The addition of BRAF-targeted therapies encorafenib (Braftovi) and binimetinib (Mektovi) to nivolumab (Opdivo) may be more therapeutically beneficial for patients with BRAF V600–mutant melanoma brain metastases, who have historically had poor outcomes with solely immunotherapy-based regimens, according to Zeynep Eroglu, MD.1
Results from the phase 2 SWOG S2000 trial (NCT04511013), presented during the 2025 ASCO Annual Meeting, showed that the encorafenib plus binimetinib and nivolumab regimen (n = 16) produced 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 plus ipilimumab (Yervoy; 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%) with the triplet and 20% (95% CI, 5%-42%) with the doublet; the 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).
Notably, nivolumab plus ipilimumab was previously evaluated in a phase 2 study (NCT02374242) for the treatment of patients with active asymptomatic melanoma brain metastasis.2 Data from the study determined that upfront ipilimumab plus nivolumab should be the standard of care in patients with melanoma brain metastasis, as patients treated with the doublet demonstrated a 7-year overall survival rate of 48%.
“If a patient [with] melanoma harbors a BRAF mutation, which is important to find out early if it is not known ahead of time, this triplet approach of combining the targeted therapy with the immunotherapy [could be] considered. It may be a [more] helpful regimen for these patients, as opposed to starting them with immunotherapy alone,” Eroglu shared with OncLive®.
In the interview, Eroglu outlined typical challenges when attempting to use immunotherapy regimens for patients with symptomatic melanoma brain metastasis; the design and eligibility criteria of SWOG S2000; key efficacy and safety data with the triplet combination; and the importance of identifying BRAF mutations early in the treatment course to inform selection.
Eroglu is a medical oncologist in the Department of Cutaneous Oncology at Moffitt Cancer Center and an assistant professor in the Department of Oncologic Sciences at the University of South Florida Morsani College of Medicine, both located in Tampa.
OncLive: What was the rationale for investigating the triplet regimen in patients with BRAF V600E-mutant melanoma harboring brain metastases?
Eroglu: We know that it is very challenging to treat patients with symptomatic melanoma brain metastases. In asymptomatic patients, immunotherapy drugs such as ipilimumab plus nivolumab are associated with high response rates of [over] 50% and median PFS exceeding 3 years. However, in patients with symptomatic brain metastases, [including] those with neurologic symptoms and/or [those] requiring corticosteroids to manage those symptoms, outcomes with immunotherapies like ipilimumab plus nivolumab are significantly poorer, with response rates of approximately 20% and median PFS of just over 1 month. This population often requires local therapies such as craniotomy or radiation, yet still experiences poor outcomes with systemic treatments.
The rationale for this study was that, for patients with melanoma harboring a BRAF V600 mutation, combining BRAF-targeted therapy with encorafenib plus binimetinib and nivolumab could be evaluated against the current standard of ipilimumab plus nivolumab to [determine whether] we could improve upon PFS and response rates.
What should be known about the trial design, enrollment criteria, and baseline characteristics?
To be eligible [for the study], patients had to have symptomatic melanoma brain metastasis that could be measurable—so either neurologic symptoms or requiring corticosteroids prior to enrollment—and had to have a BRAF V600 mutation. They had to be treatment-naive in the metastatic setting. They could have had prior neoadjuvant or adjuvant systemic treatment upon enrollment.
We had about 30 patients. They were [randomly assigned] 1:1 to either the triplet immunotherapy combination [of] encorafenib, binimetinib, and nivolumab, all using standard doses of those drugs, or to immunotherapy with ipilimumab 3 mg/kg plus nivolumab 1 mg/kg, which is standard.
Upon starting these regimens, [patients] stayed on them until they [experienced disease] progression, although they were permitted to stay on trial beyond progression if that was thought to be in their best interest. They could, for example, receive radiation to brain metastases in the event of progression and continue with the systemic treatment afterward. The study’s primary end point was PFS, including both intracranial and extracranial responses.
Patient demographics were evenly matched. It was about 15 patients per arm, and approximately half of them had received prior surgery or radiation for their brain metastases before enrollment. Nearly half had corticosteroids at the time of enrollment, and there were no significant differences between the groups in their demographics.
What efficacy and safety findings were presented?
In terms of findings, we did see a significant [PFS] improvement in patients who got the triplet regimen [vs the doublet]. The 6-month PFS rate was 54% with encorafenib plus binimetinib and nivolumab compared with 20% with ipilimumab plus nivolumab; the HR was 0.47. The median intracranial PFS was 8.7 months [with the triplet regimen] compared with 1.3 months in the [doublet arm]. Intracranial response rates were 75% with the triplet regimen versus 13% with ipilimumab plus nivolumab. There was [also] a significant difference in improving response rates.
Both study arms had high rates of grade 3/4 [treatment-related] toxicities. [In the ipilimumab/nivolumab arm], 75% of patients experienced grade 3/4 adverse effects [AEs]; this [incidence] was similar in the [triplet] arm, at 69%.
With the triplet regimen, the most common grade 3/4 [treatment-related] AEs were elevations in liver enzymes. When you have both targeted therapy and immunotherapy [in one regimen], sometimes it’s a question of which drug is causing that AE. We would often hold the targeted therapy or do a dose reduction plus start corticosteroids if we thought the AE was related to the immunotherapy. In the ipilimumab/nivolumab cohort, the most frequent grade 3/4 AEs were diarrhea and enterocolitis. High doses of corticosteroids [were typically required] to manage enterocolitis.
What are the implications of these findings for selecting triplet vs doublet regimens in clinical practice?
Symptomatic melanoma brain metastases [are] difficult to treat, and a multidisciplinary approach is very important. Oftentimes, these patients are seen by neurosurgeons if they may need surgery at some point, and radiation oncologists, as they may need stereotactic radiation.
Because of the effects of corticosteroids on decreasing the efficacy of the immunotherapy, trying to reduce the dose of corticosteroids as much as possible, if feasible, is important. [Corticosteroid use] may be one of the reasons why these patients with symptomatic brain metastases who get immunotherapy do so poorly, as oftentimes these patients require something like dexamethasone. 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 as well.
Within the triplet arm, there were patients who had to undergo either dose holds or dose reductions, which we were able to do with targeted therapy drugs and sometimes with immunotherapy. In some cases, the immunotherapy agent had to be held for several cycles for a certain AE to resolve. Similarly, within the ipilimumab/nivolumab arm, we did have to hold [the dose of an agent] in some cases or drop the ipilimumab early and have the patients just continue on the nivolumab alone. However, with immunotherapy, we cannot do a dose reduction, as those are set doses. Patients did have to undergo dose holds or, in some cases, discontinue the treatment early if we thought it was not safe to rechallenge with the immunotherapy.
References
- 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
- Long GV, Atkinson V, Lo SN, et al. Ipilimumab plus nivolumab versus nivolumab alone in patients with melanoma brain metastases (ABC): 7-year follow-up of a multicentre, open-label, randomised, phase 2 study. Lancet Oncol. 2025;26(3):320-330. doi:10.1016/S1470-2045(24)00735-6