Rechallenge with epidermal growth factor receptor inhibitors for metastatic colorectal cancer: A systematic review and meta-analysis.

Abstract

e15609 Background: Clonal evolution is a mechanism of treatment resistance against epidermal growth factor receptor inhibitors (EGFRi) in metastatic colorectal cancer (mCRC). Upon EGFRi discontinuation, EGFRi-resistant subclones decay with time, which allows for EGFRi rechallenge. We conducted a meta-analysis to investigate the efficacy of EGFRi rechallenge for patients with mCRC. Methods: Clinical trials and observational studies investigating the efficacy of EGFRi rechallenge for mCRC were extracted from PubMed and Embase from inception to December 8, 2024. Objective response rates (ORR) were aggregated using meta-random-effects models. Hazard ratios (HR) of overall survival (OS) and progression-free survival (PFS) were aggregated using Bayesian random-effects models. Results: Among the 404 studies initially retrieved from the databases, 29 studies (921 patients) were included in the final analysis. There were 11 single-arm trials, 5 randomized controlled trials (including 3 post-hoc analyses), and 13 observational studies. At least 522 patients (82.3%) had left-sided mCRC. In 20 studies, EGFRi rechallenge was given only to patients previously progressing on 5-fluoropyrimidine, oxaliplatin or irinotecan. In 22 (75.9%) studies, only patients with RAS-wild type mCRC received EGFRi rechallenge. The median EGFRi-free interval before EGFRi rechallenge was ≥ 4 months in 15 studies (≥10 months in 10 studies) and between 2 to 4 months in 3 studies. Twenty-six studies reported an ORR of up to 84.8%. Among these, 15 studies (51.7%) reported an ORR ≥ 10% (11 studies with ORR ≥ 20%). The pooled ORR was 15% (95% CI, 9%-24%) which is numerically higher than that achieved by FDA-approved third-line agents (trifluridine/tipiracil plus bevacizumab 6.1%, fruquintinib 2%, and regorafenib 1.5%). EGFRi rechallenge was associated with a significantly longer pooled PFS (HR 0.54; 95% CI, 0.31-0.93) and numerically longer pooled OS (HR 0.71; 95% CI, 0.46-1.09) than EGFRi-free systemic therapy. Patients without detectable RAS/RAF mutations by ctDNA right before EGFRi rechallenge had a significantly longer OS (HR, 0.428; 95% CI, 0.239-0.749) and PFS (HR, 0.403; 95% CI, 0.259-0.62) than those with RAS/RAF mutations. Acneiform rash was the most commonly reported non-hematologic grade 3-4 adverse event (7% to 81%). No treatment-related deaths were reported. Conclusions: EGFRi rechallenge is associated with a significantly longer PFS, numerically longer OS and clinically meaningful ORR as compared with EGFRi-free systemic therapy in patients with heavily-pretreated mCRC, particularly for patients with pre-rechallenge RAS/RAF-wild type mCRC.