Early Treatment Discontinuation in Patients With Deficient Mismatch Repair or Microsatellite Instability High Metastatic Colorectal Cancer Receiving Immune Checkpoint Inhibitors

Authors

Julien Taieb
Margherita Ambrosini
Emily Alouani
Sara Lonardi
Frank A Sinicrope
Marie Decraecker
Alice Boileve
Emilie Hafliger
Thibault Mazard
Simon Pernot
Pauline Parent
Javier Ros
Michael J Overman
Priya Jayachandran
Vincenzo Nasca
Lisa Salvatore
Rosine Guimbaud
Chiara Cremolini
David Tougeron
Filippo Pietrantonio

Publication Date

1-4-2025

Journal

The Journal for ImmunoTherapy of Cancer

Abstract

Background: Immune checkpoint inhibitors (ICIs) are recommended to treat patients with deficient mismatch repair/microsatellite instability high (dMMR/MSI-H) metastatic colorectal cancer (mCRC). Pivotal trials have fixed a maximum ICI duration of 2 years, without a compelling rationale. A shorter treatment duration has the potential to improve patients' quality of life and reduce both toxicity and cost without compromising efficacy. Here we examine whether early treatment discontinuation (ETD) before 13 months in patients without progressive disease (PD) can lead to similar long-term disease control compared with a longer treatment duration (LTD).

Methods: To assess whether ETD is associated with similar outcomes compared with LTD, we assembled an international cohort of patients with dMMR/MSI-H mCRC treated with ICIs who stopped treatment for a reason other than PD within 395 days (ETD group) and compared them to those who continued for >395 days (LTD group). Outcomes were adjusted for patient/tumor characteristics. Primary endpoint was progression-free survival (PFS) and secondary endpoints were objective response rate (ORR), overall survival (OS) and safety.

Results: Of 976 patients, 137 and 394 were allocated to the ETD and LTD groups, respectively. In the ETD group, treatment was discontinued due to toxicity (n=56), objective response (n=43), surgery (n=28), patient decision (n=2) or other reasons (n=8). Baseline characteristics were well balanced between the two groups: 22% in both groups received both anti-programmed death-(ligand) 1 (anti-PD-(L)1) + anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4); all others received anti-PD-(L)1 monotherapy. ORR to ICIs was 81% in both groups. Median duration of treatment was ~7 months in the ETD and ~24 months in the LTD group. After a median follow-up of 44 months (IQR: 30-67), similar PFS (HR: 0.92, 95% CI: 0.60 to 1.40, p=0.69) and OS (HR: 1.15, 95% CI: 0.66 to 1.99, p=0.62) from the start of ICIs were observed in ETD and LTD patients. In the ETD group, 28 (20%) patients had a PFS event and 9 restarted ICIs with a disease control rate of 66%.

Conclusions: In our international series of dMMR/MSI-H mCRC, ETD of ICIs in the absence of PD did not seem detrimental in terms of PFS and OS compared with continuing treatment beyond 1 year. Randomized clinical trials to compare short and long treatment duration are now warranted.

Keywords

Humans, Colorectal Neoplasms, Immune Checkpoint Inhibitors, Microsatellite Instability, Male, Female, DNA Mismatch Repair, Middle Aged, Aged, Adult, Neoplasm Metastasis, Aged, 80 and over, Colorectal Cancer, Immune Checkpoint Inhibitor, Microsatellite, Mismatch repair - MMR

DOI

10.1136/jitc-2024-010424

PMID

39755579

PMCID

PMC11749684

PubMedCentral® Posted Date

1-4-2025

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes