Activity and Safety of Cetuximab Plus Modified FOLFOXIRI Followed by Maintenance With Cetuximab or Bevacizumab for RAS and BRAF Wild-type Metastatic Colorectal Cancer A Randomized Phase 2 Clinical Trial

IMPORTANCE The combination of a triple-drug chemotherapy regimen with ananti–epidermal growth factor receptor (EGFR) agent as a first-line treatment of metastaticcolorectal cancer (mCRC) showed promising activity along with safety concerns in single-armphase 2 trials. The role of maintenance following chemotherapy and anti-EGFR and theoptimal regimen to be adopted are not established. OBJECTIVES To evaluate the activity and safety of cetuximab plus modified FOLFOXIRI(mFOLFOXIRI) and explore the role of maintenance with cetuximab or bevacizumab inRASandBRAFwild-type mCRC. DESIGN, SETTING, AND PARTICIPANTS In a prospective, noncomparative, open-label,multicenter, randomized phase 2 trial, patients aged 18 to 75 years with unresectable,previously untreatedRASandBRAFwild-type (before amendment,KRASwild-type) mCRCwere recruited from 21 oncology units in Italy from October 19, 2011, to March 1, 2015(followed up through May 31, 2017). In total, 323 patients were screened and 143 wererandomized to 2 treatment arms to receive as a first-line induction a regimen of mFOLFOXIRIplus cetuximab followed by cetuximab (arm A) or bevacizumab (arm B) until diseaseprogression. Primary analyses were conducted in a modified intention-to-treat population. INTERVENTIONS mFOLFOXIRI plus cetuximab repeated every 2 weeks for up to 8 cycles,followed by maintenance with cetuximab or bevacizumab until disease progression. MAIN OUTCOMES AND MEASURES The primary end point was the 10-month progression-freerate (PFR); secondary end points included progression-free and overall survival, responserate, rate of metastases resection, and adverse events. RESULTS Of 143 patients randomized, 116 (81.1%) (median [interquartile range (IQR)] age,59.5 [53-67] years; 34 [29.3%] women) hadRASandBRAFwild-type mCRC. At a median(IQR) follow-up of 44.0 (30.5-52.1) months, 10-month PFRs were 50.8% (90% CI,39.5%-62.2%) in arm A and 40.4% (90% CI, 29.4%-52.1%) in arm B. The overall responserate was 71.6% (95% CI, 62.4%-79.5%). Main grade 3/4 adverse events were neutropenia(occurring in 36 patients [31%]), diarrhea (in 21 patients [18%]), skin toxic effects (in 18patients [16%]), asthenia (in 11 patients [9%]), stomatitis (in 7 patients [6%]), and febrileneutropenia (in 3 patients [3%]). CONCLUSIONS AND RELEVANCE Although neither of the 2 arms met the primary end point,the findings indicate that a 4-month induction regimen of mFOLFOXIRI plus cetuximab isfeasible and provides relevant activity results, leading to a high surgical resection rate.