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. 2024 Dec 4:78:102960.
doi: 10.1016/j.eclinm.2024.102960. eCollection 2024 Dec.

When to stop immunotherapy for advanced melanoma: the emulated target trials

Mathilde Amiot  1 , Laurent Mortier  2 , Stéphane Dalle  3 , Olivier Dereure  4 , Sophie Dalac  5 , Caroline Dutriaux  6 , Marie-Thérèse Leccia  7 , Eve Maubec  8 , Jean-Philippe Arnault  9 , Florence Brunet-Possenti  10 , Julie De Quatrebarbes  11 , Florence Granel-Brocard  12 , Caroline Gaudy-Marqueste  13 , Cecile Pages  14 , Pierre-Emmanuel Stoebner  15 , Philippe Saiag  16 , Thierry Lesimple  17 , Alain Dupuy  18 , Delphine Legoupil  19 , Henri Montaudié  20   21 , Bastien Oriano  1 , Celeste Lebbe  22 , Raphael Porcher  23
Affiliations

When to stop immunotherapy for advanced melanoma: the emulated target trials

Mathilde Amiot et al. EClinicalMedicine. .

Abstract

Background: Immune checkpoint inhibitors (ICIs) have demonstrated their efficacy with a 7.5-year overall survival (OS) close to 50% for advanced stages. The design of clinical trials provides for treatment until progression or toxicity, or for a maximum duration of two years. Prolonged follow-up of responders after treatment cessation shows sustained response and a low risk of relapse in the months following cessation. To date, the optimal duration of anti-PD-1 therapy for metastatic melanoma remains unestablished. The objective of this work was to evaluate the optimal duration of ICI administration.

Methods: We emulated target trials using the cloning, weighting and censoring approach. Each emulation trial aimed to compare the effect of discontinuing versus continuing ICIs at a specific timepoint, among patients still under treatment and with disease control at that time. Patients were from MelBase between 2015 and 2021.

Findings: 435 participants in the MelBase cohort were eligible and were included in the 6-month discontinuation emulated trial. The results showed significantly lower OS when treatment was discontinued, than when treatment was prolonged for at least three months. The 48-month survival difference was 37.8% (95% confidence interval [CI] 19.8-60.5), and the corresponding restricted mean survival time difference was 8.3 months (95% CI: 4.1-12.7). Neither the 12-month nor the 18-month discontinuation emulated trials showed evidence of benefit of either discontinuing or continuing ICIs at either of these timepoints. The 24-month discontinuation emulated trial results were more in favor of discontinuing than continuing treatment at that time point, with an absolute 48-month survival rate that was 10.5% higher (95% CI 4.4-18.1).

Interpretation: These results suggest that a one-year course of immunotherapy is both necessary and sufficient for patients with advanced melanoma. Prolonged treatment beyond 2 years does not appear to be beneficial in terms of survival and could even be detrimental.

Funding: This work was supported by a grant from Bristol Myers Squibb, Merck Sharp Dhome, Pierre Fabre, Novartis, Sun Pharm, Regeneron, Sanofi, Nektar, Therapeutics and Oncyte.

Keywords: Advanced melanoma; Duration of treatment; Emulated trial; Immunotherapy.

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Conflict of interest statement

LM reports advisory board and travel expenses from Bristol Myers Squibb, Merck Sharp and Dhome, Pierre Fabre, Novartis and Sun Pharm. SD reports advisory board and travel expenses from Bristol Myers Squibb and Merck Sharp, and Dhome; research fundings from Bristol Myers Squibb, Merck Sharp and Dhome, and Pierre Fabre. FBP reports financial support outside the submitted work from Bristol Myers Squibb, Merck Sharp and Dhome, Pierre Fabre and Novartis. JDQ reports advisory board from Merck Sharp and Dhome, Pierre Fabre, Novartis and Bristol Myers Squibb. CGM reports advisory board and travel expenses from Pierre Fabre, Bristol Myers Squibb and Merck Sharp and Dhome. PS reports advisory board and travel expenses from Bristol Myers Squibb, Merck Sharp and Dhome and Pierre Fabre and Novartis; consulting fees from Bristol Myers Squibb, Merck Sharp and Dhome, Pierre Fabre, Regeneron, Sanofi, Damae and Novartis. TL reports advisory board and travel expenses from Bristol Myers Squibb, Merck Sharp and Dhome, Pierre Fabre and Novartis. HM reports advisory board from Pierre Fabre, Bristol Myers Squibb, Merck Sharp and Dhome, Novartis, Regeneron and Sun Pharma; research funding from Pierre Fabre, Bristol Myers Squibb, Merck Sharp and Dhome, Novartis, Regeneron, Nektar Therapeutics, 4SC and Incyte; and research grant from Leo Pharma and Merck Sharp and Dhome. All other authors declare no completing interests.

Figures

Fig. 1
Fig. 1
Flow chart of participants. PD: Progression Disease.
Fig. 2
Fig. 2
Weighted overall survival curves in the four emulated trials. ∗Sum of weights of at-risk individuals at each time.
Fig. 3
Fig. 3
Weighted progression-free survival curves in the four emulated trials. ∗Sum of weights of at-risk individuals at each time.
See this image and copyright information in PMC

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