ROMANCE: "Irinotecan Plus Cetuximab Rechallenge Versus Trifluridine/Tipiracil Plus Bevacizumab in Molecularly Selected Metastatic Colorectal Cancer"

This is a phase II, open-label, randomized, multicenter clinical trial designed to evaluate the efficacy and safety of an anti-EGFR rechallenge strategy compared with the current standard of care in patients with molecularly selected metastatic colorectal cancer (mCRC). Eligible patients have metastatic colorectal cancer that has progressed after standard first- and second-line therapies and have previously achieved clinical benefit from an anti-EGFR-based regimen. Patient selection is based on molecular profiling performed on circulating tumor DNA obtained from a baseline blood sample, identifying tumors that are wild-type for RAS, BRAF, EGFR, PIK3CA exon 20, MAP2K1, and MET, and without HER2 amplification. A total of 150 patients will be randomized in a 1:1 ratio to one of two treatment arms. In the experimental arm, patients will receive cetuximab in combination with irinotecan administered every two weeks. In the control arm, patients will receive trifluridine/tipiracil administered orally according to standard dosing schedules in combination with bevacizumab administered every two weeks. Treatment in both arms will continue until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-defined discontinuation criteria. Tumor assessments will be performed at regular intervals using computed tomography or magnetic resonance imaging and evaluated according to RECIST version 1.1 criteria. The primary endpoint of the study is the objective response rate. Secondary endpoints include progression-free survival, overall survival, safety and tolerability, and quality of life assessed using validated questionnaires. Adverse events will be monitored throughout the study and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Following disease progression, crossover to the alternative treatment arm may be considered at the investigator's discretion. Long-term follow-up will be conducted to assess survival outcomes.