1. Eastman, Peggy

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WASHINGTON, D.C.-Results from the CheckMate 067 clinical trial have shown that overall survival was highest among treatment-naive study subjects with advanced melanoma who received combination therapy with nivolumab and ipilimumab. The results were presented by James Larkin, PhD, FRCP, a consultant medical oncologist at The Royal Marsden in London, at the American Association for Cancer Research (AACR) Annual Meeting, held April 1-5.

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This is the first phase III trial to evaluate overall survival with the combination of anti-PD-1 and anti-CTLA-4 therapies, which have distinct and complimentary pathways, noted Larkin. Two-year overall survival was highest, 64 percent, in those patients randomized to nivolumab plus ipilimumab. The study examined 945 treatment-naive patients with advanced melanoma. Overall survival was lower, 59 percent, for those randomized to nivolumab plus placebo, and 45 percent for those randomized to ipilimumab monotherapy. Researchers noted a limitation of this study is that its design did not compare the combination of nivolumab and ipilimumab against nivolumab monotherapy.


Larkin said the purpose of the trial was to investigate whether treating patients with nivolumab alone or with a combination of nivolumab and ipilimumab could increase the percentage of patients who benefit when compared to the former standard of care, nivolumab montherapy. In 2015, early results from the CheckMate 067 clinical trial showed nivolumab alone or in combination with ipilimumab resulted in longer progression-free survival than ipilimumab alone.


These results led the FDA and the European Medicines Agency to grant approval to the combination of the two drugs for advanced melanoma. Larkin noted the FDA set as a condition of accelerated approval further investigation to show whether the data on progression-free survival would translate into data on improved overall survival. The FDA considers overall survival the gold standard in drug approval.


Overall Survival Results

In the data presented at the AACR meeting and at a news briefing, after a minimum follow-up of 28 months, the median overall survival had not been reached for the combination arm of the study or the nivolumab plus placebo arm. At 28 months, the median overall survival among patients randomly assigned ipilimumab was 20 months. Median duration of response was also higher in the combination therapy arm; it had not been reached in this presentation of study data. It was 31.1 months for the nivolumab plus placebo arm and 18.2 months for the ipililumab alone arm.


Calling the overall survival data "exciting," Larkin stated, "Results consistently favored nivolumab and ipilimumab across clinically relevant subgroups." These included PD-L1 expression and mutant BRAF. "The safety profile of the combination was consistent with earlier experience, and early discontinuation due to adverse events did not preclude benefit."


Although most adverse events were managed and resolved within 3-4 weeks, Larkin said the combination did result in "a higher rate of severe adverse events than nivolumab or ipilimumab alone, so it is important to consider this when making treatment decisions for patients." For example, it is important to take the patient's general fitness into account. Response to targeted BRAF therapy might also be another factor to consider.


Specifically, the frequency of grade 3/4 adverse events was higher among study subjects in the combination drug arm compared to those in the other two study arms: 58 percent compared to 21 percent for those in the nivolumab plus placebo arm and 28 percent for those in the ipilumumab alone arm. The most commonly observed side effects in the combination therapy arm were diarrhea/colitis and hepatitis, which were generally manageable.


Biomarkers & Immunotherapy

Asked by Oncology Times if the availability of biomarkers showing which advanced melanoma patients would respond best to the combination might be beneficial for reimbursement-given the high cost of immunotherapy agents-Larkin said, "Ultimately, I think we all want to have biomarkers. The biomarkers need to be robust. Understanding the biology is what we really need to do."


He noted the United Kingdom's National Institute for Health and Care Excellence, which publishes evidence-based guidelines, has examined and taken a favorable view of the new immunotherapy drugs for advanced melanoma.


Agreeing on the need for biomarkers was news briefing moderator Suzanne Topalian, MD, Director of the Melanoma Program at Sidney Kimmel Comprehensive Center at Johns Hopkins and Associate Director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy. "We'd like to find biomarkers to identify patients most likely to respond."


"The current report confirms what was presented in 2015," said CheckMate 067 study co-author F. Stephen Hodi, MD, Director of the Center for Immuno-Oncology and Director of the Melanoma Disease Center at the Dana-Farber Cancer Institute. In an interview, Hodi added that the trial data "are still not quite mature yet," and "it's going to be exciting to follow this data out. ...We're hoping we can improve outcomes."


Hodi noted that, now that it has been approved by the FDA, the combination of nivolumab and ipilimumab is widely used in clinical practice for selected patients with advanced melanoma, including first-line therapy. Asked about patient selection for first-line therapy with the combination, he said the decision should always be made after a discussion with the patient, based on that patient's individual health, risk profile, and preferences-taking into account the fact that the combination therapy has higher toxicity.


Asked to comment on the contribution of immunotherapy to clinical practice, Hodi said, "It's a game changer." But, he noted, that a bright view of immunotherapy and its hope for the future did not always exist. "Ten or 15 years ago, I was laughed at. ...No one understood it." Now, "we're in chapter one of what I hope will be a very long novel."


Peggy Eastman is a contributing writer.