Phase II Trial of Pembrolizumab in Combination With Bevacizumab for Untreated Melanoma Brain Metastases.

Purpose

Anti-vascular endothelial growth factor therapy enhances PD-1 inhibitor activity in preclinical models and has been used to treat perilesional cerebral edema and radiation necrosis.

Methods

We conducted a two-institution phase II trial of bevacizumab and pembrolizumab in patients with untreated melanoma brain metastasis (MBM) (ClinicalTrials.gov identifier: NCT02681549). Patients were anti-PD-(L)-1-naïve, and had ≥one asymptomatic, nonhemorrhagic 5-20 mm MBM, not requiring immediate local therapy or steroids.

Results

Thirty-seven patients received four doses of bevacizumab and pembrolizumab every 3 weeks followed by up to 2 years of pembrolizumab. The brain metastasis response rate (primary end point) was 54.1% (95% CI, 36.9 to 70.5). The extracranial response rate was 56.3% (95% CI, 37.7 to 73.6). Median intracranial progression-free survival was 2.2 years (95% CI, 0.41 to not reached [NR]). Median overall survival (OS) was 4.3 years (95% CI, 1.6 to NR). Four-year OS rate was 51.6%. Grade 3 treatment-related adverse event rates from bevacizumab and pembrolizumab were 10.8% and 18.9%, respectively. Higher pretreatment vessel density in metastatic tumors and smaller on-therapy increases in circulating angiopoietin-2 were associated with response.

Conclusion

Pembrolizumab with bevacizumab was well tolerated and demonstrated substantial activity in patients with untreated MBM with promising OS, justifying further evaluation of this regimen.

COI Statement

JC: Advisory Board/Honoraria from BMS, Replimune, Incyte, Regeneron. ZE: Advisory Boards: Pfizer, Regeneron, Sun Pharma, Incyte; Research funding: Pfizer, Novartis, Boehringer Ingelheim. SG: Research funding from AstraZeneca, Boehringer Ingelheim, and Mirati. Consulting/advisory board member for AstraZeneca, Bristol-Myers Squibb, Amgen, Sanofi Genzyme, Daiichi-Sankyo, Takeda, Janssen, Summit Therapeutics, Merck, Regeneron, and Eli Lilly. HMK: Institutional Research Grants: Merck, Bristol-Myers Squibb, Apexigen; Personal Fees: Iovance, Merck, Chemocentryx, Bristol-Myers Squibb, Signatera, Gigagen, GI reviewers, Pliant Therapeutics, Esai, Invox, Wherewolf, Teva. NK: Advisory Board/Honoraria from BMS, Merck, Novartis, Regeneron, Genzyme, Iovance, Immunocore, IO Biotech, Nektar, Replimmune, Incyte, Castle Biosciences, AstraZeneca and MyCareGorithm; stock ownership in Bellicum, Asensus Surgical; research support (all to institution) from BMS, Merck, Celgene, Novartis, GSK, HUYA, Regeneron, Replimmune, IDEAYA Biosciences, and Modulation Therapeutics; travel support from Regeneron, Castle Biosciences; scientific advisory board for T-knife Therapeutics. JM: Funding to Moffitt Cancer Center from Merck, Morphogenesis and Microba. Moffitt Cancer Center submitted a patent on behalf of Dr. Markowitz for work unrelated to this project. MS: Stock and stock options: Actym - (stock options only), Adaptive Biotechnologies– (stock options only), Asher Bio, Evolveimmune, Glaxo-Smith Kline (stock), Intensity – (stock options only), Johnson and Johnson (stock), Nextcure, Normunity, Oncohost, Rootpath, Thetis; Connsultant, SAB, DSMC: IO Biotech, Biontech (DSMC), Immatics, GII Innovation, Regeneron, Simcha (SAB), Cullinan (SAB), AsherBio (SAB), Bioinvent, Normunity (SAB), Lyvgen, Ideaya (DSMC), Nextcure (SAB), Bristol-Myers, Sanofi (DSMC), Turnstone, Pfizer, Evolveimmune (SAB), Innate pharma (SAB), Incyte, Anaptys, Pliant, Iovance, Molecular Partners, Biond (DSMC), Sumitomo, Numab, Alligator, Partner Therapeutics, Oncohost, Teva, Verastem, Rootpath, Evaxion, Dragonfly, Jazz Pharmaceuticals, Ichnos, Adaptimmune, Nimbus, Xilio, Targovax, Alkermes, PIO Therapeutics, Merck, Pierre-Fabre, Ocellaris-Lilly, Immunocore, Glaxo Smith Kline. SAW: Advisory Boards: Bristol-Myers Squibb, Incyte, Lyell Immunopharma. The remainder of the authors have no disclosures to report.

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