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.

Evolving impact of long-term survival results on metastatic melanoma treatment

“…TFS characterizes the proportion of time without both treatment or toxicity on a particular regimen; it can be further separated into time with, and time without treatment-related toxicity of a specified grade. 65 TFI captures the time interval from the last dose of study drug to subsequent systemic therapy. 12 For example, data suggest that TFI positively impacts QoL and may improve the cost-effectiveness of immune checkpoint inhibitors.…”

Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma

“…[2][3][4] Combination therapy with nivolumab plus ipilimumab has also had clinical efficacy in patients with metastatic melanoma and untreated brain metastases. 5,6 Some patients who have received nivolumab plus ipilimumab have also discontinued therapy without subsequent systemic treatment for melanoma 4,[7][8][9] ; this is one aspect of the value of combination nivolumab plus ipilimumab treatment. In this article, we provide an update of survival outcomes from the CheckMate 067 trial with a minimum of 5 years of follow-up as well as an assessment of the longterm benefit of combination nivolumab plus ipilimumab treatment with respect to outcomes in patients who have not received subsequent systemic treatment for melanoma and with respect to health-related quality of life.…”

Cost-effectiveness of pembrolizumab with axitinib as first-line treatment for advanced renal cell carcinoma

“…This approach was considered balanced given the concurrence between PFS and ToT in both arms of KEYNOTE-426. As a related limitation, in the absence of Kaplan-Meier curves for first-line ToT and time to second-line treatment initiation for all comparators, it was not feasible to explore alternative partitioned survival structures that consider treatment-free survival, defined as time from first-line discontinuation until initiation of subsequent therapy or death 54,55 . Treatment-free survival has been proposed as a distinct health state to capture the potential benefit of immune checkpoint inhibitors to induce periods of disease control without the need for treatment 54,55 .…”