Washington, DC—The combination of nivolumab plus ipilimumab improved survival compared with ipilimumab alone in patients with previously untreated advanced melanoma, according to updated results of the phase 3 CheckMate-067 clinical trial presented at the 2017 meeting of the American Association for Cancer Research. A descriptive analysis suggested that the combination was superior to nivolumab monotherapy, although that was not a prespecified end point of the study.
“The combination did better across all relevant subgroups. Median duration of response and time to subsequent therapy are not yet reached for the combination. The safety profile was consistent with earlier reports,” said lead investigator James Larkin, FRCP, PhD, Consultant Medical Oncologist, Royal Marsden Hospital, London, UK.
Despite the generally favorable results for the combination of the 2 immune checkpoint inhibitors, Dr Larkin said findings are speculative at present and do not reflect a new standard of care. Increased costs and toxicity are concerns, and an individualized approach is needed for each patient, he noted.
CheckMate-067 is the first phase 3 clinical trial to demonstrate survival outcomes with a combination of nivolumab plus ipilimumab. The regimen was approved by the FDA in 2015 after trial investigators reported extended progression-free survival in patients who were treated with this therapy.
The trial randomized 945 patients with untreated advanced melanoma 1:1:1 to treatment with nivolumab plus ipilimumab, nivolumab with ipilimumab-matched placebo, or ipilimumab with nivolumab-matched placebo. Treatment was continued until there was evidence of progressive disease or unacceptable toxicity. Patients were stratified according to the presence of BRAF mutation, M stage, and level of PD-L1 expression. The co-primary end points were progression-free survival and overall survival in an intent-to-treat analysis.
At a minimum follow-up of 28 months, median overall survival was 20 months for ipilimumab and not yet reached for the nivolumab monotherapy or the nivolumab plus ipilimumab combination (P <.0001 for ipilimumab vs the combination). Subsequent systemic therapy was needed by 32% of patients in the combination arm, 44% in the nivolumab monotherapy arm, and 62% in the ipilimumab arm. Two-year overall survival rates were 64% for the combination, 59% for nivolumab, and 46% for ipilimumab. Median progression-free survival was 11.7 months, 6.9 months, and 2.9 months, respectively. Objective response rates were 58.9%, 44.6%, and 19%, respectively. Complete response rates were 12.1%, 9.8%, and 2.2%, respectively. Median duration of response was not yet reached for the combination, 31.1 months for nivolumab, and 18.2 months for ipilimumab.
These data suggest that patients with a BRAF mutation, and those with elevated PD-L1 expression, might benefit more from the combination, but this remains speculative, Dr Larkin told listeners.
The safety profile was consistent with earlier experience using both drugs. The rate of grade 3/4 adverse events was higher in the combination arm; 58.5% versus 20.8% in the nivolumab arm and 27.7% in the ipilimumab arm. Most adverse events were manageable and resolved within 3 to 4 weeks. Just under 40% of patients receiving combination therapy stopped treatment because of adverse events.
Responding patients who stopped combination therapy continued to do well. The objective response rate was 70% among those who discontinued combination therapy because of adverse events, and median overall survival was not reached in this group of patients.
Four treatment-related deaths were reported; 2 of these deaths were included in previous reports of the trial. The 2 new deaths, which both occurred in the combination arm, were associated with cardiomyopathy and liver necrosis and occurred more than 100 days following their last treatment.
Suzanne L. Topalian, MD, Professor of Surgery and Oncology and Director, Johns Hopkins University School of Medicine; Melanoma Program, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, noted that immunotherapy combinations represent an active area of research, with hundreds of ongoing trials. She said that identifying biomarkers for response is a pressing need for patient selection for immunotherapy.
