Dr Schadendorf on Triplet Therapy in BRAF V600-Mutant Melanoma

Dirk Schadendorf, MD, discusses how results from the phase 3 STARBOARD trial may change first-line treatment selection for patients with unresectable locally advanced or metastatic BRAF V600-mutant melanoma. He explains why he believes patients who are considered for targeted therapy should now also be considered candidates for triplet therapy.

STARBOARD is a randomized, double-blind study that evaluated first-line encorafenib (Braftovi), a BRAF inhibitor, plus binimetinib (Mektovi), a MEK inhibitor, and pembrolizumab (Keytruda), an anti-PD-1 checkpoint inhibitor, compared with placebo plus pembrolizumab. The trial enrolled 220 patients with BRAF V600E/K-mutant cutaneous melanoma who had not received prior first-line systemic therapy. Patients were randomized 1:1, and the primary end point was objective response rate (ORR) by blinded independent central review, with progression-free survival (PFS) as a key secondary end point.

Both end points were met. The confirmed ORR was 70.0% with the triplet vs 32.7% with placebo plus pembrolizumab. Median PFS was 33.0 months vs 3.4 months, respectively, representing a 67% reduction in the risk of disease progression or death (HR, 0.33). Overall survival data were immature but showed a positive trend favoring the triplet (HR, 0.71). Grade 3/4 treatment-emergent adverse events occurred in 70% of patients in the triplet arm vs 39% in the control arm, with no new safety signals and no grade 5 treatment-related adverse events.

In this interview, Schadendorf addresses the decision point between targeted therapy and checkpoint blockade. He notes there is a defined group of patients for whom targeted therapy is typically considered, and that all of these patients should now be evaluated as candidates for the triplet regimen. Whether BRAF/MEK inhibition alone, without checkpoint blockade, remains a reasonable approach is what he calls the great question, because the durability of PFS seen with the triplet has not been matched by the median PFS reported in any BRAF/MEK clinical trial.

Schadendorf also identifies the patients he views as candidates for triplet therapy, including those with symptomatic disease and those with fast tumor kinetics. In these situations, where nivolumab (Opdivo) plus ipilimumab (Yervoy) would usually be considered, he describes the triplet as a strong alternative for patients with BRAF V600-mutant melanoma.