Rechallenge for Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer With Acquired Resistance to First-line Cetuximab and Irinotecan

Importance

Based on a small retrospective study, rechallenge with cetuximab-based therapy for patients withKRASwild-type metastatic colorectal cancer (mCRC) who were previously treated with the same anti–epidermal growth factor receptor–based regimen might be efficacious. Recent data suggest the role of liquid biopsy as a tool to track molecular events in circulating tumor DNA (ctDNA).

Objective

To prospectively assess the activity of cetuximab plus irinotecan as third-line treatment for patients withRASandBRAFwild-type mCRC who were initially sensitive to and then resistant to first-line irinotecan- and cetuximab-based therapy.

Design, Setting, and Participants

Multicenter phase 2 single-arm trial conducted from January 7, 2015, to June 19, 2017. Liquid biopsies for analysis of ctDNA were collected at baseline. Main eligibility criteria includedRASandBRAFwild-type status on tissue samples; prior first-line irinotecan- and cetuximab-based regimen with at least partial response, progression-free survival of at least 6 months with first-line therapy, and progression within 4 weeks after last dose of cetuximab; and prior second-line oxaliplatin- and bevacizumab-based treatment.

Interventions

Biweekly cetuximab, 500 mg/m², plus irinotecan, 180 mg/m².

Main Outcomes and Measures

Overall response rate according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included progression-free survival and overall survival and, as an exploratory analysis,RASmutations in ctDNA.

Results

Twenty-eight patients (9 women and 19 men; median age, 69 years [range, 45-79 years]) were enrolled. Six partial responses (4 confirmed) and 9 disease stabilizations were reported (response rate, 21%; 95% CI, 10%-40%; disease control rate, 54%; 95% CI, 36%-70%). Primary end point was met because lower limit of 95% CI of response rate was higher than 5%.RASmutations were found in ctDNA collected at rechallenge baseline in 12 of 25 evaluable patients (48%). NoRASmutations were detected in samples from patients who achieved confirmed partial response. Patients withRASwild-type ctDNA had significantly longer progression-free survival than those withRASmutated ctDNA (median progression-free survival, 4.0 vs 1.9 months; hazard ratio, 0.44; 95% CI, 0.18-0.98;P = .03).

Conclusions and Relevance

This is the first prospective demonstration that a rechallenge strategy with cetuximab and irinotecan may be active in patients withRASandBRAFwild-type mCRC with acquired resistance to first-line irinotecan- and cetuximab-based therapy. The evaluation ofRASmutational status on ctDNA might be helpful in selecting candidate patients.

Trial Registration

ClinicalTrials.gov Identifier:NCT02296203