CHICAGO, IL—Concurrent treatment with nivolumab plus ipilimumab resulted in “unprecedented” 2-year rates of overall survival (OS) in patients with advanced melanoma regardless of BRAF-mutation status, long-term follow-up results of patients enrolled in the initial four concurrent dosing cohorts of a phase 1 study concluded at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting.
For the 53 patients overall in cohorts 1, 2, 2a, and 3, the 2-year OS rate was 79%; for the 17 patients in cohort 2 alone, it was 95% at 1-year and 88% at 2 years. Median overall survival (OS) was 40 months, said Mario Sznol, MD, a Professor of Medical Oncology at Yale School of Medicine in New Haven, CT, nearly double that observed in previous studies of either agent alone.
The trial enrolled patients with inoperable stage 3 or 4 melanoma from 2009 to 2012 with three or fewer prior therapies to intravenous checkpoint inhibitors nivolumab (PD-1) every 3 weeks for eight cycles plus ipilimumab (CTLA-4) every 3 weeks for four cycles at four concurrent dose levels.
In patients with disease control and no lose-limiting toxicities, nivolumab plus ipilimumab was continued every 12 weeks for eight cycles.
Median age of all patients was 56 years (range, 22-80 years), and 53% were male; 45% had prior systemic therapy (including 5% with a BRAF inhibitor) and 53% had stage M1c disease at study entry.
In concurrent cohorts 1 to 3, the overall response rate (ORR) was 42% in the 53 patients; complete response (CR) was 17%. The aggregate clinical activity rate was 65%, with 42% of patients having an 80% or greater reduction in tumor burden at 36 weeks. Median progression-free survival (PFS) was 27 weeks.
During his presentation, Dr. Sznol also reported responses in a new cohort, cohort 8, of 41 patients using the phase 2/3 dosing regimen, nivolumab 1 mg/kg every 3 weeks for eight cycles plus ipilimumab 3 mg/kg every 3 weeks for four cycles followed by maintenance nivolumab 3 mg/kg every 2 weeks for a maximum of 48 doses.
In cohort 8, the ORR was 43%, CR, 10% (2 confirmed and 2 unconfirmed responses), aggregate clinical activity rate, 53%, and tumor burden reduction of 80% or greater at 36 weeks, 28%. Median OS has not been reached and median PFS was 37 weeks.
The median duration of response in the cohorts has not been reached and, in 18 of 22 patients, responses are ongoing.
Dr. Sznol said no new safety signals have been observed with 22 months of follow-up for the initial concurrent cohorts. Among all patients, 22 (23%) of 94 discontinued because of treatment-related adverse events (AEs). The most commonly occurring types of AEs were gastrointestinal, hepatic, and skin, as well as increased lipase. One drug-related death occurred as a result of multi-organ failure from colitis in cohort 8.
Mutant BRAF or low or absent PD-L1 tumor expression was not found to substantially impact activity, Dr. Sznol said.
A phase 2 and aphase 3 trial investigating concurrent nivolumab plus ipilimumab in combination versus nivolumab versus ipilimumab in patients with advanced melanoma have both completed enrollment, and the combination is being investigated in other tumor types, he concluded.
- Sznol M, Kluger HM, Callahan MK et al. Abstract LBA9003. Presented at: 2014 American Society of Clinical Oncology (ASCO) Annual Meeting; May 30-June 3, 2014; Chicago, IL.