Encorafenib/Binimetinib Plus Pembrolizumab Extends PFS in BRAF V600 Melanoma

At the 2026 European Society for Medical Oncology (ESMO) Congress, final results from the phase 3 STARBOARD trial (NCT04657991) showed that first-line encorafenib (Braftovi) and binimetinib (Mektovi) plus pembrolizumab (Keytruda) produced a statistically significant and clinically meaningful improvement in objective response rate (ORR) and progression-free survival (PFS) vs placebo plus pembrolizumab in patients with unresectable locally advanced or metastatic BRAF V600E/K–mutant melanoma.

The confirmed ORR per blinded independent central review (BICR) was 70.0% (95% CI, 60.9%-77.8%) with the triplet vs 32.7% (95% CI, 24.7%-41.9%) with placebo plus pembrolizumab (odds ratio [OR], 4.903; 90% CI, 2.870-8.125; one-sided P <.0001). The median PFS by BICR was 33.0 months (95% CI, 20.0-not estimable [NE]) vs 3.4 months (95% CI, 2.2-8.3), respectively, representing a 67% reduction in the risk of disease progression or death (HR, 0.33; 90% CI, 0.24-0.46; one-sided P <.0001).

The randomized, double-blind, placebo-controlled phase 3 portion enrolled patients with documented BRAF V600E/K–mutant unresectable or metastatic cutaneous melanoma who had received no prior systemic treatment for metastatic or locally advanced disease, had measurable disease per RECIST v1.1, and had an ECOG performance status of 1 or lower. Patients were randomly assigned 1:1 to receive encorafenib at 450 mg once daily and binimetinib at 45 mg twice daily plus pembrolizumab at 200 mg every 3 weeks (n = 110) or placebo plus pembrolizumab at 200 mg every 3 weeks (n = 110). Pembrolizumab was limited to a maximum of 35 administrations. Randomization was stratified by prior systemic adjuvant therapy with a checkpoint inhibitor or BRAF/MEK inhibitor and by disease stage. The study design was amended because of recruitment issues, which reduced the planned sample size and revised the primary and key secondary end points.

ORR by BICR served as the primary end point, and PFS by BICR was the key secondary end point. Other secondary end points included overall survival (OS), investigator-assessed PFS and ORR, duration of response (DOR), time to response, quality of life, safety, and pharmacokinetics. As of the January 12, 2026, data cutoff, the median follow-up for PFS was 24.9 months in the triplet arm and 30.2 months in the control arm, and the median follow-up for OS was 30.8 and 30.9 months, respectively.

Baseline characteristics were generally similar between arms. The median age was 59.0 years in the triplet arm and 57.5 years in the control arm, 69.1% and 75.5% of patients had an ECOG performance status of 0, and 23.6% and 20.9% had high lactate dehydrogenase (LDH) levels, respectively. Few patients had brain metastases (2.7% vs 3.6%), and 25.5% and 20.0% had received prior adjuvant therapy.

In the triplet arm, 10.9% of patients achieved a complete response (CR) and 59.1% achieved a partial response (PR), compared with 4.5% and 28.2%, respectively, in the control arm. Progressive disease was the best overall response in 4.5% of patients who received the triplet vs 42.7% of those who received control. The median time to response was 9.1 weeks vs 9.7 weeks, and the median DOR was not estimable in either arm. The ORR benefit was consistent across key subgroups, including patients with BRAF V600E mutations confirmed by central tumor tissue testing (OR, 5.91; 95% CI, 2.94-11.98), those with high LDH levels (OR, 6.38; 95% CI, 1.58-27.04), and those aged 65 years or older (OR, 4.01; 95% CI, 1.39-11.73).

PFS events occurred in 40% of patients in the triplet arm and 70% of those in the control arm. The 12-month PFS rates were 70.7% vs 34.3%, and the 24-month rates were 54.8% vs 26.4%, respectively. The PFS benefit was also consistent across key clinical subgroups, including patients with an ECOG performance status of 1 (HR, 0.22; 95% CI, 0.11-0.42), those with high LDH levels (HR, 0.33; 95% CI, 0.16-0.68), and those with stage IV disease (HR, 0.38; 95% CI, 0.26-0.55).

OS was immature at the final analysis but showed a positive trend favoring the triplet. Deaths occurred in 29.1% of patients in the triplet arm and 37.3% of those in the control arm. The median OS was not reached in either arm (HR, 0.71; 90% CI, 0.48-1.05). The 12-month OS rates were 89.5% vs 78.7%, and the 24-month rates were 76.6% vs 64.2%, respectively.

Regarding safety, treatment-emergent adverse events (TEAEs) occurred in all patients in the triplet arm and 94.5% of those in the control arm and were treatment related in 96.4% and 73.6%, respectively. Grade 3 or 4 TEAEs occurred in 70.0% vs 39.1% of patients and were treatment related in 57.3% vs 21.8%. Grade 5 TEAEs occurred in 4.5% and 9.1% of patients, respectively, none of which were considered treatment related, and no new safety signals were observed. TEAEs led to discontinuation of pembrolizumab in 31.8% of patients in the triplet arm vs 13.6% in the control arm and to discontinuation of encorafenib and binimetinib or placebo in 42.7% vs 14.5%. More than 80% of patients in the triplet arm required a dose reduction or interruption of encorafenib or binimetinib.

The most frequent all-cause TEAEs in the triplet arm included nausea, diarrhea, increased alanine aminotransferase (ALT), fatigue, pyrexia, and increased blood creatine phosphokinase. The most common grade 3 or 4 events with the triplet were increased ALT (14%), increased lipase (12%), increased aspartate aminotransferase (11%), and increased blood creatine phosphokinase (8%). Treatment-related adverse events of special interest, including immune-related events, were reported in 46.4% of patients in the triplet arm and 17.3% of those in the control arm.

Reference

Schadendorf D, Dummer R, Sullivan RJ, et al. STARBOARD phase 3: a randomized, double-blind study of first-line encorafenib, binimetinib, and pembrolizumab vs placebo and pembrolizumab for unresectable locally advanced or metastatic BRAF V600-mutant melanoma. Presented at: 2026 European Society for Medical Oncology Congress; October 23-27, 2026; Madrid, Spain. Abstract 2071O