Disease-Free Survival Gains Reported for Vemurafenib in Stage IIC-IIIB Melanoma

Karl D. Lewis, MD

Adjuvant therapy with vemurafenib (Zelboraf) for high-risk melanoma led to mixed results, as patients with stage IIIC did not benefit, but those with earlier stage disease did, according to data reported at the 2017 ESMO Congress in Madrid.

Patients with stage IIIC disease experienced a median disease-free survival (DFS) of 23.1 months in the BRAF inhibitor arm versus 15.4 months in the placebo arm. However, the difference did not achieve statistical significance. Patients with stage IIC-IIIB had a non-statistically significant 46% reduction in the hazard ratio (HR) for DFS, but the trial design defined a positive outcome on the basis of results in later-stage disease.

“Vemurafenib monotherapy is an effective and well-tolerated adjuvant option for patients with resected stage IIC to IIIB, BRAF V600-positive melanoma,” said Karl Lewis, MD, a medical oncologist at the University of Colorado Comprehensive Cancer Center in Aurora, Colorado. “Further exploration is needed to improve outcomes in patients with [resected later-stage disease].”

Effective treatment for patients with completely resected, high-risk melanoma remains elusive. Approved options for adjuvant therapy offer limited benefit with considerable toxicity, said Lewis. Vemurafenib has demonstrated clinical activity in patients with BRAF V600-positive advanced or metastatic melanoma, but the agent’s role as adjuvant therapy remained undefined.

To examine the potential role of vemurafenib in resected high-risk melanoma, investigators carried out a safety-efficacy trial in 2 cohorts of patients: those with stage IIC-IIIB (cohort 1) and patients with resectable stage IIIC disease (cohort 2).

Investigators in the multicenter trial enrolled a total of 498 patients: cohort 1 was comprised of 314 patients with stage IIC-IIIB disease and cohort 2 was comprised of 184 patients with stage IIIC disease. Patients in each cohort were randomized to vemurafenib or placebo (surgery only), and treatment continued for a year.

The trial design prespecified hierarchical testing of DFS in the later-stage cohort and required a P-value of ≤.05. Analysis of DFS in the later-stage cohort yielded a 20% reduction in the HR in favor of vemurafenib, but the difference did not meet the prespecified definition of statistical significance (95% CI 0.54-1.18, P = .2598).

The later-stage vemurafenib cohort had a 12-month DFS of 78.9% versus 58.0% with placebo. However, the 24-month DFS showed no difference between treatment groups, 46.3% with vemurafenib and 47.5% with placebo.

A different picture emerged from data analysis for the patients with resected stage IIC-IIIB melanoma. The data showed that 45 clinical events occurred in 157 patients randomized to 12 months of adjuvant vemurafenib, as compared with 72 events in 157 patients who received placebo. The median DFS had yet to be reached in the vemurafenib arm, whereas the placebo group had a median DFS of 36.9 months. The difference was associated with a HR of 0.54 (95% CI 0.37-0.78, P = .0010).

The 12-month DFS was 84.3% with vemurafenib and 66.2% with placebo. At 24 months, 72.3% of vemurafenib-treated patients remained alive without disease recurrence versus 56.5% in the placebo group.

“The magnitude of the DFS benefit [in earlier-stage disease] is of a proportion not previously demonstrated in this clinical setting,” said Lewis. “However, due to the prespecified statistical design of the study, these data cannot be described as statistically significant.”

With regard to the negative results in patients with later-stage disease, possible explanations include a different biology of the disease, as compared with stage IIC-IIIB. Additionally, the 12-month duration of adjuvant therapy might not have been sufficient for the stage IIIC-IV cohort, Lewis added.

Lewis K, Maio M, Demidov L, et al. BRIM8: a randomized, double-blind, placebo-controlled study of adjuvant vemurafenib in patients (pts) with completely resected, BRAFV600+ melanoma at high risk for recurrence. In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA7_PR.