Combo Therapy A New Standard For Melanoma
Source: Pharmacy Practice News, July 2015
ipilimumab/nivolumab combination provided a nearly 60% increase in progression-free survival (PFS) relative to ipilimumab alone. Drawn from a Phase III trial called CheckMate 067, the data were characterized as setting a new treatment standard.
“Based on the results of nivolumab alone and nivolumab plus ipilimumab arms relative to ipilimumab and the prior study comparing pembrolizumab to ipilimumab, it is my opinion that ipilimumab alone can no longer be considered a standard first-line immunotherapy for patients with advanced melanoma,”
asserted Michael B. Atkins, MD, the deputy director of Georgetown University’s Lombardi Comprehensive Cancer Center, in Washington, D.C., who was the invited discussant for this trial at the 2015 annual meeting of the American Society of Clinical Oncology (ASCO), where the data were presented during the plenary session (abstract LBA1). The study, which was published simultaneously in The New England Journal of Medicine (2015 May 31. [Epub ahead of print]), was supported by Bristol-Myers Squibb.
In this trial, presented by Jedd D. Wolchok, MD, the chief of the Melanoma and Immunotherapeutics Service at Memorial Sloan-Kettering Cancer Center, in New York City, 945 previously untreated patients with unresectable stage III or IV melanoma were randomized to the CTLA-4 checkpoint inhibitor ipilimumab (Yervoy, Bristol-Myers Squibb) alone, the PD-1 checkpoint inhibitor nivolumab (Opdivo, Bristol-Myers Squibb) alone, or a combination of the two. Both medications have indications for melanoma, but they had not been evaluated in combination in a Phase III trial.
After a median follow-up of slightly more than a year, the PFS rates were highest in the combination arm (box). The PFS advantage of the combination treatment was consistent across a large number of subgroups, including BRAF mutation status and PD-L1 expression. However, greater than 5% PD-L1 expression was a factor in relative PFS rates. In patients whose tumors had greater than 5% PD-L1 expression, the median PFS was 3.9 months in the ipilimumab-alone group but 14 months in both the combination group and the nivolumab-alone group. In patients with tumors with less than 5% PD-L1 expression, the median PFS was 2.8 months with ipilimumab alone, 5.3 months with nivolumab alone and 11.2 months with the combination.
Investigator-assessed objective re-sponse rates (57.6%) and complete response rates (11.5%) were also higher with the combination treatment relative to nivolumab alone (43.7% and 8.9%) and ipilimumab alone (19% and 2.2%).
The combination was less well tolerated than either immunotherapy alone. Discontinuations due to adverse events (AEs) occurred in 36.4% of patients in the combination arm versus 7.7% of those receiving nivolumab alone and 14.8% of those receiving ipilimumab alone.
The grade 3 or higher AEs that occurred more commonly with the combination relative to nivolumab alone and ipilimumab alone, respectively, included diarrhea (9.3% vs. 2.2% and 6.1%), rash (4.8% vs. 0.6% and 1.9%), fatigue (4.2% vs. 1.3% and 1.0%), vomiting (2.6% vs. 0.3% and 0.3%) and liver enzyme abnormalities (6.1% vs. 1.0% and 0.6%). However, immune-modulatory agents—used in nearly half of patients receiving nivolumab alone, more than half of those receiving ipilimumab alone and nearly 85% of those receiving both agents—were effective in modifying the intensity of these AEs, according to Dr. Wolchok.
Overall survival data from this trial are pending, but, as noted by Dr. Atkins, the data are already sufficiently compelling to suggest a new standard of care. According to Dr. Atkins, more work needs to be done on biomarkers to predict response and to explore whether alternative ipilimumab schedules or substitution of other immunotherapies for ipilimumab could improve the therapeutic effectiveness of this combination. However, he considered these results to be “the latest in a series of breakthroughs” that have dramatically changed the prognosis of a cancer for which the median survival just five years ago was six to nine months.
Dr. Wolchuk reported financial relationships with Bristol-Myers Squibb, EMD Serono, GlaxoSmithKline, Janssen, Jounce Therapeutics, Medimmune, Merck, Polaris, Polynoma Potenza Therapeutics, Vesuvius and Ziopharm Oncology. Dr. Atkins reported financial relationships with Alkermes, Amgen, Bristol-Myers Squibb, C-Cam, Costim, Genentech, GlaxoSmithKline, Infinity, Lilly, Merck, Neostem, Novartis, Pfizer and X4.