Sorafenib in Combination with Oxaliplatin, Leucovorin, and Fluorouracil (modified FOLFOX6) as First-line Treatment of Metastatic Colorectal Cancer: The RESPECT Trial
Mené sur 198 patients atteints d'un cancer colorectal métastatique, cet essai de phase IIb évalue, du point de vue de la survie sans progression, l'ajout de sorafenib à un traitement de première ligne FOLFOX6 modifié
Purpose:This randomized, double-blind, placebo-controlled, phase IIb study evaluated adding sorafenib to first-line modified FOLFOX6 (mFOLFOX6) for metastatic colorectal cancer (mCRC). Experimental Design:Patients were randomized to sorafenib (400 mg BID) or placebo, combined with mFOLFOX6 (oxaliplatin 85 mg/m2; levo-leucovorin 200 mg/m2; fluorouracil 400 mg/m2 bolus and 2400 mg/m2 continuous infusion) every 14 days. Primary endpoint was progression-free survival (PFS). Target sample was 120 events in 180 patients for >85% power (2-sided α=0.20) to detect a hazard ratio (HR)=0.65. Results:Of 198 patients randomized, median PFS for sorafenib plus mFOLFOX6 was 9.1 versus 8.7 months for placebo plus mFOLFOX6 (HR=0.88, 95% CI 0.64−1.23; P=.46). There was no difference between treatment arms for overall survival (OS). Subgroup analyses of PFS and OS showed no difference between treatment arms by KRAS or BRAF status (mutant and wild-type). The most common Grade 3/4 adverse events in the sorafenib and placebo arms were neutropenia (48% v 22%), peripheral neuropathy (16% v 21%), and Grade 3 hand-foot skin reaction (20% v 0%). Treatment discontinuation due to adverse events was 9% and 6%, respectively. Generally, dose intensity (duration and cumulative doses) was lower in the sorafenib arm than in the placebo arm. Conclusions: This study did not detect a PFS benefit with the addition of sorafenib to first-line mFOLFOX6 for mCRC. KRAS and BRAF status did not appear to impact treatment outcomes but the subgroups were small. These results do not support further development of sorafenib in combination with mFOLFOX6 in molecularly-unselected patients with mCRC.