Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406).

Cancers of the Colon, Rectum, and Anus
Session Type and Session Title: 
Welcome and General Session 7: The Tumor Genome—Molecular Subtypes in Colorectal Cancer
Poster Session C: Cancers of the Colon, Rectum, and Anus
Abstract Number: 


Poster Board Number: 
Poster Session C Board #A2
J Clin Oncol 35, 2017 (suppl 4S; abstract 520)
Scott Kopetz, Shannon L McDonough, Van Karlyle Morris, Heinz-Josef Lenz, Anthony Martin Magliocco, Chloe Evelyn Atreya, Luis A. Diaz, Carmen Joseph Allegra, Stephen E. Wang, Christopher Hanyoung Lieu, S. Gail Eckhardt, Thomas John Semrad, Kimberly Kaberle, Katherine A Guthrie, Howard S. Hochster; The University of Texas MD Anderson Cancer Center, Houston, TX; Fred Hutchinson Cancer Research Center, Seattle, WA; USC Norris Comprehensive Cancer Center, Los Angeles, CA; H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; University of California, San Francisco, San Francisco, CA; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; University of Florida, Gainesville, FL; Kaiser Permanente, Sacramento, CA; University of Colorado, Denver, CO; University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO; University of California, Davis, Sacramento, CA; Southwest Oncology Group, San Antonio, TX; Yale Cancer Center, New Haven, CT

Abstract Disclosures


Background: BRAF V600 mutations are associated with rare objective responses to the mutated BRAF inhibitor vemurafenib in patients with mCRC. Blockade of BRAFV600 by vemurafenib causes feedback upregulation of EGFR, whose signaling activities can be impeded by cetuximab. In murine models of BRAFV600 mCRC, the combination of irinotecan, cetuximab, and vemurafenib leads to greater anti-tumor activity, as suggested by a prior Phase 1B study. Methods: Patients (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). Patients had received 1 or 2 prior regimens, with no prior anti-EGFR agents, although prior irinotecan was allowed. Crossover from the control arm to the experimental arm 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 patients were enrolled (54 in the experimental arm) from 12/2014 to 4/2016, with ECOG PS ≤ 1. Median age of 62 years, 59% female, and prior irinotecan therapy in 39%. PFS was improved with the addition of vemurafenib (HR = 0.42, 95% confidence interval [CI] of 0.26 to 0.66, P < 0.001) with median PFS of 4.4 (95% CI: 3.6 – 5.7) months vs 2.0 (95% CI: 1.8 – 2.1). Response rate was 16% vs 4% (P = 0.09), with disease control rate of 67% vs 22% (P < 0.001). Grade 3/4 adverse events higher in the experimental arm included neutropenia (28% vs 7%), anemia (13% vs 0%), and nausea (15% vs 0%). There was no increase in skin toxicity or fatigue. No new safety signal was observed. Approximately 50% of patients in the control aim crossed over at the time of progression. Overall survival and efficacy at cross-over data remain immature. Conclusions: The addition of vemurafenib to the combination of cetuximab and irinotecan resulted in a prolongation of progression-free survival and a higher disease control rate, indicating that simultaneous EGFR and BRAF inhibition is effective in BRAFV600 mutated CRC. Clinical trial information: NCT02164916