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

Alexander M Menzies^{1

2}, Georgina V Long^{1

2}, Amiee Kohn³, Hussein Tawbi⁴, Jeffrey Weber⁵, Keith Flaherty⁶, Grant A McArthur⁷, Paolo A Ascierto⁸, Yanina Pfluger⁹, Karl Lewis¹⁰, Katy K Tsai¹¹, Omid Hamid¹², Hans Prenen¹³, Luis Fein⁹, Erjian Wang¹⁴, Carolin Guenzel¹⁴, Fan Zhang¹⁴, Joseph F Kleha¹⁴, Alessandra di Pietro¹⁵, Michael A Davies⁴

Affiliations

¹ Melanoma Institute Australia, NSW, Australia, and The University of Sydney, Sydney, Australia.
² Royal North Shore and Mater Hospitals, The University of Sydney, Sydney, Australia.
³ Division of Hematology/Medical Oncology, School of Medicine, Oregon Health Sciences University, Portland, Oregon, USA.
⁴ Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁵ Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, New York, USA.
⁶ Massachusetts General Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁷ Sir Peter MacCallum Department of Oncology, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia.
⁸ Unit of Melanoma Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy.
⁹ Alexander Fleming Institute, Buenos Aires, Argentina.
¹⁰ Medical Oncology, University of Colorado, Health Center, Denver, Colorado, USA.
¹¹ Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, USA.
¹² The Angeles Clinic and Research Institute, A Cedars-Sinai Affiliate Los Angeles, California, USA.
¹³ Oncology Department, University Hospital Antwerp, Antwerp, Belgium.
¹⁴ Formerly Pfizer, New York, New York, USA.
¹⁵ Pfizer Srl, Milan, Italy.

PMID: 38725995
PMCID: PMC11079948
DOI: 10.1093/noajnl/vdae033

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

Alexander M Menzies et al. Neurooncol Adv. 2024.

. 2024 Mar 18;6(1):vdae033.

doi: 10.1093/noajnl/vdae033. eCollection 2024 Jan-Dec.

Authors

Affiliations

¹ Melanoma Institute Australia, NSW, Australia, and The University of Sydney, Sydney, Australia.
² Royal North Shore and Mater Hospitals, The University of Sydney, Sydney, Australia.
³ Division of Hematology/Medical Oncology, School of Medicine, Oregon Health Sciences University, Portland, Oregon, USA.
⁴ Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁵ Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, New York, USA.
⁶ Massachusetts General Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁷ Sir Peter MacCallum Department of Oncology, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia.
⁸ Unit of Melanoma Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy.
⁹ Alexander Fleming Institute, Buenos Aires, Argentina.
¹⁰ Medical Oncology, University of Colorado, Health Center, Denver, Colorado, USA.
¹¹ Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, USA.
¹² The Angeles Clinic and Research Institute, A Cedars-Sinai Affiliate Los Angeles, California, USA.
¹³ Oncology Department, University Hospital Antwerp, Antwerp, Belgium.
¹⁴ Formerly Pfizer, New York, New York, USA.
¹⁵ Pfizer Srl, Milan, Italy.

PMID: 38725995
PMCID: PMC11079948
DOI: 10.1093/noajnl/vdae033

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: BRAF V600; Binimetinib; Encorafenib; Melanoma; POLARIS.

PubMed Disclaimer

Conflict of interest statement

A.M.M.: Reports personal fees from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Roche, Pierre Fabre, and QBiotics. G.V.L.: Reports personal fees from Agenus, Amgen, Array BioPharma, AstraZeneca, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S. L., IO Biotech Immunocore, Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, PHMR Ltd, Pierre Fabre, and Regeneron. A.K.: No declaration of interests to report. H.T.: Reports consulting or advisory roles for Array BioPharma, Bristol Myers Squibb, Merck, Novartis, and Roche; and research funding from Bristol Myers Squibb, Celgene, GlaxoSmithKline, Merck, and Roche. J.W.: Reports being a paid consultant for Bristol Myers Squibb, Merck, Genentech, Pfizer, and AstraZeneca, and was named on a PD-1 biomarker patent by Biodesix and a CTLA4 biomarker patent by Moffitt Cancer Center. K.F.: Reports stock and other ownership interests for Clovis Oncology, Loxo, X4 Pharma, Strata Oncology, PIC Therapeutics, Apricity Health, Oncoceutics, FogPharma, Tvardi Therapeutics, Checkmate Pharmaceuticals, Kinnate Biopharma, Scorpion Therapeutics, ALX Oncology, xCures, Monopteros Therapeutics, Vibliome Therapeutics, Transcode Therapeutics, Soley Therapeutics, and Nextech Invest; and a consulting or advisory role with Novartis, Lilly, Oncoceutics, Tvardi Therapeutics, Takeda, and Debiopharm Group. G.A.M: Reports research funding from Bristol Myers Squibb and Roche-Genentech. P.A.A.: Reports a consultant/advisory role with Anaveon, Bayer, Bio-Al Health, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Erasca, Immunocore, Italfarmaco, Lunaphore, Medicenna, Merck Serono, MSD, Nouscom, Novartis, Pfizer, Philogen, Pierre Fabre, Regeneron, Replimune, Roche-Genentech, Sandoz, Sanofi, Sun Pharma, and ValoTX; research grants from Bristol Myers Squibb, Roche-Genentech, Pfizer, and Sanofi and travel support from Pfizer, Bio-Al Health, Replimune, MSD, and Pierre Fabre. Y.P.: Reports having no conflicts of interest. K.L.: Reports institutional research funding from Pfizer. K.T.: Reports institutional research funding from ABM Therapeutics, AstraZeneca, BioAtla, Bristol Myers Squibb, Genentech, Oncosec, OnKure, Pfizer, Regeneron, and Replimune; and honoraria from Bristol Myers Squibb. O.H.: Reports consulting fees from Aduro, Akeso, Amgen, Beigene, Bioatia, Bristol Myers Squibb, Roche-Genentech, GlaxoSmithKline, Immunocore, Idera, Incyte, Janssen, Merck, Nextcure, Novartis, Pfizer, Sanofi Regeneron, SeaGen, Tempus, and Zelluna; and honoraria from Bristol Myers Squibb, Novartis, Pfizer, and Sanofi Regeneron. H.P.: Reports being a consultant to Biocartis and Cureteq; and honoraria from Amgen, Roche, Sanofi, AstraZeneca, and Bayer. L.F.: Reports having no conflicts of interest. E.W., C.G., F.Z., J.F.K., A.d.P.: Report being employees of Pfizer. M.A.D.: Reports being a consultant to Roche/Genentech, Array, Pfizer, Novartis, Bristol Myers Squibb, GlaxoSmithKline, Sanofi-Aventis, Vaccinex, Apexigen, Eisai, Iovance, Merck, and ABM Therapeutics; and serving as the PI of research grants to MD Anderson by Roche/Genentech, GlaxoSmithKline, Sanofi-Aventis, Merck, Myriad, Oncothyreon, Pfizer, ABM Therapeutics, and LEAD Pharma.

Figures

**Figure 1.**
POLARIS study design flow chart. A randomized, multicenter, open-label, phase 2 study evaluating a safety lead-in high-dose (encorafenib 300 mg BID + binimetinib 45 mg BID) and phase 2 standard-dose (encorafenib 450 mg QD + binimetinib 45 mg BID) with intrapatient dose escalation (encorafenib 600 mg QD + binimetinib 45 mg BID) in patients with *BRAF* V600-mutant melanoma with brain metastases. AE, adverse event; BID, twice daily; BMRR, brain metastasis response rate; BRAFi, BRAF inhibitor; DCR, duration of complete response; DLT, dose-limiting toxicity; DOR, duration of response; MEKi, MEK inhibitor; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetics; QD, once daily; RECIST, Response Evaluation Criteria in Solid Tumors; SRS, stereotactic radiosurgery; SRT, superficial radiation therapy; WBRT, whole-brain radiotherapy. ^aAt least 1 brain lesion ≥0.5 cm and ≤4 cm. ^bBRAFi/MEKi, safety lead-in ≥12 months adjuvant setting allowed; phase 2 ≥6 months adjuvant setting allowed. ^cEvaluable patients must have a DLT or have received ≥75% of the planned cumulative dose of both study drugs during Cycle 1 (28 days).

**Figure 2.**
Efficacy results for the safety lead-in and phase 2 parts. Best response after safety lead-in high-dose (encorafenib 300 mg BID + binimetinib 45 mg BID) and phase 2 standard-dose (encorafenib 450 mg QD + binimetinib 45 mg BID) with intrapatient dose escalation (encorafenib 600 mg QD + binimetinib 45 mg BID). Stacked bar graph depicting tumor response in patients with BRAF V600-mutant melanoma with brain metastases. BID, twice daily: BMRR, brain metastasis response rate; QD, once daily. ^aBMRR is per modified RECIST 1.1. ^bGraph represents BMRR per modified RECIST 1.1.

See this image and copyright information in PMC

References

1. Ascierto PA, Dreno B, Larkin J, et al.. 5-Year outcomes with cobimetinib plus vemurafenib in BRAFV600 mutation-positive advanced melanoma: extended follow-up of the coBRIM Study. Clin Cancer Res. 2021;27(19):5225–5235. - PMC - PubMed
1. Ascierto PA, McArthur GA, Dreno B, et al.. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016;17(9):1248–1260. - PubMed
1. Dummer R, Ascierto PA, Gogas HJ, et al.. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018;19(5):603–615. - PubMed
1. Dummer R, Lebbe C, Atkinson V, et al.. Combined PD-1, BRAF and MEK inhibition in advanced BRAF-mutant melanoma: safety run-in and biomarker cohorts of COMBI-i. Nat Med. 2020;26(10):1557–1563. - PubMed
1. Dummer R, Flaherty KT, Robert C, et al.. COLUMBUS 5-year update: a randomized, open-label, Phase III trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF V600-mutant melanoma. J Clin Oncol. 2022;40(36):4178–4188. - PMC - PubMed

LinkOut - more resources

Full Text Sources

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Affiliations

Abstract

Conflict of interest statement

Figures

References

LinkOut - more resources

Full Text Sources