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Treatment-Free Survival as an Outcome Measure of Nivolumab/Ipilimumab Therapy in Advanced Melanoma


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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

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.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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