Encorafenib/Binimetinib/Nivolumab Improves PFS in BRAF V600+ Melanoma with Symptomatic Brain Metastases

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Treatment with the triplet combination of encorafenib (Braftovi), binimetinib (Mektovi), and nivolumab (Opdivo) improved progression-free survival (PFS) compared with nivolumab plus ipilimumab (Yervoy) in patients with BRAF V600–mutant melanoma brain metastases, according to data from the phase 2 SWOG S2000 trial (NCT04511013) presented at the 2025 ASCO Annual Meeting.

During the presentation, lead study author Zeynep Eroglu, MD, of Moffitt Cancer Center in Tampa, Florida, noted that more research and improved guidelines are needed for the optimal treatment of this patient population, who have historically had poor outcomes with immunotherapy.

Findings from the phase 2 study showed that patients treated with the triplet (n = 16) achieved a median PFS of 6.2 months (95% CI, 3-14.4) compared with 1.5 months (95% CI, 0.7-1.7) for those given nivolumab plus ipilimumab (n = 15; HR, 0.47; 1-sided 90% CI, 0-0.82; P = .04). The 6-month PFS rates were 54% (95% CI, 27%-75%) and 20% (95% CI, 5%-42%), respectively.

The median intracranial PFS was 8.7 months (95% CI, 3-19.4) in the encorafenib plus binimetinib and nivolumab arm vs 1.5 months (95% CI, 0.7-1.7) in the doublet arm (HR, 0.39; 1-sided 90% CI, 0-0.68; P = .01).

Notably, the 18-month overall survival (OS) rates were 36% (95% CI, 13%-60%) in the encorafenib plus binimetinib and nivolumab group vs 37% (95% CI, 12%-62%) in the nivolumab plus ipilimumab group (HR, 1.21; 95% CI, 0.49-2.98; P = .66).

“In this still difficult-to-treat patient population, a triplet regimen may be therapeutically useful but is still in need of further study,” Eroglu said during the presentation.

Phase 2 Trial Rationale and Design

Eroglu explained that even with radiation and/or surgery, outcomes for patients with symptomatic brain metastases from melanoma remain poor. Triplet regimens have demonstrated feasibility in the first-line setting for patients with advanced melanoma; however, she explained that clinical improvements with these regimens have been minimal, and they have not been compared with up-front immunotherapy.

Due to the poor outcomes associated with immunotherapy in melanoma brain metastases, SWOG S2000 was launched to compare a triplet regimen in this setting.

SWOG S2000 enrolled patients at least 18 years of age with melanoma with brain metastases of at least 0.5 cm in size who had an ECOG performance status of 0 to 2. Brain metastases needed to be symptomatic at baseline, defined as neurological symptoms and/or the need for steroids. Patients were allowed to have leptomeningeal disease, but extracranial disease was not allowed

Patients needed to harbor a BRAF V600 mutation and be treatment naive in the metastatic setting. Patients were allowed to receive corticosteroids at up to 8 mg of dexamethasone per day, or an equivalent regimen. Permitted prior treatments included neoadjuvant or adjuvant immunotherapy or targeted therapy; and local therapy for brain metastases, as long as one measurable, progressing metastatic site remained.

Patients were randomly assigned to receive encorafenib at 450 mg once per day plus binimetinib at 45 mg twice per day and nivolumab at 480 mg once every 4 weeks; or nivolumab at 480 mg once every 4 weeks plus ipilimumab at 1 mg/kg once every 3 weeks for 4 cycles. Treatment continued for up to 2 years or until disease progression or unacceptable toxicity. Notably, patients were allowed to continue treatment beyond disease progression if patients were experiencing clinical benefit in the opinion of the treating physician, and patients were allowed to receive stereotactic radiosurgery in this scenario.

PFS per RECIST 1.1 criteria served as the primary end point. Secondary end points comprised overall response rate (ORR), intracranial PFS and ORR, OS, safety, and radiographic response.

Baseline Characteristics

Patients in the triplet arm had a median age of 66.9 years (range, 35.8-88.9) compared with 60.8 years (range, 32.4-75.2) in the doublet arm. The majority of patients were male (triplet, 63%; doublet, 80%), White (94%; 80%), and had a BRAF V600E mutation (56%; 87%). Elevated lactate dehydrogenase levels were reported in 44% of patients in the triplet arm and 73% of patients in the control arm. Corticosteroid use was reported in 38% and 47% of patients, respectively.

Thirty-one percent of patients in the triplet arm received prior brain surgery, and 13% had prior brain-directed radiotherapy. These respective rates were 53% and 6.7% in the doublet arm. No patients in either arm received neoadjuvant therapy alone; 6.3% of patients in the triplet arm had adjuvant therapy alone compared with 13% of patients in the doublet arm. One patient in the triplet arm (6.3%) received both neoadjuvant and adjuvant therapy.

Most patients in the triplet (75%) and doublet (53%) arms had 1 or 2 brain metastases. The median brain metastases size was 1.4 cm (range, 0.5-9.6) and 2.3 cm (range, 0.5-7.9), respectively.

Further Efficacy and Safety Findings

Among evaluable patients, the ORR was 67% (95% CI, 43%-91%) in the encorafenib plus binimetinib and nivolumab arm (n = 15) and 14% (95% CI, 0%-33%) in the nivolumab plus ipilimumab arm (n = 14). All responses in both arms were partial, and the rates of stable disease were 7% in both groups. Thirteen percent of patients in the triplet arm had progressive disease vs 79% of patients in the control arm. Symptomatic deterioration prior to treatment was reported in 14% of patients in the triplet arm.

The intracranial ORR was 75% (95% CI, 54%-96%) in the triplet arm (n = 16) vs 13% (95% CI, 0%-31%) in the doublet arm (n = 15). One patient in each arm had an intracranial complete response. The rates of stable disease and progressive disease were both 6% in the experimental arm; these rates were 7% and 80%, respectively, in the control arm.

Regarding safety, grade 3/4 treatment-related adverse effects (TRAEs) occurred in 69% of patients in the triplet group vs 75% of patients in the doublet arm. TRAEs led to treatment discontinuation in 19% and 32% of patients, respectively. Dose modifications due to TRAEs were reported in 75% and 32% of patients, respectively. Eroglu noted that the toxicity profiled of both regimens were consistent with the known profiles of each agent.

Eroglu concluded by noting that the trial was limited by the difficulty in enrolling highly symptomatic patients to the study, and the study was not designed to compared the triplet with sequential targeted therapy and immunotherapy approaches.

Reference

Eroglu Z, Moon J, Najjar Y, et al. A randomized phase 2 trial of encorafenib + binimetinib + nivolumab vs ipilimumab + nivolumab in BRAFV600-mutant melanoma brain metastases: SWOG S2000 (NCT04511013). J Clin Oncol. 2025;43(suppl 17):LBA9507. doi:10.1200/JCO.2025.43.17_suppl.LBA9507