Randomized Phase II and Biomarker Study of Pembrolizumab plus Bevacizumab versus Pembrolizumab Alone for Patients with Recurrent Glioblastoma

Abstract

Purpose: VEGF is upregulated in glioblastoma and may contribute to immunosuppression. We performed a phase II study of pembrolizumab alone or with bevacizumab in recurrent glioblastoma.

Patients and methods: Eighty bevacizumab-naïve patients with recurrent glioblastoma were randomized to pembrolizumab with bevacizumab (cohort A, n = 50) or pembrolizumab monotherapy (cohort B, n = 30). The primary endpoint was 6-month progression-free survival (PFS-6). Assessed biomarkers included evaluation of tumor programmed death-ligand 1 expression, tumor-infiltrating lymphocyte density, immune activation gene expression signature, and plasma cytokines. The neurologic assessment in neuro-oncology (NANO) scale was used to prospectively assess neurologic function.

Results: Pembrolizumab alone or with bevacizumab was well tolerated but of limited benefit. For cohort A, PFS-6 was 26.0% [95% confidence interval (CI), 16.3-41.5], median overall survival (OS) was 8.8 months (95% CI, 7.7-14.2), objective response rate (ORR) was 20%, and median duration of response was 48 weeks. For cohort B, PFS-6 was 6.7% (95% CI, 1.7-25.4), median OS was 10.3 months (95% CI, 8.5-12.5), and ORR was 0%. Tumor immune markers were not associated with OS, but worsened OS correlated with baseline dexamethasone use and increased posttherapy plasma VEGF (cohort A) and mutant IDH1, unmethylated MGMT, and increased baseline PlGF and sVEGFR1 levels (cohort B). The NANO scale contributed to overall outcome assessment.

Conclusions: Pembrolizumab was ineffective as monotherapy and with bevacizumab for recurrent glioblastoma. The infrequent radiographic responses to combinatorial therapy were durable. Tumor immune biomarkers did not predict outcome. Baseline dexamethasone use and tumor MGMT warrant further study as potential biomarkers in glioblastoma immunotherapy trials.

Figure 1.

Study profile. CONSORT diagram showing the number of patients who were enrolled, treated with pembrolizumab plus bevacizumab (cohort A) or pembrolizumab (cohort B), discontinued treatment, and were analyzed for efficacy and safety.

Figure 2.

PFS and OS in all patients. A, The number of events; median PFS; PFS rates at 6, 12, and 18 months; and the Kaplan–Meier curve for PFS in all patients treated with nivolumab or nivolumab plus bevacizumab. B, The number of events; median OS; OS rates at 6, 12, and 18 months; and the Kaplan–Meier curve for OS per investigator assessment in patients treated with nivolumab or nivolumab plus bevacizumab. Symbols indicate censored observations. HRs and CIs were estimated using a Cox proportional hazards model. HR, hazard ratio; OS, overall survival; PFS, progression-free survival.

Figure 3.

OS in patient subgroups. Forest plot of univariate HR for death of patient and tumor characteristics in the analysis of treatment effect in patient subgroups by cohort.