Merck announced results from the randomized, pivotal Phase III study, KEYNOTE-006, in the treatment of unresectable advanced melanoma. In the study, pembrolizumab was statistically superior to ipilimumab for progression-free survival (PFS), overall survival (OS), and overall response rate (ORR). On March 24, 2015, Merck announced that KEYNOTE-006 would be stopped early based on these data. The results will be presented today at the American Association for Cancer Research (AACR) Annual Meeting by Dr. Antoni Ribas of Jonsson Comprehensive Cancer Center, University of California, Los Angeles (abstract # CT101, included in the AACR press program), and were also published today in the New England Journal of Medicine.

Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blocking the interaction with the receptor ligands, pembrolizumab releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumour immune response.

Merck is advancing a broad and fast-growing clinical development program for pembrolizumab with more than 85 clinical trials – across more than 30 tumour types and more than 14,000 patients—both as a monotherapy and in combination with other therapies.

"Improving survival is the ultimate objective in treating patients with cancer. In this important study in advanced melanoma, pembrolizumab was statistically superior to ipilimumab for progression-free survival and overall survival, and also demonstrated a lower frequency of severe adverse events," said Dr. Caroline Robert, head of Dermatology at Gustave Roussy, Villejuif and Paris-Sud University Cancer Campus, Grand Paris and lead author of the New England Journal of Medicine publication.

"Our goal with the pembrolizumab development program is to help improve long-term disease control and survival for people with a wide range of cancers," said Dr. Roger Perlmutter, president, Merck Research Laboratories. "The KEYNOTE-006 study compared two immunotherapies that target distinct immune checkpoint pathways, PD-1 and CTLA-4. In this study, our investigational anti-PD-1 antibody, pembrolizumab, improved overall survival by more than 30 percent compared to ipilimumab, an anti-CTLA-4 antibody, in the treatment of advanced melanoma. We look forward to filing these data with health authorities around the world."

"Metastatic melanoma is a devastating disease with a very poor prognosis and historically, therapeutic options have been limited," explained Dr. Teresa Petrella, Head of the Melanoma Disease Site Group at the Odette Cancer Centre, Sunnybrook Health Sciences Centre. "However, new agents and treatment strategies are changing the landscape of the management of melanoma. The rapidly evolving field of immuno-oncology is finally bringing new hope to cancer patients in Canada."  She adds, "Many Canadian melanoma patients participated in the KEYNOTE-006 trial. This is an exciting time in melanoma, and new therapies that have now shown an improvement in overall survival represent a potential new treatment option in a population with a high unmet need."

KEYNOTE-006 is a global, open-label, randomized, pivotal, Phase III study (ClinicalTrials.gov, NCT01866319) of 834 patients from 16 countries with unresectable stage III or IV advanced melanoma with no more than one prior systemic therapy. Patients received pembrolizumab 10 mg/kg every two weeks (n=279), pembrolizumab 10 mg/kg every three weeks (n=277), or four cycles of ipilimumab 3 mg/kg every three weeks (n=278). The primary endpoints were PFS and OS; secondary endpoints were ORR, duration of response, and safety. Tumour response was assessed at week 12, then every six weeks thereafter by independent central review per RECIST 1.1. This first presentation of data from KEYNOTE-006 is based on interim analyses conducted for PFS with a data cut-off of September 3, 2014 (median follow-up, 7.9 months) and for OS with a data cut off of March 3, 2015 (median follow-up, 13.8 months).

The median PFS for pembrolizumab was 5.5 months (2-week group) and 4.1 months (3-week group) compared to 2.8 months for ipilimumab (HR 0.58, P<0.00001 for the pembrolizumab groups vs. ipilimumab, 95% CI, 0.46-0.72 for 2-week group and 0.47-0.72 for 3-week group, respectively). The estimated 6-month PFS rates for the pembrolizumab and ipilimumab arms were 47.3 percent, 46.4 percent and 26.5 percent, respectively. One-year OS for pembrolizumab was 74.1 percent (2-week group) and 68.4 percent (3-week group) compared to 58.2 percent for ipilimumab (HR 0.63 [95% CI, 0.47-0.83, P=0.00052] for the 2-week group and HR 0.69 [95% CI, 0.52-0.90, P=0.00358] for the 3-week group). At the time of analysis, median overall survival was not reached in any treatment group.

ORR for pembrolizumab was 33.7 percent (2-week group) and 32.9 percent (3-week group) compared to 11.9 percent for ipilimumab (P=0.00013 for 2-week group; P=0.00002 for 3-week group); complete response rates were 5.0 percent, 6.1 percent, and 1.4 percent, respectively. Responses were ongoing in 89.4 percent (2-week group) and 96.7 percent (3-week group) of pembrolizumab-treated patients and in 87.9 percent of ipilimumab-treated patients. Median duration of response was not reached for pembrolizumab 3-week group (42+ to 246+) and ipilimumab (33+ to 239+).

The efficacy and safety profiles were similar between the two pembrolizumab schedules evaluated in the study. Two previous studies, KEYNOTE-001 and KEYNOTE-002, demonstrated that the efficacy and safety were similar among the pembrolizumab doses and schedules evaluated; 10 mg/kg every two weeks, 10 mg/kg every three weeks, and 2 mg/kg every three weeks. 

The safety profile of pembrolizumab in this study was generally consistent with previously reported safety data. The most common treatment-related adverse events of any grade occurring in the pembrolizumab groups were fatigue, diarrhea, rash, and pruritus. For ipilimumab, the most frequent treatment-related adverse events were pruritus, diarrhea, fatigue, and rash. Grade 3 to 4 treatment-related adverse events occurred in 13.3 percent (2-week group) and 10.1 percent (3-week group) of patients treated with pembrolizumab and in 19.9 percent for ipilimumab. Discontinuation due to treatment-related adverse events was less frequent with pembrolizumab (2-week group and 3-week group) than with ipilimumab (4.0%, 6.9%, and 9.4%, respectively). One death in the ipilimumab group was attributed to study treatment.

Treatment-related adverse events of an autoimmune or immune-related nature most frequently observed with pembrolizumab (2-week group and 3-week group) were hypothyroidism (10.1% and 8.7%) and hyperthyroidism (6.5% and 3.2%). With ipilimumab, colitis occurred in 8.2 percent of patients. Grade 3 to 4 inflammatory or immune-mediated treatment events reported in more than 1 percent of pembrolizumab-treated patients (2-week group and 3-week group) were colitis (1.4% and 2.5%) and hepatitis (1.1% and 1.8%), and in ipilimumab-treated patients were colitis (7.0%) and hypophysitis (1.6%).