Circulating tumour DNA to guide rechallenge with cetuximab plus irinotecan in RAS/BRAF wild-type metastatic colorectal cancer: A nonrandomised clinical trial.

Mutant subclones driving anti-EGFR resistance may progressively decline after therapy cessation, potentially reversing resistance to EGFR-targeted treatment. We therefore examined whether rechallenge with cetuximab plus irinotecan is active and tolerable in patients selected by circulating tumour DNA (ctDNA) testing, focusing on metastatic colorectal cancer (mCRC) with RAS/BRAF wild-type (WT) status. This single-arm, Phase II clinical trial enrolled patients between November 2019 and February 2025. Eligible patients had histologically confirmed RAS/BRAF WT mCRC at diagnosis, prior cetuximab-based first-line therapy with clinical benefit, radiographic progression while on cetuximab or within 3 months after stopping it, subsequent progression after at least 1 additional systemic therapy, a cetuximab washout period of at least 4 months, and ctDNA-confirmed RAS/BRAF WT status before rechallenge. Each 2-week cycle delivered intravenous cetuximab (500 mg/m2) together with irinotecan (180 mg/m2). The primary endpoint was the objective response rate (ORR). We additionally assessed progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). This study enrolled 36 patients. Partial response was seen in 6 patients (16.7%), stable disease in 10 (27.8%), and progressive disease in 16 (44.4%); the remaining 4 patients were unevaluable due to early loss to follow-up. The ORR reached 16.7% (95% CI: 7.9-31.9), with a disease control rate of 44.4% (95% CI: 29.5-60.4). The median PFS and OS were 3.9 months (95% CI: 3.1-4.7) and 13.0 months (95% CI: 8.1-17.9). Multivariate Cox regression analyses identified screening time interval (STI) as an independent predictor of PFS (HR = 0.93 per additional month; 95% CI: 0.88-0.99). TRAEs of grade 3-4 were uncommon and clinically manageable. These findings suggest that ctDNA-guided rechallenge with cetuximab plus irinotecan may offer benefit in RAS/BRAF WT mCRC, with STI potentially informing patient selection. Nevertheless, further validation in larger randomised trials is warranted. ClinicalTrials.gov Identifier: NCT04224415. RAS/BRAF wild-type status confirmed by ctDNA may identify candidates for cetuximab rechallenge. A longer screening time interval was associated with improved progression-free survival. These hypothesis-generating findings warrant validation in larger randomised trials.