Pembrolizumab Improves Overall Survival in Patients with Advanced Melanoma
Interim results from an international randomized phase III trial show that patients with advanced melanoma who received pembrolizumab (Keytruda®) had longer progression-free survival and overall survival than those who received ipilimumab (Yervoy®) and experienced fewer adverse effects.
New England Journal of Medicine, April 19, 2015 (see the journal abstract.)
Pembrolizumab and ipilimumab are targeted therapies known as immune checkpoint inhibitors. Both agents were designed to harness the body’s immune system to fight cancer. However, the drugs have different molecular targets and affect the immune response to cancer in different ways.
Ipilimumab, a monoclonal antibody, binds to a protein called CTLA4, which is found on the surface of T cells. CTLA4 is a checkpoint protein that normally acts to keep immune responses in check to prevent overly strong responses that might damage normal cells as well as abnormal cells. The binding of ipilimumab to CTLA4 relieves this suppression. Ipilimumab was the first immune checkpoint inhibitor to be approved by the Food and Drug Administration (in 2011) to treat advanced melanoma.
Pembrolizumab, also a monoclonal antibody, binds to PD-1, another protein on T cells. 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, pembrolizumab was approved by the Food and Drug Administration as a second-line treatment for advanced melanoma that has progressed (gotten worse) during treatment with ipilimumab or BRAF inhibitors.
The current study is the first head-to-head comparison of pembrolizumab and ipilimumab for treating advanced melanoma.
In the KEYNOTE-006 trial, 834 patients with advanced melanoma were randomly assigned to receive one of three treatment regimens: pembrolizumab at a dose of 10 milligrams per kilogram of body weight every 2 weeks; the same dose of pembrolizumab every 3 weeks; or four cycles of ipilimumab at 3 milligrams per kilogram of body weight every 3 weeks.
The primary endpoints of the study were progression-free survival and overall survival. Secondary endpoints included the objective response rate (defined as the percentage of patients with complete responses or partial responses), the duration of response, and safety.
Caroline Robert, M.D., Ph.D., of Gustave Roussy and INSERM, was the first author of the study, which was sponsored by Merck Sharp & Dohme, the maker of pembrolizumab.
At the first interim analysis, the 6-month progression-free survival rates were 47.3 percent for patients receiving pembrolizumab every 2 weeks, 46.4 percent for patients receiving pembrolizumab every 3 weeks, and 26.5 percent for patients receiving ipilimumab. Median progression-free survival was 5.5 months, 4.1 months, and 2.8 month, respectively.
At the second interim analysis, the estimated 12-month overall survival rates were 74.1 percent for patients receiving pembrolizumab every 2 weeks, 68.4 percent for patients receiving pembrolizumab every 3 weeks, and 58.2 percent for patients receiving ipilimumab. Because the interim analysis showed a clear overall survival advantage for the two pembrolizumab groups over the ipilimumab group, an independent data safety and monitoring committee recommended stopping the trial early to allow patients in the ipilimumab group the option to receive pembrolizumab.
Patients in the pembrolizumab groups had higher objective response rates than those in the ipilimumab group: 33.7 percent for patients receiving pembrolizumab every 2 weeks, 32.9 percent for patients receiving pembrolizumab every 3 weeks, and 11.9 percent for patients receiving ipilimumab. The study authors found no apparent differences in effectiveness between the two pembrolizumab dosing regimens evaluated in the clinical trial.
The two pembrolizumab groups had fewer treatment-related adverse events of grade 3 or higher compared with the ipilimumab group: 13.3 percent and 10.1 percent versus 19.9 percent, respectively. There was one treatment-related death in the ipilimumab group. The patient had a history of type 2 diabetes and died from “cardiac arrest secondary to metabolic imbalances associated with ipilimumab-induced diarrhea,” the study authors noted.
Among patients in the pembrolizumab groups, the most common side effects included fatigue, rash, and itchy skin (pruritus); in the ipilimumab group, the most common side effects were pruritus, diarrhea, fatigue, and rash.
Information on long-term survival is needed to get a better measure of the comparison over time. The study will continue safety and survival follow-up until the final analysis.
The study authors noted that more research is needed to determine the most appropriate treatments for melanomas that include BRAF mutation. “The treatment of patients with BRAF V600 mutations and, in particular, the most effective sequence of immunotherapy and BRAF or MEK inhibitors remains one of the most critical, yet unanswered, questions,” the authors wrote.
“This study should help to establish pembrolizumab as a single-drug treatment for first-line metastatic melanoma and will improve the lives of many patients,” said Howard Streicher, M.D., of NCI’s Cancer Therapy Evaluation Program, who was not involved in the trial. The results for each agent are very much in line with previous studies, he added.
Pembrolizumab and ipilimumab have distinct effects on the immune system, Dr. Streicher continued, and there are critical questions that remain to be answered, including whether they can be used together. “The combination of these two types of drugs may be the best choice of treatment for some patients, and this needs to be explored further,” he said.
A related question is whether other drugs that inhibit PD-1 would have similar benefits for patients with advanced melanoma. “I would expect that to be the case, but it needs to be tested,” Dr. Streicher said.