IMPORTANCE Based on a small retrospective study, rechallenge with cetuximab-based therapy for patients with KRAS wild-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 with RAS and BRAF wild-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 included RAS and BRAF wild-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/m 2 , plus irinotecan, 180 mg/m 2 . 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, RAS mutations 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%. RAS mutations were found in ctDNA collected at rechallenge baseline in 12 of 25 evaluable patients (48%). No RAS mutations were detected in samples from patients who achieved confirmed partial response. Patients with RAS wild-type ctDNA had significantly longer progression-free survival than those with RAS mutated 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 with RAS and BRAF wild-type mCRC with acquired resistance to first-line irinotecan-and cetuximab-based therapy. The evaluation of RAS mutational status on ctDNA might be helpful in selecting candidate patients. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02296203A, Hazard ratio, 0.44 (95% CI, 0.18-0.98; P = .03). B, Hazard ratio, 0.58 (95% CI, 0.22-1.52; P = .24). Research Original InvestigationRechallenge for Patients With RAS and BRAF Wild-Type mCRC With Resistance to Cetuximab and Irinotecan Additional Contributions: We are grateful to all participating patients, their fa...

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Although no difference in the overall adverse effect profile exists between transdermal opiates and slow release oral morphine, the difference in some adverse effects (mainly constipation) seems to favor transdermal opiates in the preference of patients with moderate-severe cancer pain.

The investigated panel of genomic alterations allows refining the selection of RAS and BRAF wild-type metastatic colorectal cancer patients candidates for anti-EGFRs, partially explaining and further corroborating the predictive ability of primary tumour sidedness.