In a pooled analysis reported in the Journal of Clinical Oncology, Regan et al evaluated treatment-free survival as an outcome measure among patients with advanced melanoma receiving nivolumab/ipilimumab or either agent alone in the CheckMate 067 and 069 trials.
Meredith M. Regan, ScD
Study Details
The study involved data from 1,077 patients initiating treatment with nivolumab/ipilimumab (n = 407), nivolumab (n = 313), or ipilimumab (n = 357) in the two randomized, double-blind trials. In the phase III CheckMate 067 trial, patients received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks, nivolumab 3 mg/kg every 2 weeks plus ipilimumab-matched placebo, or ipilimumab 3 mg/kg every 3 weeks for four doses plus nivolumab-matched placebo followed by placebo every 2 weeks.
In the phase II CheckMate 069 trial, patients received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks or ipilimumab 3 mg/kg with placebo every 3 weeks for four doses followed by placebo every 2 weeks.
In both trials, study treatment continued until disease progression, unacceptable toxicity, or patient decision to withdraw.
Treatment-free survival was defined as the area between Kaplan-Meier curves for two time-to-event endpoints, each defined as time from random assignment: time to immune checkpoint inhibitor protocol therapy cessation, and time to subsequent systemic therapy initiation or death. Treatment-free survival was partitioned as time with and without toxicity using a third endpoint of time to cessation of both immune checkpoint inhibitor therapy and toxicity. In this analysis, toxicity was defined as persistent and late-onset grade ≥ 3 treatment-related adverse events. The area under each Kaplan-Meier curve was estimated using 36-month restricted mean time.
Treatment-Free Survival
At 36 months, 47% of patients in the nivolumab/ipilimumab group, 37% of patients in the nivolumab group, and 15% of patients in the ipilimumab group who initiated therapy had survived free of subsequent therapy initiation. Restricted mean treatment-free survival was 11.1 months with nivolumab/ipilimumab vs 4.6 months with nivolumab (difference = 6.5 months, 95% confidence interval [CI] = 5.0–8.0 months) and 8.7 months with ipilimumab (difference = 2.4 months, 95% CI = 0.8–4.1 months). The restricted mean treatment-free survival accounted for 31% (3% with and 28% without toxicity), 13% (1% with and 11% without toxicity), and 24% (< 1% with and 23% without toxicity) of the 36-month period in the nivolumab/ipilimumab, nivolumab, and ipilimumab groups, respectively.
Restricted mean treatment-free survival without toxicity was 10.1 months with nivolumab/ipilimumab vs 4.1 months with nivolumab (difference = 6.0 months, 95% CI = 4.2–7.7 months) and 8.5 months with ipilimumab (difference = 1.7 months, 95% CI = -0.4–3.6 months).
The investigators concluded, “The analysis of [treatment-free survival] between immune checkpoint inhibitor cessation and subsequent therapy initiation revealed longer [treatment-free survival] without toxicity for patients with advanced melanoma who received nivolumab/ipilimumab compared with nivolumab or ipilimumab. Regardless of treatment, a small proportion of the [treatment-free survival] involved grade 3 or higher [treatment-related adverse events].”
Meredith M. Regan, ScD, of the Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by grants from the National Cancer Institute and National Institutes of Health, Bristol-Myers Squibb, and ONO Pharmaceutical Co. For full disclosures of the study authors, visit jco.ascopubs.org.
