Date: 2015-12-19
Type of information: Publication of results in a medical journal
phase: 2-3
Announcement: publication of results in The Lancet
Company: Merck&Co (USA - NJ)
Product: Keytruda® (pembrolizumab)
Action
mechanism: monoclonal antibody/immune checkpoint inhibitor. Keytruda® (pembrolizumab - MK-3475) is an investigational, highly selective monoclonal anti-PD-1 antibody designed to restore the natural ability of the immune system to recognize and target cancer cells by selectively achieving dual ligand blockade (PD-L1 and PD-L2) of the PD-1 protein. By blocking PD-1, MK-3475 enables activation of the immune system’s T-cells that target cancer by essentially releasing a brake on the immune system. MK-3475 is currently being studied in three clinical trials for advanced melanoma including a Phase III trial of MK-3475 versus ipilimumab in ipilimumab-naïve advanced melanoma patients (PN 006). Enrollment is complete in the advanced melanoma cohorts in the company’s Phase IB trial (PN 001) and the Phase II trial (PN 002) comparing two doses of MK-3475 versus chemotherapy in patients with advanced melanoma who have progressed after prior therapy. Pembrolizumab is being evaluated across more than 30 types of cancers, as monotherapy and in combination. It is anticipated that by the end of 2014, the pembrolizumab development program will grow to more than 24 clinical trials, enrolling an estimated 6,000 patients at nearly 300 clinical trial sites worldwide. In April 2013, MK-3475 has received a Breakthrough Therapy designation for advanced melanoma from the FDA. In October 2014, the FDA has gralso anted Breakthrough Therapy Designation to Keytruda® (pembrolizumab) for the treatment of patients with Epidermal Growth Factor Receptor (EGFR) mutation-negative, and Anaplastic Lymphoma Kinase (ALK) rearrangement-negative non-small cell lung cancer (NSCLC) whose disease has progressed on or following platinum-based chemotherapy. In November 2015, the FDA has granted Breakthrough Therapy Designation to Keytruda® for the treatment of patients with microsatellite instability high (MSI-H)metastatic colorectal cancer. Keytruda® is the first approved drug that blocks the PD-1 cellular pathway. The Keytruda® clinical development program includes patients with more than 30 tumor types in more than 160 clinical trials, including more than 80 trials that combine Keytruda® with other cancer treatments. Registration-enabling trials of Keytruda® 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.
Disease: patients with non-small cell lung cancer (NSCLC) who have experienced disease progression after platinum-containing systemic therapy
Therapeutic area: Cancer - Oncology
Country:
Trial
details: KEYNOTE-010 is a global, open-label, randomized, pivotal Phase 2/3 study 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. (NCT01905657) 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® 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.
Latest
news: * On December 19, 2015, Merck&Co announced 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). 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) Asia 2015 Congress. Merck&Co plans to submit a supplemental Biologics License Application (sBLA) to theFDA 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). 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]).
