Window-of-Opportunity Clinical Trial of Pembrolizumab in Recurrent Glioblastoma (GBM) Patients

Background: We sought to ascertain the immune effector function of pembrolizumab within the glioblastoma (GBM) microenvironment during the therapeutic window. Methods: In an open-label, single-center, single-arm phase 2 "window-of-opportunity" trial, 15 patients with recurrent GBM, who were eligible for operation, were enrolled. Patients were treated with up to two doses of pembrolizumab (21 days and 1 day) before surgery and afterwards (every three weeks) until disease progression occurred or unacceptable toxicities developed. Findings: The most common adverse event was grade 1 or 2 fatigue in 40% of patients, and there was one case of cerebral edema requiring early reoperation. No treatment-related deaths occurred; 5 of 15 patients (33%) died from disease progression. The median follow-up time for all patients was 15 months (95% CI: 3-37). Of the 14 patients with radiographic follow up, 10 patients had progressive disease, 3 had a partial response, and 1 had stable disease. The longest response duration exceeded 37 months in two patients (one IDH1 mutant, one wild-type). The median progression-free survival (PFS) time was 5 months (95% CI: 3 months-8 months) and 6-month PFS (PFS6) rate was 40% (95% CI: 22%-74%). The median overall survival (OS) rate was 21 months (95% CI: 9 months to not reached), with an estimated 1-year OS rate of 65% (95% CI: 44%-95%). Immune monitoring on surgical specimens from GBM patients revealed a paucity of T cells but an enrichment of CD68 macrophages in the tumor microenvironment ofrecurrent GBM patients. The T cells in the GBM microenvironment were severly deficient in markers of immune activity. Interpretation: Although pembrolizumab was well tolerated, the immune analysis indicated that anti-PD-1 monotherapy is insufficient to induce effector immunologic response in most GBM patients, probably owing to a marked scarcity of T cells within the tumor microenvironment and a preponderance of CD68 macrophages. Clinical Trial Number: NCT02337686 Funding Statement: Merck Pharmaceuticals and The University of Texas MD Anderson Moon Shot Program Declaration of Interests: JdG and ABH have received clinical trial research support from Merck. JA owns stock in and has acted as a consultant or on advisory boards for Jounce, Kite Pharma, Evelo, Constellation, BristolMyers Squibb, GlaxoSmithKline, AstraZeneca, Amgen, and Neon. PSh owns stock in and has acted as a consultant for Jounce, Kite Pharma, Neon, Bristol-Myers Squibb, GlaskoSmithKline, AstraZeneca, Amgen, Constellation, and Evelo. ABH owns stock in Celldex Therapeutics and Caris Life Sciences, serves on the advisory board of Caris, and has acted as a consultant for BristolMyers Squibb, Celegene, Curtana Therapeutics, and Carthera Therapeutics. The remaining authors declare no competing interests. Ethics Approval Statement: Approval for the study was granted through the institutional review board at MD Anderson and all patients were provided written informed consent before study entry. This trial was performed according to the Declaration of Helsinki’s principles.