CHICAGO—Ipilimumab and the investigational anti-PD-1 agent, nivolumab, have greater clinical activity when administered concurrently than either agent alone in patients with advanced melanoma, the first phase I study to evaluate this combination concluded at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting.
Rapid and deep tumors responses—80% or greater tumor reduction at 12 weeks—were observed in 16 (31%) of the 52 patients treated. These results were published online in The New England Journal of Medicine at the conclusion of the presentation.
“The complete and near-complete response rates we’re seeing are unprecedented for an immunotherapy in melanoma. We were particularly impressed that the drugs work together so well,” said Jedd D. Wolchok, MD, PhD, a medical oncologist at Memorial Sloan-Kettering Cancer Center, New York, NY.
Patients with inoperable stage III/IV melanoma and three or more prior therapies received intravenous nivolumab (BMS-936558, ONO-4538) and ipilimumab concurrently every 3 weeks for four doses, followed by nivolumab alone every 3 weeks for four doses. “The combined treatment was subsequently administered every 12 weeks for up to 8 doses,” he noted.
A total of 86 patients were treated from December 2009 through February 2013. Among the 52 patients who had completed the concurrent cohorts, objective response rate (ORR) was 40% (95% CI: 27%-55%); three patients had a complete response and 16, a partial response.
The maximum-tolerated dose (MTD), ipilimumab 3 mg/kg plus nivolumab 1 mg/kg, was reached in cohort 2 (n=17); ORR was 53% and seven patients (41%) had 80% or greater tumor reduction at 12 weeks. In cohort 2a, ipilimumab 1 mg/kg plus nivolumab 3 mg/kg, ORR was 40% (95% CI: 16%-68%) and five patients (33%) had an 80% or greater tumor reduction at 12 weeks. For cohort 3, ipilimumab 3 mg/kg plus nivolumab 3 mg/kg, ORR was 50% (95% CI: 12%-88%); none of the patients had 80% or greater tumor reduction at 12 weeks.
After approximately 13 months of follow-up, for all concurrent cohorts, 90% of all responding patients continue to respond.
Preliminary survival for the patients treated with the concurrent regimen was 82% (95% CI: 69.0%-94.4%).
Related adverse events (AEs) for concurrent therapy were similar, with some higher in frequency than those typically seen for the monotherapies and were generally manageable using immunosuppressants.
Cohort 3, which exceeded the MTD at ipilimumab 3 mg/kg plus nivolumab 3 mg/kg, had a dose-limiting toxicity of grade 3/4 increased lipase. At the MTD, grade 3/4 related AEs occurred in 59% of patients and included uveitis/choroiditis, colitis, and reversible laboratory abnormalities. There were no treatment-related deaths.
“Based on these results, a phase 3 trial is open to investigate the efficacy of the concurrent nivolumab/ipilimumab combination versus nivolumab versus ipilimumab in patients with advanced melanoma,” Dr. Wolchok said. This combination is also being investigated in non-small cell lung and renal cancers.
This research was supported by Bristol-Myers Squibb.
Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus Ipilimumab in advanced melanoma. N Engl J Med. Epub June 2, 2013.