Merck (MRK) Announces Significant Data from KEYTRUDA in Adv. Bladder Cancer

November 14, 2016 6:30 AM EST

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Merck (NYSE: MRK) announced 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. 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’s (SITC) 31st Annual Meeting are the first publicly presented findings from this study.

“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 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.



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