Dr Eroglu on Safety Considerations for Encorafenib/Binimetinib/Nivolumab in BRAF V600+ Melanoma

"The reason that patients in this study on the triplet arm who got the targeted therapy together with immunotherapy may have done better is that the targeted therapy shrinks the metastases, both within the brain and outside, more quickly. That allowed the patients to come off the corticosteroids faster and may allow the immunotherapy to be more effective."

Zeynep Eroglu, MD, a medical oncologist in the Department of Cutaneous Oncology at Moffitt Cancer Center and assistant professor in the Department of Oncologic Sciences at the University of South Florida Morsani College of Medicine, discussed dosing measures and safety considerations for the use of encorafenib (Braftovi), binimetinib (Mektovi), and nivolumab (Opdivo) in patients with BRAF V600–mutant melanoma with brain metastases.

Findings from the phase 2 SWOG S2000 trial (NCT04511013), presented at the 2025 ASCO Annual Meeting, showed that encorafenib/ binimetinib/nivolumab (n = 16) achieved a median progression-free survival (PFS) of 6.2 months (95% CI, 3-14.4) vs 1.5 months (95% CI, 0.7-1.7) with nivolumab/ipilimumab (Yervoy; n = 15; HR, 0.47; 1-sided 90% CI, 0-0.82; P = .04). Six-month PFS rates were 54% (95% CI, 27%-75%) with the triplet and 20% (95% CI, 5%-42%) with the doublet. Median intracranial PFS was 8.7 months (95% CI, 3-19.4) vs 1.5 months (95% CI, 0.7-1.7), respectively (HR, 0.39; 1-sided 90% CI, 0-0.68; P = .01).

When considering the use of this triplet in clinical practice, minimizing corticosteroid use is critical, as corticosteroids can reduce the efficacy of immunotherapy, Eroglu explained. Many patients with symptomatic brain metastases require agents such as dexamethasone, which may partly explain the limited benefit seen with immunotherapy in this population. The triplet regimen may enable faster corticosteroid tapering by inducing rapid intracranial and extracranial tumor shrinkage, potentially enhancing immunotherapy activity, she reiterated.

Dose modifications were required in the triplet arm, including temporary treatment holds and dose reductions of targeted agents, Eroglu noted. She added that immunotherapy was sometimes withheld for multiple cycles to allow resolution of adverse effects (AEs). In the nivolumab/ipilimumab arm, treatment holds and early discontinuation of ipilimumab were also necessary, with some patients continuing on nivolumab monotherapy. Immunotherapy doses cannot be reduced, and treatment discontinuation is warranted if rechallenge is deemed unsafe, Eroglu stated.

These data support a potential role for triplet therapy in select patients with BRAF V600–mutant melanoma and brain metastases, particularly those who may benefit from rapid disease control to facilitate corticosteroid reduction, Eroglu concluded.