Sensitivity of treatment-free survival to subgroup analyses in patients with advanced melanoma treated with immune checkpoint inhibitors

Abstract

Patients with advanced melanoma treated with immune checkpoint inhibitors can experience ongoing disease control after treatment discontinuation without subsequent systemic anticancer therapy. We previously defined a novel outcome, treatment-free survival (TFS), as the time between protocol therapy cessation and subsequent therapy initiation/death. We assessed the effect of established prognostic variables [lactate dehydrogenase (LDH), programmed death ligand 1 status, BRAF mutation status, performance status, and sex] on TFS in different treatment scenarios: treatment until toxicity/progression with frequent early cessation (nivolumab plus ipilimumab), treatment until toxicity/progression with a well-tolerated regimen (nivolumab), and treatment for a short fixed duration (ipilimumab). Data were pooled from 1077 patients with advanced melanoma treated in the CheckMate 069 and 067 trials. TFS was defined as the area between the Kaplan-Meier curves for time to therapy cessation and time to subsequent therapy initiation/death. TFS was estimated by restricted mean (r-mean) survival time at 36 months since randomization. Clinically meaningful TFS (r-mean TFS 3.7-12.7 months) was observed across all patient subgroups. TFS was longest in patients treated with nivolumab plus ipilimumab. The largest differences in r-mean TFS were observed with LDH in the nivolumab plus ipilimumab and ipilimumab treatment groups (TFS difference 4.7 and 4.9 months, respectively). In the nivolumab group, there was little difference in TFS across subgroups (r-mean TFS 3.7-5.5 months). TFS was sensitive to prognostic subgroup differences; however, duration of treatment affected the sensitivity of TFS. These results provide further support for TFS as a clinical outcome measure.

Trial registration: ClinicalTrials.gov NCT01927419 NCT01844505.

Conflict of interest statement

L.W. has worked as a consultant to Bristol Myers Squibb. B.S. is an employee of and stockholder in Bristol Myers Squibb. C.R. is an employee of Bristol Myers Squibb. A.A.T. has received institutional research grants from Bristol Myers Squibb, Genentech/Roche, Merck, and OncoSec; and served as a consultant/advisor for Array Biopharma, BioNTech, Bristol Myers Squibb, EMD Serono, Genentech/Roche, Immunocore, Merck, NewLink Genetics, Novartis, Partner Therapeutics, Pfizer, and Sanofi-Genzyme/Regeneron. M.B.A. has served as an advisor for Arrowhead, Aveo, Bristol Myers Squibb, Eisai, Elpis, Genetech/Roche, Leads, Merck, Novartis, Pfizer, Pneuma, Pyxis Oncology, Werewolf; and as a consultant to Adagene, Agenus, Apexigen, Exelixis, Idera, ImmunoCore, Iovance, and Neoleuken. D.F.M. has served as a consultant to Alkermes, Bristol Myers Squibb, Eisai, Eli Lilly and Company, EMD Serono, Iovance, Merck, and Pfizer; received research support from Alkermes, Bristol Myers Squibb, Exelixis, Genentech, Merck, Pfizer, and X4 Pharma. M.M.R. has served as a consultant to Ipsen/Debiopharm; received research support from Bayer and Bristol Myers Squibb; received institutional research support from Bristol Myers Squibb, Ipsen, Ferring, Merck, Novartis, Pfizer, Pierre Fabre, Roche, and TerSera; received personal fees from Bristol Myers Squibb and Tolmar Pharmaceuticals; and received nonfinancial support from Bristol Myers Squibb. For the remaining author, there is no conflicts of interest.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.

Figures

Fig. 1

Schematic illustration of the end points that partition the area under the OS curve into TFS and other resulting health states. ICI, immune checkpoint inhibitor; OS, overall survival; TFS, treatment-free survival. Adapted from J Clin Oncol [7] under Creative Commons License 4.0 [CC BY 4.0].

Fig. 2

Estimates of TFS and other health states over the 36-month period in patients treated with nivolumab plus ipilimumab according to patient subgroups based on (a) LDH status, (b) PD-L1 status and (c) BRAF mutation status; r-mean times (months) are annotated on the health state areas. ICI, immune checkpoint inhibitor; LDH, lactate dehydrogenase; PD-L1, programmed death 1; TFS, treatment-free survival.

Fig. 3

Estimates of TFS and other health states over the 36-month period in patients treated with nivolumab according to patient subgroups based on (a) LDH status, (b) PD-L1 status and (c) BRAF mutation status; r-mean times (months) are annotated on the health state areas. ICI, immune checkpoint inhibitor; LDH, lactate dehydrogenase; PD-L1, programmed death 1; TFS, treatment-free survival.

Fig. 4

Estimates of TFS and other health states over the 36-month period in patients treated with ipilimumab according to patient subgroups based on (a) LDH status, (b) PD-L1 status and (c) BRAF mutation status; r-mean times (months) are annotated on the health state areas; r-mean times (months) are annotated on the health state areas. ICI, immune checkpoint inhibitor; LDH, lactate dehydrogenase; PD-L1, programmed death 1; TFS, treatment-free survival.