Adjuvant BRAF/MEK Inhibition Improves Survival in Resectable Melanoma

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FOR PATIENTS with locally advanced, resectable melanoma harboring BRAF mutations, adjuvant treatment with BRAF/ MEK inhibition significantly improves overall survival, results of the COMBI-AD trial have shown. The study was presented at the European Society for Medical Oncology (ESMO) 2017 Congress1 and simultaneously published in The New England Journal of Medicine.2 

COMBI-AD evaluated the combination dabrafenib (Tafinlar) and trametinib (Mekinist), vs placebo, in 870 patients with stage III BRAF V600E/K-mutant melanoma. Patients received the drugs within 12 weeks of complete surgical resection and were treated for 1 year. Combination treatment with dabrafenib and trametinib significantly improved relapse-free survival, the primary endpoint, and showed an overall survival benefit as well. 

“The results of COMBI-AD actually exceeded even my personal high expectations,” said Axel Hauschild, MD, Professor of Dermatology at the University of Kiel in Germany. “The Kaplan-Meier survival curve is the best ever seen in the adjuvant treatment of melanoma…. The benefit is maintained over the entire observation period, which is as long as almost 3 years.” 

The BRIM8 trial of the BRAF inhibitor vemurafenib (Zelboraf) as a single agent, however, did not meet its primary endpoint, in another study reported at the ESMO Congress.3 Although the statistical design of the study accounted for this overall negative outcome, single-agent vemurafenib did improve outcomes in a subset of patients, according to Karl Lewis, MD, of the University of Colorado Denver School of Medicine. 

COMBI-AD Details 

AFTER A MEDIAN FOLLOW-UP of 2.8 years, median relapse-free survival time was not reached with the combination and was 16.6 months with placebo, representing a highly significant 53% risk reduction. Relapse-free survival rates were 67% vs 44% at 2 years and 59% vs 39% at 5 years. 

“The Kaplan-Meier survival curve is the best ever seen in the adjuvant treatment of melanoma….”
— Axel Hauschild, MD

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The Kaplan-Meier curve revealed a hazard ratio [HR] of 0.47 (P < .001), and Dr. Hauschild noted, “This is a remarkable hazard ratio, with a very narrow confidence interval (95th CI = 0.39–0.57), for this new treatment.” 

Median distant metastasis–free survival was not reached with either arm. At 3 years, survival rates were 71% with the combination and 57% with placebo (HR = 0.51; nominal P < .001). 

In the first of three interim analyses to come, overall survival was also improved, with 91% of patients alive with the combination at 2 years, compared with 83% in the placebo arm, and 86% and 77%, respectively, at 3 years (HR = 0.57; P = .0006). Median survival was not reached in either arm. 

Postrecurrence therapy was received by about one-third of patients in the combination arm and half of patients in the placebo arm, but systemic therapies were equally distributed between progressive patients. 

Subgroup Analyses and Toxicity 

DR. HAUSCHILD REPORTED that similar benefit was seen across all subgroups. “Not a single subgroup was an outlier,” he said. “All stages of disease benefited the same.” 

Hazard ratios for several subsets follow: 0.48 for V600E mutations and 0.54 for V600K; 0.38 for ≥ 65 years and 0.51 for < 65; 0.44 for stage IIIA and 0.45 for IIIC; 0.43 for micrometastasis and no ulceration and 0.33 for macrometastasis and ulceration; 0.52 for one nodal metastasis and 0.37 for two to three positive nodes. 

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

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Grade 3/4 adverse events occurred in 41% of patients on the combination and in 14% of the placebo arm. Adverse events leading to treatment discontinuation were seen in 26% and 3%, respectively. “This was a bit more than we expected, but treatment in the adjuvant setting is maybe not the same as for stage IV patients,” he suggested. 

Which Adjuvant Approach Will Be Preferred? 

DR. HAUSCHILD PREDICTED that in Europe, BRAF-mutated patients will initially receive the dabrafenib/trametinib combination or nivolumab (Opdivo), which also strongly improved relapse-free survival outcomes in the CheckMate 238 trial, presented at the ESMO Congress as well.4 Although adjuvant ipilimumab has already been approved in the United States, this is not the case in Europe. Furthermore, there are practical considerations, such as the route of delivery (dabrafenib/trametinib is an all-oral regimen) and toxicity profiles. 

“There are patients who are not good candidates for one or the other. We can speculate whether one treatment is superior to the other, but I think this would be unfair,” he said. “Let’s say they are equivalent, and the choice is based on the discussion between physician and patient as to whether they prefer oral kinase inhibitors or intravenous nivolumab immunotherapy.” 

BRIM8: Effect Was Not Statistically Significant 

BRIM8 WAS A PHASE III international multicenter double-blind study that assessed the efficacy of 1 year of vemurafenib (960 mg twice daily) in two cohorts: stage IIC–IIIB melanoma patients (cohort 1) and stage IIIC (cohort 2) patients. Hierarchical testing of disease-free survival in cohort 2 was prespecified in a way in which only a P value ≤ .05 would allow for the findings in the earlier-stage patients of cohort 1 to be considered statistically significant, Dr. Lewis explained. 

In cohort 2, 1 year of adjuvant vemurafenib increased the median disease-free survival vs placebo, but the risk reduction was not statistically significant. Median disease-free survival was 23.1 month with vemurafenib and 15.4 months with placebo (HR = 0.80; P = .2598), and approximately 47% in each arm were alive at 24 months. 

“The potential role of disease biology and treatment duration and intensity may explain the lack of disease-free survival benefit in these patients,” suggested Dr. Lewis. 

A beneficial effect in cohort 1, however, was demonstrated, but because of the statistical design, it was not considered significant. For these earlier-stage patients, median disease-free survival was not reached with vemurafenib and was 36.9 months with placebo (HR = 0.54; P = .0010). At 24 months, 72.3% and 56.5%, respectively, were free of disease. 

In a prespecified exploratory analysis in the pooled intent-to-treat population, a substantial benefit was also observed, as median disease-free survival was not reached with vemurafenib and was 25.8 months with placebo (HR = 0.65; P = .0013). Overall survival data are immature. 

“Vemurafenib monotherapy is an effective and well-tolerated adjuvant option for patients in cohort 1, with resected stage IIC/IIIA/IIIB BRAF V600–positive melanoma,” Dr. Lewis concluded. “Further exploration is needed to improve outcomes in patients with resected stage IIIC melanoma.” ■

DISCLOSURE: Dr. Hauschild reported no conflicts of interest. Dr. Lewis has received research grants from and is a consultant for Roche/Genentech. 


1. Hauschild A, Santinami M, Long GV, et al: COMBI-AD: Adjuvant dabrafenib plus trametinib for resected stage III BRAF V600E/K-mutant melanoma. ESMO 2017 Congress. Abstract LBA6_PR. Presented September 11, 2017. 

2. Long GV, Hauschild A, Santinami M, et al: Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. September 10, 2017 (early release online). 

3. Lewis K, Maio M, Demidov L, et al: BRIM8: A randomized, double-blind, placebo-controlled study of adjuvant vemurafenib in patients with completely resected BRAF V600+ melanoma at high risk for recurrence. ESMO 2017 Congress. Abstract LBA7_PR. Presented September 11, 2017. 

4. Weber J, Mandala M, Del Vecchio M, et al: Adjuvant therapy with nivolumab vs ipilimumab after complete resection of stage III/IV melanoma: A randomized, double-blind, phase 3 trial (CheckMate 238). ESMO 2017 Congress. Abstract LBA8_PR. Presented September 11, 2017.