Efficacy of immune checkpoint inhibitors for metastatic colorectal cancer with microsatellite instability in second or latter line using synthetic control arms: A non-randomised evaluation

Cohen, Romain, Raeisi, Morteza, Chibaudel, Benoist, Yoshino, Takayuki, Shi, Qian, Zalcberg, John R., Adams, Richard ORCID: https://orcid.org/0000-0003-3915-7243, Cremolini, Chiara, Grothey, Axel, Mayer, Robert J., Van Cutsem, Eric, Tabernero, Josep, Bando, Hideaki, Misumi, Toshihiro, Overman, Michael J, André, Thierry and de Gramont, Aimery 2024. Efficacy of immune checkpoint inhibitors for metastatic colorectal cancer with microsatellite instability in second or latter line using synthetic control arms: A non-randomised evaluation. European Journal of Cancer 199 , p. 113537. 10.1016/j.ejca.2024.113537

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Abstract

Purpose Immune checkpoint inhibitors (ICIs) appeared active in single-arm trials for patients with chemoresistant metastatic colorectal cancer (mCRC) harboring microsatellite instability (MSI). Given the paucity of randomised controlled trials (RCTs) in this setting, we evaluated the effect size of ICIs using intra-patients comparison and ARCAD database as historical controls. Patients and methods Individual-patient data from NIPICOL and CheckMate 142 phases II trials that evaluated a combination of ICIs for MSI mCRC patients (N=176) and from five non-ICI mCRC historical RCTs in second-line or latter (N=4026) were analyzed. Firstly, promising of ICIs was identified using intra-patient comparison based on growth modulation index (GMI). Survival outcomes of ICIs-treated patients were then compared with those matched non-ICIs treated from ARCAD database historical RCTs. Results Among ICIs-treated patients, median progression-free survival (PFS) on ICIs was 32.66 (range 0.10-74.25) versus 4.07 months (range 0.7-49.87) on prior therapy, resulting on median GMI of 4.97 (range 0.07-59.51; hazard-ratio (HR)=0.16 (95%CI=0.11-0.22, P<0.001)). Compared to matched non-ICI patients, in third-line, median overall survival (OS) was not reached with ICIs versus 3.52 months with placebo (HR=0.20, 95%CI=0.10-0.41, P<0.001), and 6.51 months with active drugs (HR=0.30, 95%CI=0.15-0.60, P=0.001). In second-line, median OS was not reached with ICIs versus 11.7 months with chemotherapy+placebo (HR=0.12, 95%CI=0.07-0.22, P<0.001), and 16.3 months with chemotherapy+targeted therapy (HR=0.10, 95%CI=0.05-0.19, P<0.001). Conclusion ICIs demonstrates high effect size for MSI mCRC patients in second-line and later. This work might be useful as an example of methodology to avoid RCTs when benefit from experimental therapy is likely to be high.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Centre for Trials Research (CNTRR)
Additional Information:	License information from Publisher: LICENSE 1: Title: This article is under embargo with an end date yet to be finalised.
Publisher:	Elsevier
ISSN:	0959-8049
Date of Acceptance:	5 January 2024
Last Modified:	18 Jan 2024 10:15
URI:	https://orca.cardiff.ac.uk/id/eprint/165634

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