Pembrolizumab Plus Bevacizumab Shows Promise for Melanoma Brain Metastases

Anti-VEGF therapy with bevacizumab (Avastin) may enhance the clinical activity of the PD-1 inhibitor pembrolizumab (Keytruda) in patients with untreated melanoma brain metastases (MBM), according to findings from a phase 2 study (NCT02681549) published in the Journal of Clinical Oncology.¹

The combination led to a brain metastasis response rate—the primary end point of the study—of 54.1% (95% CI, 36.9-70.5) and an extracranial response rate of 56.3% (95% CI, 37.7-73.6). The median intracranial progression-free survival (PFS) was 2.2 years (95% CI, 0.41 to not reached [NR]), and the median overall survival (OS) was 4.3 years (95% CI, 1.6-NR). The 4-year OS rate with the combination was 51.6%.

The overall response rate among the 37 patients was 54%, including 10 (27%) complete responses and 10 (27%) partial responses. Two patients (5.4%) had stable disease. The researchers identified 2 potential biomarkers that were associated with response: higher pretreatment vessel density in metastatic tumors and smaller on-therapy increases in circulating angiopoietin-2.

Regarding safety, the researchers noted that the 2 drugs were well tolerated overall. Seven patients (18.9%) experienced a treatment-related adverse event (TRAE) related to pembrolizumab, and 4 patients (10.8%) experienced a TRAE related to bevacizumab. There were no grade 4 or grade 5 TRAEs.

“Pembrolizumab with bevacizumab was well tolerated and demonstrated substantial activity in patients with untreated MBM with promising OS, justifying further evaluation of this regimen,” first study author Sarah A. Weiss, MD, Medical Oncology, Rutgers Cancer Institute, New Brunswick, NJ, and coauthors wrote in their conclusion.

Study Background and Patient Characteristics

Overall, the evaluated population included 37 patients with untreated MBM who had at least 1 non-hemorrhagic MBM (5-20 mm), no prior anti–PD-1/PD-L1 treatment, and did not need immediate local therapy or steroids.

Baseline characteristics for the 37 patients showed that the median age at enrollment was 66 years (range 33-88), 76% were male, and 24% were female. Patients had an ECOG performance status of 0 (68%) or 1 (32%). Overall, 32% of patients had elevated serum lactate dehydrogenase. Mutation status showed that 24% of patients had BRAF V600E mutations, 16% had BRAF V600K mutations, and 3% of patients had BRAF mutations of unknown V600 type. Eleven percent of patients had NRAS mutations.

Characterization of MBM at enrollment showed that 95% of patients had new intracranial lesions and 5% of patients had progression in previously irradiated lesions. Additionally, 62% of patients had 1 to 2 intracranial target lesions, and 38% of patients had 3 to 5 intracranial target lesions. Overall, 86% of patients had extracranial metastases.

Seven patients (19%) had prior systemic therapy, which included IL-2 (n = 1), ipilimumab (Yervoy; n = 3), and BRAF/MEK inhibitors (n = 6). About half (51%) of patients had prior local therapy for MBM, which included craniotomy (n = 2), radiation (n = 14), or craniotomy plus radiation (n = 3).

All patients were treated with 4 doses of bevacizumab and pembrolizumab every 3 weeks, followed by pembrolizumab for up to 2 years.

“This prospective study provides data to support a comparative trial of combined PD-1/vascular endothelial growth factor inhibition versus PD-1/CTLA-4 inhibition for untreated MBMs, and could later impact treatment of brain metastases from other diagnoses,” Journal of Clinical Oncology Associate Editor Robert G. Maki, MD, PhD, FACP, FASCO, wrote in the journal’s relevance section published alongside the article.

Reference

Weiss SA, Djureinovic D, Wei W, et al. Phase II Trial of Pembrolizumab in Combination With Bevacizumab for Untreated Melanoma Brain Metastases [published online ahead of print March 6, 2025]. J Clin Oncol. doi: 10.1200/JCO-24-02219