Treatment-Free Survival: A Novel Outcome Measure of the Effects of Immune Checkpoint Inhibition-A Pooled Analysis of Patients With Advanced Melanoma

Abstract

Purpose: Outcome measures that comprehensively capture attributes of immuno-oncology agents, including prolonged treatment-free time and persistent treatment-related adverse events (TRAEs), are needed to complement conventional survival end points.

Methods: We pooled data from the CheckMate 067 and 069 clinical trials of nivolumab and ipilimumab, as monotherapies or in combination, for patients with advanced melanoma. Treatment-free survival (TFS) was defined as the area between Kaplan-Meier curves for two conventional time-to-event end points, each defined from random assignment: time to immune checkpoint inhibitor (ICI) protocol therapy cessation and time to subsequent systemic therapy initiation or death. TFS was partitioned as time with and without toxicity by a third end point, time to cessation of both ICI therapy and toxicity. Toxicity included persistent and late-onset grade 3 or higher TRAEs. The area under each Kaplan-Meier curve was estimated by the 36-month restricted mean time.

Results: At 36 months, many of the 1,077 patients who initiated ICI therapy were surviving free of subsequent therapy initiation (47% nivolumab plus ipilimumab, 37% nivolumab, 15% ipilimumab). The restricted mean TFS was longer for nivolumab plus ipilimumab (11.1 months) compared with nivolumab (4.6 months; difference, 6.5 months; 95% CI, 5.0 to 8.0 months) or ipilimumab (8.7 months; difference, 2.4 months; 95% CI, 0.8 to 4.1 months); restricted mean TFS represented 31% (3% with and 28% without toxicity), 13% (1% and 11%), and 24% (less than 1% and 23%) of the 36-month period, respectively, in the three treatment groups. TFS without toxicity was longer for nivolumab plus ipilimumab than nivolumab (difference, 6.0 months) or ipilimumab (difference, 1.7 months).

Conclusion: The analysis of TFS between ICI cessation and subsequent therapy initiation revealed longer TFS without toxicity for patients with advanced melanoma who received nivolumab plus ipilimumab compared with nivolumab or ipilimumab. Regardless of treatment, a small proportion of the TFS involved grade 3 or higher TRAEs.

FIG 1.

Illustration of the end points that partition the area under the overall survival curve into treatment-free survival (TFS) and other resulting health states. (*) Time after cessation of immuno-oncology (IO) protocol therapy without toxicity before initiation of subsequent systemic anticancer therapy or death. (†) Time after cessation of IO protocol therapy with toxicity while treatment free. (‡) Includes toxicity that persisted since protocol therapy and toxicity that newly presented after protocol therapy cessation.

FIG 2.

Swimmer plots of treatment-free interval between immuno-oncology (IO) protocol therapy cessation and subsequent systemic anticancer (SSAC) therapy initiation for individual patients with advanced melanoma in the CheckMate 067 and 069 trials. Plotted is a random sample of 100 patients per treatment group for (A) nivolumab (NIVO) plus ipilimumab (IPI), (B) NIVO, and (C) IPI. The x-axis is oriented relative to cessation of IO protocol therapy and is truncated at 24 months before and 30 months after cessation. (*) Patients who remained on IO protocol therapy had therapy duration censored at the origin. (†) Treatment-free intervals were highlighted by setting the origin of the x-axis as the point of IO protocol therapy cessation and sorting the individual patients by duration of the treatment-free interval.

FIG 3.

Kaplan-Meier estimates of overall survival (OS) over the 36-month period since random assignment and restricted mean OS according to treatment group. IPI, ipilimumab; NIVO, nivolumab.

FIG 4.

Estimates of treatment-free survival (TFS) and other health states over the 36-month period since random assignment according to treatment group. Data labels represent the mean number of months in any health state and the percentage of time in the 36-month period. IO, immuno-oncology; IPI, ipilimumab; NIVO, nivolumab; SSAC, subsequent systemic anticancer therapy.

FIG 5.

Estimates of treatment-free survival (TFS) with and without toxicity and other health states over the 36-month period since random assignment, according to treatment group. Toxicity is defined alternatively by (A) grade 3 or higher treatment-related adverse events (TRAEs), (B) grade 2 or higher TRAEs, and (C) immunomodulatory medication use for any-grade TRAE. IO, immuno-oncology; IPI, ipilimumab; NIVO, nivolumab, SSAC, subsequent systemic anticancer therapy.