Circulating tumor DNA to guide rechallenge with cetuximab plus irinotecan in Chinese RAS/BRAF wild type metastatic colorectal cancer: A phase II trial.

154 Background: Standard third-line therapies for metastatic colorectal cancer (mCRC) yield limited clinical benefit. Emerging evidence revealed that mutant RAS and EGFR extracellular domain variants detected in circulation during EGFR-targeted therapy exhibit diminished prevalence upon treatment cessation, correlating with restored therapeutic sensitivity. This study aimed to prospectively identify patients with RAS/BRAF WT mCRC via circulating tumor DNA (ctDNA) screening and to evaluate the efficacy and safety of cetuximab with irinotecan. As we know, this represents the first interventional study in Chinese mCRC employing liquid biopsy-driven molecular surveillance to direct cetuximab rechallenge strategies. Methods: This single-arm phase II trial enrolled patients from November 2019 to June 2025. Eligibility required histologically confirmed RAS/BRAF wild-type status at initial diagnosis via tumor tissue analysis, prior first-line cetuximab-based therapy achieving objective response (complete/partial response) or stable disease with progression-free survival ≥6 months, radiologically confirmed disease progression either during cetuximab treatment or within 3 months post-discontinuation, subsequent progression after ≥1 line of systemic therapy, a minimum 4-month washout period from last cetuximab exposure, and current plasma circulating tumor DNA (ctDNA) analysis demonstrating maintained RAS/BRAF wild-type status. The treatment regimen consisted of cetuximab (500 mg/m²) plus irinotecan (180 mg/m²) every 2 weeks. The primary endpoint was objective response rate (ORR), while secondary endpoints included PFS, overall survival (OS), and treatment-related adverse events (TRAEs). Results: A total of 36 patients were enrolled (12 women and 24 men; median age, 58 years range, 29–73). Of these, 6 patients achieved partial response, 11 had stable disease, 15 experienced progressive disease, 4 were not evaluable, and 1 patient switched treatment without documented progression. The primary endpoint was met, with ORR of 16.7% (95% CI, 5.6–30.6%) and the DCR of 47.2% (95% CI, 30.6–63.9%). Median PFS was 4.3 months (95% CI, 3.5–5.1), and median OS was 13.0 months (95% CI, 8.1–17.9). Grade 3-4 TRAEs included skin rash (n = 3, 8.3%), neutropenia (n = 3, 8.3%), anemia (n = 2, 5.6%), and diarrhea (n = 1, 2.8%). Conclusions: We found that ctDNA-guided selection for rechallenge with cetuximab plus irinotecan provides an effective and well-tolerated treatment option for mCRC patients who retain RAS/BRAF WT after prior lines of therapy. Clinical trial information: NCT04224415 .