Adjuvant BRAF and MEK Inhibition for Melanoma: 'Impressive'

Jeffrey S. Weber, MD, PhD


October 31, 2017

Hello. I'm Dr Jeffrey Weber. I'm a medical oncologist at the Laura and Isaac Perlmutter Cancer Center at the New York University Langone Health System in New York City.

Today we will be talking about a very interesting abstract from the 2017 European Society for Medical Oncology (ESMO) meeting that described relapse-free and overall survival data from the COMBI-AD trial.[1] This large, randomized, phase 3, blinded, placebo-controlled trial studied the use of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib in patients with resected stage III melanoma. The critical endpoint of this study was relapse-free survival. Secondary endpoints were distant metastasis-free [survival], overall survival, and toxicity.

This was a dramatically positive study. Dr Axel Hauschild, who presented at the 2017 ESMO Presidential Symposium, made it clear that the difference was so dramatic that the P value had more zeros than had ever been seen in any large randomized study to date. The P value for the difference in relapse-free survival between the dabrafenib/trametinib arm and placebo was .00000000000001, which is 13 zeros. The 1-year relapse-free survival for the treatment arm was 88%. At 2 years it was 67%, and at 3 years it was 58%, with what looks like a plateau beginning somewhere around the 50% range.

These data were achieved with a median follow-up of almost 3 years, which gives it a longer follow-up than other similar studies presented at ESMO. The average patient was in their early 50s—a little younger than in many such trials—but in all other respects, the study was well balanced for gender, age, stage (IIIA versus IIIB versus IIIC), macroscopic versus microscopic disease, and ulceration of the primary [site] versus no ulceration of the primary [site]. In all respects, it was a very well-conducted trial. And again, a very positive trial with respect to its primary endpoint of relapse-free survival.

Looking at the forest plot by different subgroups, there was virtually no overlap of the 95% confidence intervals (CIs) reaching 1. The vast majority of patients had a BRAF V600E mutation; only about 9% had a V600K mutation. There, the CI just reached 1, but in all other respects —especially by IIIA, B, and C substage —the forest plots showed benefit well to the left of the line of 1.

In terms of the distant metastasis-free survival, again [there were] very impressive data. The 1-year and 2-year distant metastasis-free survival figures were 91% and 77%, respectively, with what looks like a plateau of 71% at 3 years. The nominal P value was .001 with a hazard ratio of 0.51, showing a 49% reduction in the risk for distant metastasis.

In the first interim analysis, dabrafenib/trametinib survival rates were 97% at 1 year, 91% at 2 years, 86% at 3 years, and what may be a plateau beyond 3 years, with a P value of 0.0006 and a 43% reduction in the risk for death. I believe there was something like 38 deaths out of 870 patients.

The safety summary was somewhat of a surprise. In the treatment arm, 41% had any grade 3/4 adverse event compared with about 14% in the placebo arm —presumably not treatment-related, of course. The one surprise was that there was minimal discontinuation in the placebo arm but a 26% rate of discontinuation owing to adverse events in the dabrafenib/trametinib treatment arm. I think of dabrafenib/trametinib as a pretty benign regimen. I think investigators were probably pretty quick to pull the plug, given that this was a blinded, adjuvant trial. The most common adverse events with dabrafenib/trametinib were pyrexia, fatigue, nausea, headache, and chills.

In conclusion, this was a very positive adjuvant trial for dabrafenib/trametinib in stage III melanoma versus placebo, showing a 53% reduction in the risk for relapse and a 49% reduction in the risk for death, with very early data and very few deaths. Nonetheless, the estimated 1-, 2-, and 3-year survivals were just excellent, with 88% 1-year relapse-free survival and 58% 3-year relapse-free survival. Again, relapse-free survival was seen at each planned subgroup, so very impressive data. And we hope, for BRAF-mutated stage III melanoma patients, there will soon be a new approval and potentially a new standard of care.

Please feel free to write with questions. Thank you for listening. This is Dr Jeffrey Weber.


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