1181TiP - BEPCOME-MB: Treatment of BRAFV600 mutated melanoma brain metastases with encorafenib + binimetinb + pembrolizumab with or without stereotactic radiosurgery

Background

Melanoma is an aggressive disease with a high propensity to metastasize to the central nervous system. Melanoma brain metastases (MBM) were associated with poor overall survival (OS), with a median OS of 4–5 months before the era of immune checkpoint inhibition (ICI). Nowadays, first-line treatment with BRAF/MEK inhibitors in patients (pts) with BRAFV600 mutated melanoma and MBM induces ∼60% intracranial response, which are unfortunately short-lived. Combined ICI with ipilimumab + nivolumab demonstrated longer-lasting efficacy, but is associated with high rates of toxicity and very limited efficacy in patients with symptomatic MBM. Stereotactic radiosurgery (SRS) for single or multiple lesions is an effective modality to achieve MBM control. Its place upfront or later has not been established. A triplet therapy with BRAF/MEK inhibitors encorafenib (E) + binimetinib (B) and anti-PD-1 monoclonal antibody pembrolizumab (P) is an attractive strategy in BRAFV600 mutated MBM, with a rapid disease response (attributed to E+B) and durable disease control (attributed to P), even in symptomatic MBM, with potentially better tolerability than ipilimumab + nivolumab. This trial aims to test the feasibility of this regimen with or without upfront SRS.

Trial design

This phase II, randomised, controlled, open-label trial assesses the efficacy and safety of adding upfront SRS to E+B+P in the treatment of pts with BRAFV600 mutated melanoma and MBM. Patients are randomly assigned (1:1) to receive (a) E+B+P, or (b) upfront SRS of all cerebral metastases ≥5 mm in diameter, followed by E+B+P. Patients will be treated until disease progression. An amendment to allow previous treatment with anti-PD-1 is ongoing. Using intracranial progression-free survival (IC-PFS) assessed by central review as the primary endpoint, 150 patients will be needed to detect an increase in the median IC-PFS in the SRS + E+B+P arm (HR of 0.60 with 80% power and 2-sided 5% significance level). Secondary endpoints include response rate, disease control, OS, toxicity and quality of life. Exploratory endpoints include predictive factors of response and mechanisms of primary and acquired resistance.

Clinical trial identification

EudraCT n°: 2021-006331-26; NCT04074096.

Editorial acknowledgement

Legal entity responsible for the study

Unicancer.

Funding

Pierre Fabre Médicament.

Disclosure

All authors have declared no conflicts of interest.