Addition of Vemurafenib to Irinotecan/Cetuximab Delayed Progression in BRAF-Mutated mCRC

The addition of the BRAF inhibitor vemurafenib to irinotecan and cetuximab prolonged progression-free survival and resulted in a higher disease control rate than treatment with irinotecan and cetuximab alone in patients with BRAF-mutant metastatic colorectal cancer, according to the results of SWOG 1406 (abstract 520) presented at the 2017 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, held January 19–21 in San Francisco.

“These results suggest that vemurafenib indeed sensitizes BRAF-mutant colorectal tumors to cetuximab and irinotecan, and are consistent with multiple preclinical and early phase I studies,” said Scott Kopetz, MD, PhD, of The University of Texas MD Anderson Cancer Center, who presented the results.

About 7% of patients with metastatic colorectal cancer have BRAF V600E mutations, which are associated with aggressive biology and limited response to standard chemotherapy, resulting in shorter overall survival. Although vemurafenib is a BRAF V600-specific inhibitor, prior studies have shown limited activity with single-agent treatment or with cetuximab-based chemotherapy. 

The study included 106 patients with BRAF-mutated disease and extended RAS wild-type disease. Patients were randomly assigned to treatment with irinotecan and cetuximab with or without (n = 54) vemurafenib. All enrolled patients had received one or two prior therapies with no prior anti-EHGR agents. Patients were allowed to crossover from the control arm to the vemurafenib arm if progression occurred. The primary endpoint was progression-free survival.

Patients assigned to vemurafenib had significant improvements in progression-free survival (hazard ratio = 0.42; 95% CI, 0.26-0.66; P = .0002). Treatment with vemurafenib resulted in an increase in median progression-free survival from 2 months with irinotecan/cetuximab alone to 4.4 months. Response rates were also increased from 4% in the control arm to 16% in vemurafenib arm. Stable disease also increased, for an overall disease control rate of 22% for the control arm compared with 67% for the vemurafenib arm.

“Importantly, the duration of responses were higher with the addition of vemurafenib and the two responders in the control arm had very short duration of response,” Kopetz said.

Grade 3/4 anemia, neutropenia, and nausea were statistically increased in the vemurafenib arm. According to Kopetz, these increased rates may be attributed to increased duration of exposure and are similar to those seen in prior second-line studies of cetuximab plus irinotecan.

Arthralgias were also numerically higher with the addition of vemurafenib, which is a known side effect of the agent. However, dermatologic toxicities were not substantially increased with the addition of vemurafenib. Overall, 18% of patients assigned vemurafenib discontinued treatment compared with 8% of patients in the control arm.

“Overall novel therapies such as this are needed for this rare and aggressive subset of colorectal cancer where our standard chemotherapy regimens are failing to provide substantial and meaningful clinical benefit,” Kopetz concluded.