Rechallenge for Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer With Acquired Resistance to First-line Cetuximab and Irinotecan: A Phase 2 Single-Arm Clinical Trial.

摘要: Importance Based on a small retrospective study, rechallenge with cetuximab-based therapy for patients withKRASwild-type metastatic colorectal cancer (mCRC) who were previously treated the same anti–epidermal growth factor receptor–based regimen might be efficacious. Recent data suggest role of liquid biopsy as tool to track molecular events in circulating tumor DNA (ctDNA). Objective To prospectively assess activity cetuximab plus irinotecan third-line treatment withRASandBRAFwild-type mCRC initially sensitive and then resistant first-line irinotecan- therapy. Design, Setting, Participants Multicenter phase 2 single-arm trial conducted from January 7, 2015, June 19, 2017. Liquid biopsies analysis ctDNA collected at baseline. Main eligibility criteria includedRASandBRAFwild-type status tissue samples; prior least partial response, progression-free survival 6 months therapy, progression within 4 weeks after last dose cetuximab; second-line oxaliplatin- bevacizumab-based treatment. Interventions Biweekly cetuximab, 500 mg/m2, irinotecan, 180 mg/m2. Outcomes Measures Overall response rate according Response Evaluation Criteria Solid Tumors, version 1.1. Secondary end points included overall and, an exploratory analysis,RASmutations ctDNA. Results Twenty-eight (9 women 19 men; median age, 69 years [range, 45-79 years]) enrolled. Six responses (4 confirmed) 9 disease stabilizations reported (response rate, 21%; 95% CI, 10%-40%; control 54%; 36%-70%). Primary point was met because lower limit CI higher than 5%.RASmutations found baseline 12 25 evaluable (48%). NoRASmutations detected samples achieved confirmed response. Patients withRASwild-type had significantly longer those withRASmutated (median survival, 4.0 vs 1.9 months; hazard ratio, 0.44; 0.18-0.98;P = .03). Conclusions Relevance This is first prospective demonstration that strategy may active acquired resistance The evaluation ofRASmutational helpful selecting candidate patients. Trial Registration ClinicalTrials.gov Identifier:NCT02296203