Rechallenge for Patients With <i>RAS</i> and <i>BRAF</i> Wild-Type Metastatic Colorectal Cancer With Acquired Resistance to First-line Cetuximab and Irinotecan
Authors: Chiara Cremolini, Daniele Rossini, Emanuela Dell’Aquila, Sara Lonardi, Elena Conca, Marzia Del Re, Adele Busico, Filippo Pietrantonio, Romano Danesi, Giuseppe Aprile, Emiliano Tamburini, Carlo Barone, Gianluca Masi, Francesco Pantano, Francesca Pucci, Domenico C. Corsi, Nicoletta Pella, Francesca Bergamo, Eleonora Rofi, Cecilia Barbara, Alfredo Falcone, Daniele Santini
Journal: JAMA Oncology (2018)

<h3>Importance</h3> Based on a small retrospective study, rechallenge with cetuximab-based therapy for patients with<i>KRAS</i>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). <h3>Objective</h3> To prospectively assess the activity of cetuximab plus irinotecan as third-line treatment for patients with<i>RAS</i>and<i>BRAF</i>wild-type mCRC who were initially sensitive to and then resistant to first-line irinotecan- and cetuximab-based therapy. <h3>Design, Setting, and Participants</h3> 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<i>RAS</i>and<i>BRAF</i>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. <h3>Interventions</h3> Biweekly cetuximab, 500 mg/m<sup>2</sup>, plus irinotecan, 180 mg/m<sup>2</sup>. <h3>Main Outcomes and Measures</h3> 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,<i>RAS</i>mutations in ctDNA. <h3>Results</h3> 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%.<i>RAS</i>mutations were found in ctDNA collected at rechallenge baseline in 12 of 25 evaluable patients (48%). No<i>RAS</i>mutations were detected in samples from patients who achieved confirmed partial response. Patients with<i>RAS</i>wild-type ctDNA had significantly longer progression-free survival than those with<i>RAS</i>mutated ctDNA (median progression-free survival, 4.0 vs 1.9 months; hazard ratio, 0.44; 95% CI, 0.18-0.98;<i>P</i> = .03). <h3>Conclusions and Relevance</h3> This is the first prospective demonstration that a rechallenge strategy with cetuximab and irinotecan may be active in patients with<i>RAS</i>and<i>BRAF</i>wild-type mCRC with acquired resistance to first-line irinotecan- and cetuximab-based therapy. The evaluation of<i>RAS</i>mutational status on ctDNA might be helpful in selecting candidate patients. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT02296203