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.