On December 19, 2015 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported results from the pivotal KEYNOTE-010 study, the first study of its kind to evaluate the potential of an immunotherapy compared to chemotherapy based on prospective measurement of PD-L1 expression in patients with advanced non-small cell lung cancer (NSCLC) (Press release, Merck & Co, DEC 19, 2015, View Source [SID:1234508607]). In the Phase 2/3 study, KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 (programmed death receptor-1) therapy, significantly improved overall survival (OS) compared to chemotherapy in patients with any level of PD-L1 expression, as defined by a tumor proportion score (TPS) of 1 percent or more. The results were published in The Lancet and will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Asia 2015 Congress.

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"Because lung cancer remains one of the most common and most challenging cancers to treat, understanding the role that KEYTRUDA can play in helping patients was essential to our development program. In this study in patients with PD-L1 expression of one percent or greater, KEYTRUDA demonstrably improved overall survival compared to chemotherapy in previously-treated patients with non-small cell lung cancer, including both squamous and non-squamous histologies," said Dr. Roger M. Perlmutter, president, Merck Research Laboratories.

Merck plans to submit a supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration for KEYTRUDA based on findings from KEYNOTE-010 by the end of 2015. The Company plans to submit a Marketing Authorization Application to the European Medicines Agency in early 2016.

Overall Survival Findings from KEYNOTE-010

The Phase 2/3 KEYNOTE-010 study included 1,034 patients with advanced NSCLC with PD-L1 expression (TPS of 1% or more). Similar findings were shown in patients who received the FDA-approved dose of KEYTRUDA (pembrolizumab) (2 mg/kg every three weeks) (n=345) and an investigational dose of KEYTRUDA (10 mg/kg every three weeks) (n=346). Both groups of patients who received KEYTRUDA were compared to patients who received docetaxel (n=343). PD-L1 expression was assessed by the immunohistochemistry companion diagnostic test PD-L1 IHC 22C3 PharmDx, made by Dako North America, Inc., an Agilent Technologies Company. The findings from KEYNOTE-010 are based on the final study analysis. The median follow-up was 13.1 months (IQR, 8.6-17.7).

In the total study population (all levels of PD-L1 expression), both doses of KEYTRUDA studied significantly improved OS compared with docetaxel. Specifically, KEYTRUDA resulted in a 29 percent improvement in OS for the 2 mg/kg dose (HR 0.71, P=0.0008; 95% CI, 0.58-0.88) and a 39 percent improvement in OS for the 10 mg/kg dose (HR 0.61, P<0.0001; 95% CI, 0.49-0.75), compared to docetaxel. The estimated 1-year OS rates for KEYTRUDA were 43.2 percent and 52.3 percent, respectively, compared to 34.6 percent for docetaxel. Median OS for KEYTRUDA were 10.4 months (95% CI, 9.4-11.9) and 12.7 months (95% CI, 10.0-17.3), respectively, compared to 8.5 months for docetaxel (95% CI, 7.5-9.8).

Among patients with higher levels of PD-L1 expression (a TPS score of 50 percent or greater), OS was superior for both KEYTRUDA doses compared with docetaxel. Specifically, KEYTRUDA improved OS by 46 percent for the 2 mg/kg dose (HR 0.54, P=0.0002; 95% CI, 0.38-0.77) and by 50 percent for the 10 mg/kg dose (HR 0.50, P<0.0001; 95% CI, 0.36-0.70), compared to docetaxel. Median OS for KEYTRUDA (2 mg/kg and 10 mg/kg, respectively) was 14.9 months (95% CI, 10.4 to not reached) and 17.3 months (95% CI, 11.8 to not reached), compared to 8.2 months for docetaxel (95% CI, 6.4-10.7).

"This is an exciting time, and studies such as KEYNOTE-010 with KEYTRUDA are paving the way to a better understanding of how to identify the right medicine for each patient," said Dr. Roy Herbst, Chief of Medical Oncology, Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven. "These study findings show KEYTRUDA provided superior overall survival in patients with advanced lung cancer who had positive PD-L1 expression, and support its potential in the treatment of this disease."

Additional Findings from KEYNOTE-010

In the total study population, KEYTRUDA (pembrolizumab) prolonged progression-free survival (PFS) at both doses, though statistical significance was not met (HR 0.88 [95% CI, 0.74-1.05], P=0.07 for 2 mg/kg; HR 0.79 [95% CI, 0.66-0.94], P=0.004 for 10 mg/kg). Among patients treated with KEYTRUDA (2 mg/kg and 10 mg/kg, respectively), median PFS was 3.9 months (95% CI, 3.1-4.1) and 4.0 months (95% CI, 2.7-4.3), compared to 4.0 months for docetaxel (95% CI, 3.1-4.2).

Patients with higher levels of PD-L1 expression (a TPS score of 50 percent or greater) who were treated with KEYTRUDA had significantly prolonged PFS compared to docetaxel (HR 0.59 [95% CI, 0.44-0.78, P=0.0001] for 2 mg/kg; HR 0.59 [95% CI, 0.45-0.78, P<0.0001] for 10 mg/kg). Among patients treated with KEYTRUDA (2 mg/kg and 10 mg/kg, respectively), median PFS was 5.0 months (95% CI, 4.0-6.5) and 5.2 months (95% CI, 4.1-8.1), compared to 4.1 months for docetaxel (95% CI, 3.6-4.3).

Additionally, the safety of KEYTRUDA was consistent with what has been seen in previous trials among advanced lung cancer patients. Grade 3-5 treatment-related adverse events for KEYTRUDA (2 mg/kg and 10 mg/kg, respectively) included: decreased appetite (n=3, n=1), fatigue (n=4, n=6), nausea (n=1, n=2), rash (n=1, n=1), diarrhea (n=2, n=0), asthenia (n=1, n=2), stomatitis (n=0, n=1), and anemia (n=3, n=1). The most common immune-mediated adverse events for KEYTRUDA (2 mg/kg and 10 mg/kg, respectively) included: hypothyroidism (8% [n=28], 8% [n=28]), hyperthyroidism (4% [n=12], 6% [n=20]), and pneumonitis (5% [n=16], 4% [n=15]). There were three treatment-related deaths among patients receiving KEYTRUDA at the 2 mg/kg dose (pneumonitis [n=2], pneumonia [n=1]) and three treatment-related deaths among patients receiving KEYTRUDA at the 10 mg/kg dose (myocardial infarction [n=1], pneumonia [n=1], and pneumonitis [n=1]).

About KEYNOTE-010 and the KEYTRUDA Development Program

KEYNOTE-010 is a global, open-label, randomized, pivotal Phase 2/3 study (ClinicalTrials.gov, NCT01905657) evaluating two doses of KEYTRUDA (2 mg/kg or 10 mg/kg every three weeks) compared to docetaxel (75 mg/m^2 every three weeks) in 1,034 patients with squamous and non-squamous NSCLC who experienced disease progression after platinum-containing systemic therapy and whose tumors expressed PD-L1. The primary endpoints were OS and PFS. Tumor response was assessed at week 9, then every 9 weeks thereafter per RECIST 1.1 criteria by independent, central, blinded, radiographic review and investigator-assessed, immune-related response criteria.

The KEYTRUDA program currently addresses more than 30 tumor types in more than 160 clinical trials, including more than 80 combinations of KEYTRUDA with other cancer treatments. In lung cancer, KEYTRUDA is being studied across lines of therapy, both as a monotherapy and in combination with chemotherapy. Registration-enabling trials of KEYTRUDA (pembrolizumab) are currently enrolling patients in melanoma, NSCLC, head and neck cancer, bladder cancer, gastric cancer, colorectal cancer, esophageal cancer, breast cancer, Hodgkin lymphoma, multiple myeloma and other tumors, with further trials in planning for other cancers.