On July 20, 2015 National Cancer Institute reported that Interim results from a randomized controlled phase II trial show that pembrolizumab (Keytruda) improves progression-free survival in patients with melanoma that has gotten worse during treatment with ipilimumab (Yervoy), and with a BRAF or MEK inhibitor (if the tumor carried the BRAF V600 mutation), compared with chemotherapy (Press release, , JUL 20, 2015, View Source [SID:1234506700]).

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The findings were published online in The Lancet Oncology on June 24. Antoni Ribas, M.D., Ph.D., of the University of California, Los Angeles, was the first author of the study, which was sponsored by Merck Sharp & Dohme, the maker of pembrolizumab.

Pembrolizumab is a targeted therapy known as an immune checkpoint inhibitor. The drug, a monoclonal antibody, binds to a protein on T cells called PD-1. When PD-1 is activated by binding to a protein that is produced by many tumor cells, the immune response is suppressed. Binding of pembrolizumab to PD-1 blocks activation of the PD-1 pathway, allowing the immune response to proceed.

In September 2014, the Food and Drug Administration (FDA) granted accelerated approval to pembrolizumab as a second-line therapy for advanced melanoma that has progressed (gotten worse) during treatment with ipilimumab or BRAF inhibitors. The approval was based on results from a randomized phase IB trial, called KEYNOTE-001. As a condition of this accelerated approval, Merck was required to conduct a multicenter randomized trial to establish the superiority of pembrolizumab over standard therapy and to describe its clinical benefit.

In the current trial, called KEYNOTE-002, 540 patients with advanced melanoma were randomly assigned to receive one of three treatment regimens: pembrolizumab at a dose of 2 milligrams per kilogram of body weight every 3 weeks, pembrolizumab at a dose of 10 milligrams per kilogram of body weight every 3 weeks, or chemotherapy selected by the patient’s physician. Neither the patients nor the investigators knew which dose of pembrolizumab individual patients received, although they knew whether the treatment was pembrolizumab or chemotherapy.

Overall survival will be the primary endpoint at the final analysis. At this interim analysis, the primary endpoint was progression-free survival, and the secondary endpoints included safety.

The 6-month progression-free survival rates were 34 percent for patients who received the lower dose of pembrolizumab, 38 percent for patients who received the higher dose of pembrolizumab, and 16 percent for patients who received chemotherapy.

Patients in the pembrolizumab groups had lower incidences of treatment-related grade 3-4 adverse events than patients in the chemotherapy group. Such side effects were seen in 20 patients who received the lower dose of pembrolizumab (11 percent), 25 patients who received the higher dose of pembrolizumab (14 percent), and 45 patients who received chemotherapy (26 percent).

The most common treatment-related grade 3-4 adverse events in the lower-dose pembrolizumab group were fatigue, edema, and myalgia. In the higher-dose pembrolizumab group, the most common treatment-related grade 3-4 adverse events included colitis, decreased appetite, and diarrhea. And for the chemotherapy group, the most common grade 3-4 treatment-related adverse events included anemia, fatigue, and neutropenia.

Study participants were surveyed about their health-related quality of life (HRQoL). Overall, patients in the pembrolizumab groups scored better on HRQoL measures than patients in the chemotherapy group. "The inclusion of HRQoL data is a real strength and reflects the favorable tolerability of pembrolizumab, particularly in a group of patients with poor prognosis and who have been heavily pretreated," wrote the authors of an accompanying editorial.

Although more data are needed to assess overall survival, the current results suggest that the two doses of pembrolizumab are associated with similar outcomes, the study authors noted.

"These findings corroborate published results as well as the FDA’s decision to grant accelerated approval to pembrolizumab," said Howard Streicher, M.D., of NCI’s Cancer Therapy Evaluation Program, who was not involved in the trial. "The study clearly demonstrates the improvement of progression-free survival at either dose of pembrolizumab across every group in the study without regard to age or the number of prior treatments."

Based on the published studies to date, Dr. Streicher added, the emerging standard of care for the initial treatment of metastatic melanoma will involve giving sequences and combinations of the BRAF/MEK inhibitors and PD1/PDL1/CTLA4 monoclonal antibodies, such as ipilimumab, pembrolizumab, and nivolumab (Opdivo).