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Two-drug immunotherapy combination may offer better survival in advanced melanoma

  • F. Stephen Hodi, Jr., MD

    Combining two immunotherapy drugs upfront for advanced melanoma appears to increase the two-year survival rate over that achieved with a single agent, according to an analysis of results from a multi-center phase II clinical trial, scientists report.

    In a group of patients who received both nivolumab (Opdivo) and ipilimumab (Yervoy), the two-year survival rate was 63.8 percent compared to 53.6 percent treated with ipilimumab alone, reported researchers from Dana-Farber Cancer Institute and Memorial Sloan Kettering Cancer Center.

    Although the difference wasn’t statistically significant, the authors of the study in The Lancet Oncology said the results suggest that the combination “might lead to improved outcomes compared with ipilimumab alone in patients with advanced melanoma.” Thus far, the median survival rate has not been reached in either treatment group.

    The report represents the longest follow-up to date of patients with advanced melanoma who received the nivolumab-ipilimumab combination in a randomized clinical trial, say the authors. First author is F. Stephen Hodi, Jr., MD, director of Dana-Farber’s Melanoma Center and its Center for Immuno-Oncology. The analysis of results from the CheckMate 069 Phase II trial is based on results in 140 patients treated at 19 centers in the United States and France.

    Both drugs target checkpoint molecules – protein switches that cancer cells can exploit to avoid recognition and attack by defender T cells of the immune system. Drugs that disable the checkpoint switches are designed to allow immune system T cells to home in on cancer cells and destroy them. Ipilimumab targets as checkpoint called CTLA-4, while nivolumab blocks the PD-1 checkpoint.

    Until the advent of new immunotherapy drugs, advanced metastatic melanoma had a median overall survival of about 8 months, with a five-year survival rate of only 10 percent. Ipilimumab was the first agent to improve survival, achieving a two-year survival of 25 percent and a three-year survival rate of 22 percent in pooled clinical trials.

    Newer PD-1 checkpoint blocking drugs like nivolumab and pembrolizumab (Keytruda) have proven to be more effective than ipilimumab as single agents.

    In the current study, patients were randomized to receive ipilimumab plus nivolumab, or ipilimumab plus a placebo. Treatment continued as long as the drugs were having clinical benefit until unacceptable side effects occurred or the patient asked to stop treatment. Patients whose disease began to progress while being treated with ipilimumab alone were allowed to “cross over” and receive nivolumab as well.

    Along with improved survival, patients who received the two-drug combination had a higher proportion of responses – tumor shrinkage or disappearance – as well as longer time until the disease worsened.

    As expected, patients who underwent combined treatment had a higher rate of side effects, including those classified as more severe (grade 3 or 4). Three patients in the combination group died from treatment-related side effects. The investigators said these results reflect an acceptable risk-benefit profile and noted that further research will be done to reduce the most severe side effects of combination immunotherapy treatment.

    The trial is funded by Bristol-Myers Squibb, which manufactures nivolumab.

Posted on September 08, 2016

  • F. Stephen Hodi, MD
  • Immunotherapy
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