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.

Preclinical Modeling of Surgery and Steroid Therapy for Glioblastoma Reveals Changes in Immunophenotype that are Associated with Tumor Growth and Outcome

“…In particular, interactions with surgical resection, steroids, chemotherapy, and radiation must be assessed, as must the importance of their timings relative to administration of immune-modulating agents. This was highlighted in recent findings that dexamethasone treatment negatively impacts OS in the context of immunotherapy (15,16). This is in contrast to our findings in immunotherapy-naïve patients that dexamethasone prior to surgery was beneficial, in multivariate analyses (Fig.…”

“…S17A-S17D; ref. 15). After identifying that the absolute lymphocyte count is correlated with PFS and OS, we sought to understand whether the lymphocyte count is consistent over time in patients with GBM based on their initial CBC w/diff.…”

“…Although neoadjuvant immunotherapy prior to surgical resection may lead to more effective treatment responses (14), the impact of standard surgical resection and steroid treatment otherwise remains largely unexplored. Recently, two studies highlighted the importance of investigating steroid use in GBM: these studies found that the dose of dexamethasone reduces immunotherapy response in mouse models, and a clinical trial showed a similar reduction in overall survival (OS) due to steroid treatment (15,16). As part of these studies, it was also observed that low-dose anti-VEGF treatment reduced edema, providing an alternative to dexamethasone that can be rapidly applied to future clinical trials (15,16).…”

“…Recently, two studies highlighted the importance of investigating steroid use in GBM: these studies found that the dose of dexamethasone reduces immunotherapy response in mouse models, and a clinical trial showed a similar reduction in overall survival (OS) due to steroid treatment (15,16). As part of these studies, it was also observed that low-dose anti-VEGF treatment reduced edema, providing an alternative to dexamethasone that can be rapidly applied to future clinical trials (15,16). However, these studies do not take into account the impact of surgical resection of the bulk tumor or the size of the tumor on immune response.…”

“…To investigate the immunologic changes that occur due to standard-of-care treatment, we developed a mouse model of surgical resection that also employs a clinically relevant steroid dose, similar to those shown in the same mouse models to reduce immunotherapy activity (15). We utilized two syngeneic murine GBM models (GL261 and CT-2A; ref.…”