The research that I presented was the results of the BRIM8 trial which is an adjuvant trial of single agent vemurafenib in patients with malignant melanoma at high risk of recurrence that harbour a BRAF mutation. It was a two cohort study: cohort one was lower risk patients with stage 2c to stage 3b disease; cohort two was the highest risk patient cohort who had stage 3c disease. They were randomised one to one to receive placebo or vemurafenib monotherapy.
The statistical design of this study was a hierarchical design where cohort two was analysed before cohort one and only if cohort two was positive would cohort one be considered positive as well. The primary endpoint was disease free survival. In the analysis of cohort two there was an improvement in median disease free survival for those who received vemurafenib versus those who received placebo but the results were not statistically significant. At one year there was a striking difference, about a 20% absolute improvement, but at the point where drug is stopped those curves come together and people are relapsing when the drug is stopped in that higher risk group.
For the stage 2c to stage 3b patients, cohort one, there was a meaningful difference in disease free survival across the endpoints that were looked at.
That leaves the question of if the response stopped at the time of treatment being stopped would continued treatment result in continued response or supplementary treatment with something else to try and extend that initial benefit?
That’s a good question and we just don’t know the answer to that. It looks like in the lower stage diseases, still high risk but probably lower circulating tumour burden, one year of treatment was adequate to clear disease and those patients can remain without relapse. But in the higher risk patients it does appear, based on those data, that continued treatment might be of benefit although we can’t say that with certainty but it certainly looks like that might be the case.
Or perhaps trying to consolidate that benefit with an added therapy in a combination?
Or an added therapy. The results of the other adjuvant trials presented included high risk patients. The dabrafenib/trametinib trial included patients with stage 3 disease; the nivolumab trial included patients with stage 3c disease and stage 4. Treatment was stopped there, they weren’t analysed separately, they were as one big group, so it will be interesting to see those subsets of patients and how they do.
By way of conclusion, how would you say that your research leaves BRAF melanoma? Trying to treat it with single agent therapy what is the best practice going forward, learning from this trial?
The results of the study with BRIM8 being vemurafenib monotherapy certainly were encouraging in that a group of patients can benefit from BRAF monotherapy. But taken in context with the other trials presented today, probably combination targeted therapy with BRAF and MEK inhibitor will be a standard as well as PD-1 antibody as the standard immunotherapy.