Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG S1406).

Abstract

3505 Background: Metastatic colorectal cancer (mCRC) patients (pts) with BRAFV600 mutations have poor outcomes with standard of care chemotherapy and rarely respond to the BRAF inhibitor vemurafenib. In preclinical models, blockade of BRAFV600 by vemurafenib (V) causes feedback upregulation of EGFR, whose signaling activities can be impeded by cetuximab (C) with anti-tumor activity augmented by irinotecan (I). Methods: Pts with BRAFV600 mutated and extended RAS wild-type mCRC were randomized to irinotecan (180 mg/m2 IV every 14 days) and cetuximab (500 mg/m2 IV every 14 days) with or without vemurafenib (960 mg PO twice daily). Eligible pts had ECOG PS ≤1, and had received 1 or 2 prior regimens with no prior anti-EGFR agents. Randomization was stratified for prior irinotecan. Crossover from the control arm (IC) to the experimental arm (VIC) was allowed after documented progression. The primary endpoint was progression-free survival (PFS, investigator assessed), with 90% power to detect a HR of 0.5, with two-sided type 1 error of 5%. Results: 106 pts were enrolled (99 eligible, 49 in the experimental arm) from 12/2014 to 4/2016, with median age 62 years, 59% female, and 39% with prior irinotecan therapy. PFS was improved with the addition of vemurafenib (HR 0.42, 95% confidence interval [CI] 0.26 to 0.66, P < 0.001) with median PFS of 4.4 (95% CI 3.6 – 5.7) mos vs 2.0 (95% CI 1.8 – 2.1) months. Response rate was 16% vs 4% (P = 0.08), with disease control rate of 67% vs 22%. In…