Efficacy and safety of cetuximab-irinotecan rechallenge versus regorafenib in ras wild-type metastatic colorectal cancer: a single-center exploratory randomized trial

BACKGROUND: Anti‐epidermal growth factor receptor (EGFR) antibodies are widely used in the treatment of RAS wild‐type metastatic colorectal cancer (mCRC) across various lines of therapy, including after disease progression. However, evidence from randomized controlled trials regarding the efficacy of cetuximab rechallenge in patients who initially responded to prior cetuximab but subsequently progressed after a cetuximab‐free interval remains limited. METHODS: This single‐center, prospective, exploratory randomized trial (ChiCTR1900026961) evaluated cetuximab plus irinotecan rechallenge versus regorafenib in patients with RAS wild‐type, microsatellite‐stable mCRC who had previously responded to then progressed off cetuximab. Progression‐free survival (PFS) was the primary endpoint, with overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety as secondary endpoints. Univariate and multivariate Cox regression analyses were performed to identify potential prognostic factors, and an exploratory nomogram was developed for hypothesis generation. RESULTS: Among 68 randomized patients, cetuximab plus irinotecan rechallenge was associated with longer median PFS and OS than regorafenib. The DCR and ORR were numerically higher in the rechallenge group. Median PFS was 5.5 months versus 2.6 months, and median OS was 18.8 months versus 10.4 months. Adverse events in the cetuximab group were predominantly grade 1‐2 and manageable with supportive care. Univariate and multivariate analyses identified age, ECOG status, and cetuximab‐free interval as potential prognostic factors. An exploratory nomogram was constructed based on these factors. CONCLUSIONS: These findings suggest that cetuximab plus irinotecan rechallenge may be associated with clinical benefit and acceptable toxicity in selected patients with RAS/BRAF wild‐type mCRC. The exploratory nomogram requires further validation. These results support further investigation of rechallenge strategies and biomarker‐guided approaches in advanced CRC. TRIAL REGISTRATION: This study was registered with the Chinese Clinical Trial Registry on October 27, 2019 (registration number: ChiCTR1900026961).