The improved overall survival for patients receiving KEYTRUDA in this trial are clinically significant and could impact how physicians consider treating patients with previously treated advanced urothelial cancer," said Dr. Roger Dansey, senior vice president, oncology late-stage development, Merck Research Laboratories. "These data add to the growing body of evidence from our clinical development program for KEYTRUDA in a range of cancers, including advanced urothelial cancer."

Study findings are being presented by Dr. Joaquim Bellmunt from Dana-Farber Cancer Institute on Saturday, Nov. 12th from 11:45 a.m. – 12:00 p.m. ET (Abstract #470).

"There have been few advancements in the treatment of bladder cancer in the past several decades, with chemotherapy being the only option," said Dr. Dean F. Bajorin, study investigator and medical oncologist at Memorial Sloan Kettering Cancer Center. "These data demonstrate the potential for pembrolizumab to provide a meaningful improvement in overall survival for patients with advanced urothelial cancer who previously have received platinum-containing chemotherapy."

The KEYTRUDA (pembrolizumab) clinical development program includes more than 30 tumor types in more than 360 clinical trials, including nearly 200 trials that combine KEYTRUDA with other cancer treatments. Currently, Merck has the largest immuno-oncology clinical development program in bladder cancer, with 27 trials underway involving KEYTRUDA as monotherapy and in combination, including four registration-enabling studies.

Findings from KEYNOTE-045

KEYNOTE-045 is a randomized, pivotal, phase 3 study evaluating KEYTRUDA monotherapy compared to investigator-choice chemotherapy (paclitaxel, docetaxel, vinflunine) in the treatment of patients with metastatic or locally advanced, unresectable (inoperable) urothelial cancer (urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra) that has recurred or progressed following platinum-based chemotherapy. The co-primary endpoints are OS and progression-free survival (PFS); secondary endpoints are overall response rate (ORR), duration of response, and safety. The study randomized 542 patients to receive KEYTRUDA (200 mg every three weeks) (n=270) or investigator-choice chemotherapy (n=272) – either paclitaxel (175 mg/m2 every three weeks), docetaxel (75 mg/m2 every three weeks), or vinflunine (320 mg/m2 every three weeks). The study was designed to assess key endpoints in patients with or without PD-L1 expression (the total study population, n=542), as well as in patients with PD-L1 expressing tumors (expression of 10% or more) (n=74/270 in the KEYTRUDA arm; n=90/272 in the chemotherapy arm).

Findings presented at SITC (Free SITC Whitepaper) from the total study population showed a significant improvement in OS with KEYTRUDA compared to chemotherapy, with a 27 percent reduction in the risk of death (HR: 0.73 [95% CI, 0.59 – 0.91], p-value: 0.0022). Median OS was 10.3 months (95% CI, 8.0 – 11.8) with KEYTRUDA, compared to 7.4 months (95% CI, 6.1 – 8.3) in the chemotherapy arm. The estimated one-year OS rate was 43.9 percent with KEYTRUDA, compared to 30.7 percent in the chemotherapy arm.

In the OS analysis of patients with PD-L1 expression, there was a 43 percent reduction in the risk of death with KEYTRUDA, compared to chemotherapy (HR: 0.57 [95% CI, 0.37 – 0.88], p-value: 0.0048). Median OS was 8.0 months (95% CI, 5.0 – 12.3) with KEYTRUDA, compared to 5.2 months (95% CI, 4.0 – 7.4) in the chemotherapy arm. The estimated one-year OS rate was 39.8 percent with KEYTRUDA, compared to 26.9 percent in the chemotherapy arm.

An analysis of the study’s second primary endpoint, PFS, in the total study population showed a median PFS of 2.1 months (95% CI, 2.0 – 2.2) with KEYTRUDA, compared to 3.3 months (95% CI, 2.3 – 3.5) in the chemotherapy arm (HR: 0.98 [95% CI, 0.81 – 1.19], p-value: 0.42). The six-month PFS rate was 28.8 percent with KEYTRUDA, compared to 26.8 in the chemotherapy arm; the one-year PFS rate was 16.8 percent with KEYTRUDA, compared to 6.2 percent in the chemotherapy arm.

The difference in response rates between the two arms was 9.6 percentage points (p-value: .0011), which was statistically significant and in favor of KEYTRUDA. The ORR was 21.1 percent with KEYTRUDA (7.0% were complete responses), compared to 11.4 percent in the chemotherapy arm (3.3% were complete responses). In patients with PD-L1 expression, ORR was 21.6 percent with KEYTRUDA (6.8% were complete responses), compared to 6.7 percent in the chemotherapy arm (2.2% were complete responses).

The median duration of response for patients treated with KEYTRUDA had not yet been reached at the time of analysis (range: 1.6+ to 15.6+ months) – with 68 percent of responses estimated to last for 12 months or more. In the chemotherapy arm, the median duration of response was 4.3 months (range: 1.4+ to 15.4+ months) – with 35 percent of responses estimated to last for 12 months or more.

The safety profile of KEYTRUDA in this trial was consistent with that observed in previously reported studies involving patients with advanced urothelial cancer. The treatment-related adverse events observed in this trial (any grade occurring in 10 percent or more) were pruritus (19.5% with KEYTRUDA; 2.7% with chemotherapy), fatigue (13.9% with KEYTRUDA; 27.8% with chemotherapy), nausea (10.9% with KEYTRUDA; 24.3% with chemotherapy), diarrhea (9.0% with KEYTRUDA; 12.9% with chemotherapy), decreased appetite (8.6% with KEYTRUDA; 16.1% with chemotherapy), asthenia (5.6% with KEYTRUDA; 14.1% with chemotherapy), anemia (3.4% with KEYTRUDA; 24.7% with chemotherapy), constipation (2.3% with KEYTRUDA; 20.4% with chemotherapy), peripheral sensory neuropathy (0.8% with KEYTRUDA; 11.0% with chemotherapy), peripheral neuropathy (0.4% with KEYTRUDA; 10.6% with chemotherapy), neutrophil count decreased (0.4% with KEYTRUDA (pembrolizumab); 14.1% with chemotherapy), alopecia (37.6% with chemotherapy) and neutropenia (15.3% with chemotherapy). Immune-mediated adverse events were thyroid abnormalities (9.4% with KEYTRUDA (pembrolizumab); 1.6% with chemotherapy), pneumonitis (4.1% with KEYTRUDA; 0.4% with chemotherapy), colitis (2.3% with KEYTRUDA; 0.4% with chemotherapy), infusion reactions (0.8% with KEYTRUDA; 3.9% with chemotherapy), severe skin toxicity (0.8% with KEYTRUDA; 1.2% with chemotherapy), nephritis (0.8% with KEYTRUDA), adrenal insufficiency (0.4% with KEYTRUDA) and myositis (0.4% with chemotherapy). Fifteen patients in the KEYTRUDA arm and 28 patients in the chemotherapy arm discontinued treatment due to a treatment-related adverse event; there were four treatment-related deaths in each arm.

About Bladder Cancer

Bladder cancer begins when cells in the urinary bladder start to grow uncontrollably. As more cancer cells develop, they can form a tumor and spread to other areas of the body. Urothelial carcinoma, the most common type of bladder cancer, starts in the urothelial cells that line the inside of the bladder. In 2012, approximately 430,000 people worldwide were diagnosed with bladder cancer and 165,000 died from the disease. The incidence of bladder cancer is elevated in North America, Europe, North Africa, the Middle East, Australia and New Zealand.

About KEYTRUDA (pembrolizumab)

KEYTRUDA is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA 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.

KEYTRUDA is administered as an intravenous infusion over 30 minutes every three weeks for the approved indications. KEYTRUDA for injection is supplied in a 100 mg single use vial.

KEYTRUDA Indications and Dosing

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a dose of 2 mg/kg every three weeks until disease progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA 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 (pembrolizumab) 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.

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.

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.

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 (pembrolizumab) 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 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.

KEYTRUDA can cause other clinically important immune-mediated adverse reactions. 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 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%), exfoliative dermatitis, bullous pemphigoid, rash (1.4%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma.

KEYTRUDA can cause severe or life-threatening infusion-related reactions, 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.

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 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 (pembrolizumab).

In KEYNOTE-002, KEYTRUDA was discontinued due to adverse reactions in 12% of 357 patients with advanced melanoma; 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 (pembrolizumab) occurred in 14% of patients; the most common (≥1%) were dyspnea (1%), diarrhea (1%), and maculopapular rash (1%). The most common adverse reactions with KEYTRUDA vs chemotherapy were fatigue (43% with KEYTRUDA), pruritus (28% vs 8%), rash (24% vs 8%), constipation (22% vs 20%), nausea (22% with KEYTRUDA), diarrhea (20% vs 20%), and decreased appetite (20% with KEYTRUDA). Corresponding incidence rates are listed for chemotherapy only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.

KEYTRUDA 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%).

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.

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.

Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.