Georgina V. Long, MD, PhD, on BRAF-Mutated Melanoma: Long-Term Follow-up of Adjuvant Dabrafenib Plus Trametinib vs Placebo

COMBI-AD trial is a randomized phase three clinical trial of adjuvant dabrafenib combined with trametinib versus placebo for resected stage three BRAF mutated melanoma. The final analysis, the long-term data and the overall survival data were presented and show a durable and sustained benefit in terms of relapse-free survival when patients received dabrafenib plus trametinib versus placebo. There was a 48% reduction in the risk of recurrence with nearly 10 years of follow-up. In fact, the median follow-up was 100 months for dabrafenib plus trametinib and 82 months for placebo, and the maximum follow-up was 125 months. So when we look at the relapse-free survival and look at the eight-year relapse-free survival landmark, we saw 50% for dabrafenib and trametinib, which was much higher than the 35% we saw for placebo. Again, we saw a sustained and durable improvement in the distant metastasis-free survival with a hazard ratio of 0.56, that's a 44% reduction in the risk of distant metastasis at first recurrence. So therefore, the two major endpoints were statistically significant with confidence intervals that did not cross one demonstrating this durable and sustained impact of adjuvant dabrafenib-trametinib. The overall survival showed a separation of the Kaplan-Meier curves with a 20% reduction in the risk of death from any cause using adjuvant dabrafenib-trametinib versus placebo. This is a hazard ratio of 0.80. However, the confidence interval just nudged over one, 1.01, and the P-value is 0.063 so this was not statistically significant. We will not see an adjuvant trial which has any separation of the Kaplan-Meier curves. So this is substantial for the modern era of melanoma treatments when we know that we can cure patients in the advanced setting to see any separation of the overall survival curves in the stage three setting. What was remarkable is if we looked at the subgroup of V600E, they seem to benefit the most in terms of overall survival. The dabrafenib-trametinib hazard ratio versus placebo was 0.75, that's a 25% risk reduction terms of death using adjuvant dabrafenib and trametinib for those with the V600E and that was 91% of the trial population. However, for V600K, which was a small subgroup, there was a reversal, the placebo arm seemed to do better than dabrafenib-trametinib, but we have to exercise caution with only 40 and 37 patients in each arm for that analysis, but it does suggest that the main benefit seems to be in patients with V600E melanoma. Interestingly, the relapse-free survival benefit with dabrafenib and trametinib was seen for both V600E, and V600K. So it was only the overall survival where we saw really the substantial benefit in the V600E. So what does this mean for the future? It means that we have a treatment that can be used for BRAF V600 mutated patients for adjuvant therapy for resected stage three. There were no irreversible toxicities with this long-term follow-up data, and we saw a sustained and durable impact on the relapse-free survival, the distant metastasis-free survival, and we did see a numerical improvement in the overall survival as well as the melanoma-specific survival, a very important endpoint as we cure more patients with melanoma.