Vemurafenib regimen extends PFS in BRAF V600E-mutant metastatic colorectal cancer
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The addition of vemurafenib to irinotecan and cetuximab improved PFS and response rates among patients with BRAF V600E-mutant metastatic colorectal cancer, according to study results published in Journal of Clinical Oncology.
“This research was prompted by an appreciation that BRAF inhibition alone was not active in [patients with colorectal cancer] due to an adaptive feedback through the EGFR pathway,” Scott Kopetz, MD, PhD, FACP, professor of gastrointestinal medical oncology at The University of Texas MD Anderson Cancer Center, told Healio. “While the EGFR pathway is not a critical pathway in BRAF-mutated colorectal cancer tumors, after inhibition of BRAF, the tumor rapidly adapts and increases signaling through EGFR to maintain growth signaling via the MAPK pathway. Therefore, combined inhibition of both BRAF and EGFR is needed to inhibit the growth signaling.
Previous preclinical and clinical data showed that the addition of irinotecan to a combination of BRAF and EGFR inhibitors improved response rates, according to Kopetz. “On the basis of this, the three-drug combination was evaluated in this randomized phase 2 study,” he said.
The SWOG S1406 study included 100 patients with BRAF V600E metastatic colorectal cancer who received one or two prior regimens. Kopetz and colleagues randomly assigned 50 patients (median age, 61.9 years; 74% women; 98% white) to the EGFR inhibitor cetuximab (Erbitux, Eli Lilly), dosed at 500 mg/m², and irinotecan, dosed at 180 mg/m², every 2 weeks via IV. The other 50 patients (median age, 59.7 years; 58% men; 88% white) received the doublet regimen plus vemurafenib (Zelboraf, Genentech), dosed at 960 mg twice daily.
Patients in the control group could cross over to the vemurafenib group upon documented disease progression if they continued to meet certain eligibility criteria.
PFS served as the primary endpoint.
Results showed the addition of vemurafenib to the doublet regimen significantly improved PFS (median, 4.2 months vs. 2 months; HR = 0.5; 95% CI, 0.32-0.76), with higher rates of response (17% vs. 4%; P = .05) and disease control (65% vs. 21%; P < .001).
At week 9, 80% of patients assigned the triplet regimen and 39% of those assigned the doublet regimen were free of progression and death, according to the researchers.
After 42% of patients in the control group crossed over to the vemurafenib group, median PFS was 5.4 months, the response rate was 19% and disease control rate was 76%.
Researchers additionally observed a decrease in circulating tumor DNA of the BRAF V600E variant allele frequency among 87% of patients who received the triplet regimen, compared with no patients assigned the doublet regimen (P < .001), as well as low incidence of acquired RAS alterations at the time of progression.
Among 11 patients with PIK3CA mutations, researchers observed improved PFS (HR = 0.3) compared with those with wild-type mutations (HR = 0.6), although they acknowledged that the small sample size prohibits definitive conclusions.
The clinical benefit occurred regardless of microsatellite stability status, with an HR for PFS treatment effect of 0.5 among patients with microsatellite instability-high and microsatellite-stable tumors.
Compared with only 8% of patients in the control group who discontinued treatment, 22% in the vemurafenib group discontinued treatment due to adverse events. Grade 3 and grade 4 adverse events occurred more often among those in the vemurafenib group and included neutropenia (30% vs. 7%), anemia (13% vs. 0%) and nausea (19% vs. 2%).
“This study demonstrated evidence of activity with the primary study endpoint — improved PFS,” Kopetz said. “Based in part on this work, a phase 3 study combining chemotherapy with BRAF and EGFR inhibition in previously untreated patients has been initiated.”
For more information:
Scott Kopetz, MD, PhD, FACP, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; email: skopetz@mdanderson.org.
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