Efficacy and safety of cetuximab-irinotecan rechallenge versus regorafenib in <i>RAS</i> wild-type metastatic colorectal cancer.

3537 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. Methods: A single-center, prospective, randomized controlled trial (ChiCTR1900026961) evaluated the efficacy of cetuximab rechallenge in mCRC patients with RAS wild-type tumors who had initially responded to cetuximab-based therapy but subsequently progressed on a cetuximab-free regimen. The trial compared cetuximab plus irinotecan with regorafenib, with progression-free survival (PFS) as the primary endpoint and overall survival (OS), disease control rate (DCR), objective response rate (ORR), and safety as secondary endpoints. Results: Among 68 patients with microsatellite-stable (MSS), RAS wild-type tumors, 35 received cetuximab rechallenge therapy and 33 received regorafenib. The cetuximab group achieved a DCR of 68.6% and an ORR of 8.6%, both significantly higher than those observed in the regorafenib group. Median PFS was 5.5 months in the rechallenge group compared with 2.6 months in the regorafenib group, while median OS was 18.8 months versus 10.4 months, respectively. Adverse events in the cetuximab group were predominantly grade 1–2 and manageable with supportive care. Univariate and multivariate Cox regression analyses identified age, ECOG performance status, and washout period duration as independent prognostic factors. A nomogram was developed to predict the efficacy of cetuximab rechallenge therapy. Conclusions: These findings suggest that cetuximab rechallenge offers promising clinical activity with acceptable toxicity in RAS/BRAF wild-type mCRC, supporting further investigation of rechallenge strategies and biomarker-guided approaches to optimize outcomes in advanced CRC. Clinical trial information: ChiCTR1900026961.