Adjuvant vemurafenib confers clinical benefit in resected BRAF V600-positive melanoma

MADRID — Adjuvant vemurafenib conferred substantial clinical benefit to patients with completely resected stage IIC to stage IIIB BRAF V600-positive melanoma at high risk for recurrence, according to study results presented at the European Society for Medical Oncology Congress.

However, the study did not meet its primary endpoint of improved DFS compared with placebo among patients with stage IIIC disease.

Vemurafenib (Zelboraf, Genentech), a BRAF inhibitor, previously demonstrated strong clinical activity in patients with advanced or metastatic BRAF V600-positive melanoma.

Karl Lewis, MD, associate professor in the division of medical oncology at Colorado University School of Medicine, Lewis and colleagues conducted the double-blind, placebo-controlled BRIM8 study to evaluate adjuvant vemurafenib in patients with BRAF V600-positive disease at high risk for recurrence.

The two-cohort study included 498 patients. Cohort 1 included 314 patients with stage IIC, IIIA or IIIB melanoma, and cohort 2 included 184 patients with stage IIIC disease.

Researchers implemented a two-cohort design to address the concern that patients with stage IIIC disease would drive the analysis, as events would occur at a faster rate in that cohort than among patients with earlier-stage disease.

Researchers randomly assigned patients 1:1 to vemurafenib 960 mg twice daily or placebo for 52 weeks.

DFS served as the primary endpoint. Secondary endpoints included distant metastasis-free survival, OS, safety and health-related quality of life.

At data cutoff, median follow-up was 31 months in cohort 1 and 34 months in cohort 2.

In cohort 1, a year of adjuvant vemurafenib conferred a 46% reduction in risk for DFS (median DFS, not estimable vs. 36.9 months; HR = 0.54; 95% CI, 0.37-0.78). This result suggests a substantial clinical benefit compared with placebo among patients with earlier disease stages.

However, due to the prespecified statistical design of the study, these data cannot be considered statistically significant because the study did not meet its primary endpoint in cohort 2.

In that group, a year of adjuvant treatment with vemurafenib increased DFS compared with placebo, but the difference was not statistically significant (median DFS, 23.1 months vs. 15.4 months; HR = 0.8; 95% CI, 0.54-1.18).

“The potential role of disease biology of later-stage patients in cohort 2, coupled with treatment duration and treatment intensity, may explain the observed results,” Lewis said.

OS data are immature, Lewis added.

Researchers reported similar rates of serious adverse events in vemurafenib-treated patients in cohort 1 and cohort 2 (16.2% vs. 16.1%), but a slightly higher percentage of vemurafenib-treated patients in cohort 1 than cohort 2 discontinued treatment due to adverse events (22.7% vs. 15.1%).

In the entire study population, more patients assigned vemurafenib developed cutaneous squamous cell carcinoma (7% vs. 1%) or keratoacanthoma (10% vs. < 1%), but incidence appeared consistent with vemurafenib’s known safety profile, Lewis said.

Researchers reported no noncutaneous squamous cell carcinomas or gastrointestinal malignancies.

“Vemurafenib monotherapy is an effective and well tolerated adjuvant option for patients ... with resected stage IIC/IIIA/IIIB BRAF V600-positive melanoma,” Lewis said. “Further exploration is needed to improve in ... patients with resected stage IIIC melanoma.”

Reference: Lewis K, et al. LBA7_PR. Presented at: European Society for Medical Oncology Congress; Sept. 8-12, 2017. Madrid.

Disclosures : F. Hoffman-La Roche sponsored this study. Lewis reports research grants from Genentech/Roche during the conduct of this study, as well as personal fees from Genentech/Roche outside of the submitted work. Please see the abstract for a list of all other researchers’ relevant financial disclosures.