POLARIS: A Phase 2 Trial of Encorafenib Plus Binimetinib Evaluating High-Dose and Standard-Dose Regimens in Patients With BRAF V600-Mutant Melanoma With Brain Metastasis

Authors

Alexander M Menzies
Georgina V Long
Amiee Kohn
Hussein Tawbi
Jeffrey Weber
Keith Flaherty
Grant A McArthur
Paolo A Ascierto
Yanina Pfluger
Karl Lewis
Katy K Tsai
Omid Hamid
Hans Prenen
Luis Fein
Erjian Wang
Carolin Guenzel
Fan Zhang
Joseph F Kleha
Alessandra di Pietro
Michael A Davies

Publication Date

1-1-2024

Journal

Neuro-Oncology Advances

Abstract

Background: POLARIS (phase 2 [ph2]; NCT03911869) evaluated encorafenib (BRAF inhibitor) in combination with binimetinib (MEK1/2 inhibitor) in BRAF/MEK inhibitor-naïve patients with BRAF V600-mutant melanoma with asymptomatic brain metastases.

Methods: The safety lead-in (SLI) assessed tolerability for high-dose encorafenib 300 mg twice daily (BID) plus binimetinib 45 mg BID. If the high dose was tolerable in ph2, patients would be randomized to receive high or standard dose (encorafenib 450 mg once daily [QD] plus binimetinib 45 mg BID). Otherwise, standard dose was evaluated as the recommended ph2 dose (RP2D). Patients who tolerated standard dosing during Cycle 1 could be dose escalated to encorafenib 600 mg QD plus binimetinib 45 mg BID in Cycle 2. Safety, efficacy, and pharmacokinetics were examined.

Results: RP2D was standard encorafenib dosing, as >33% of evaluable SLI patients (3/9) had dose-limiting toxicities. Overall, of 13 safety-evaluable patients (10 SLI, 3 ph2), 9 had prior immunotherapy. There were 9 treatment-related adverse events in the SLI and 3 in ph2. Of the SLI efficacy-evaluable patients (n = 10), 1 achieved complete response and 5 achieved partial responses (PR); the brain metastasis response rate (BMRR) was 60% (95% CI: 26.2, 87.8). In ph2, 2 of 3 patients achieved PR (BMRR, 67% [95% CI: 9.4, 99.2]). Repeated encorafenib 300 mg BID dosing did not increase steady-state exposure compared with historical 450 mg QD data.

Conclusions: Despite small patient numbers due to early trial termination, BMRR appeared similar between the SLI and ph2, and the ph2 safety profile appeared consistent with previous reports of standard-dose encorafenib in combination with binimetinib.

Keywords

Binimetinib, BRAF V600, Encorafenib, Melanoma, POLARIS

DOI

10.1093/noajnl/vdae033

PMID

38725995

PMCID

PMC11079948

PubMedCentral® Posted Date

3-18-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes