Irinotecan Plus Cetuximab Rechallenge Versus Trifluridine/Tipiracil Plus Bevacizumab as Third-Line Treatment in Circulating Tumor DNA–Selected Metastatic Colorectal Cancer (ROMANCE Trial)

Background and Rationale: In patients with RAS/BRAF wild-type (WT) metastatic colorectal cancer (mCRC), anti–epidermal growth factor receptor (EGFR) monoclonal antibodies combined with chemotherapy represent an established first-line option and may provide clinically meaningful tumor shrinkage. However, acquired resistance may develop through the emergence of mechanism/s of acquired resistance. After progression to first- and second-line regimens, the prognosis of patients with mCRC remains poor. Available later-line options exhibit a cytostatic activity and are associated with limited objective response rate (ORR). Of note, the dynamic decay of resistant subclones after withdrawal of EGFR blockade supports the rationale to explore anti-EGFR rechallenge therapy. Methods: ROMANCE trial is a multicenter, randomized phase II study. Overall, 150 patients with mCRC with circulating tumor RAS/BRAF/EGFR/PIK3CA exon 20/MAP2K1/MET WT and HER2 nonamplified (negative hyperselected tumors) mCRC, at baseline liquid biopsy, will be randomized 1:1 to irinotecan plus cetuximab rechallenge compared with trifluridine/tipiracil plus bevacizumab as third-line therapy. The primary endpoint is ORR assessed by Response Evaluation Criteria in Solid Tumors 1.1 by blinded independent central review; secondary endpoints include progression-free survival, overall survival, safety, and quality of life. Conclusions: Given the limited ORRs achieved with currently available options after second-line treatment for refractory mCRC, strategies capable of inducing clinically meaningful tumor shrinkage are urgently required. ROMANCE will evaluate whether cetuximab plus irinotecan retreatment can improve ORR compared with standard third-line trifluridine/tipiracil plus bevacizumab in patients with circulating tumor DNA–negative hyperselected mCRC and will clarify the role of anti-EGFR rechallenge in the continuum of care of refractory mCRC. Trial Registration: This trial is registered at clinicaltrials.gov (NCT07381764).