Key Considerations for Detecting and Targeting BRAF Mutations - Episode 11
Hussein A. Tawbi, MD, PhD: The choice of what to use first for our patients with metastatic melanoma in the first-line setting is complex because we have effective immunotherapy and effective targeted therapy, and we’ve never had them compared head-to-head. However, there’s strong preclinical and clinical data indicating that the combination of targeted therapy with immunotherapy can be highly effective. In fact, targeted therapy can modulate the tumor microenvironment to make it more responsive to immunotherapy.
And so, there have been several triplet trials that add a PD-1 [programmed cell death protein 1] antibody to a BRAF and a MEK inhibitor combination. Most of them have been phase I, phase II trials. Most notably, a randomized phase II trial called KEYNOTE-022 randomized 120 patients—60 on each arm—with pembrolizumab, dabrafenib, and trametinib versus dabrafenib and trametinib alone. The interesting results from most of these early phase trials suggest that it’s a combination that has a higher rate of toxicity. However, the toxicities are generally manageable with dose reductions and dose interruptions.
Those combinations seem to have a high response rate, so they’ve actually already moved into phase III testing. There are 2 clinical trials that have actually completed accrual already. One is called TRILOGY, which combines vemurafenib and cobimetinib with the anti—PD-L1 [anti–programmed death-ligand 1] antibody atezolizumab. Again, this trial randomized patients to that triplet versus the targeted therapy alone. And there’s COMBI-i, which is a combination of dabrafenib, trametinib, and spartalizumab, which is an anti–PD-1 antibody, and compares that triplet to targeted therapy alone. Both of those studies have fully accrued and are in the follow-up phase to try to determine whether this triplet approach is going to be more effective than targeted therapy alone.
I can tell you that at this ASCO [American Society of Clinical Oncology] meeting, COMBI-i has actually reported more biomarker data from a couple of parts of the study that were kind of biomarker-driven, and some safety and efficacy data from those patients who were enrolled in part 1 and part 2, which were almost like a phase I and a biomarker study that were part of COMBI-i. Both of these posters show some really interesting results. They show, again, the same thing, that this is a triplet regimen that would be manageable. The toxicity is manageable, although there is definitely a higher rate of toxicity than targeted therapy alone. And then, the efficacy looks promising.
Transcript Edited for Clarity