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Window-of-opportunity clinical trial of a PD-1 inhibitor in patients with recurrent glioblastoma.
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2018
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Window-of-opportunity Clinical TrialImmunologyImmunotherapeuticsRecurrent GlioblastomaImmunotherapyGliomaNeuro-oncologyOncologyClinical TrialsTumor ImmunityNeurologyAnti-cancer AgentRadiation OncologyNovel TherapyMolecular OncologyHealth SciencesPd-1 InhibitorRecurrent Gbm PatientsCancer TreatmentPharmacologyCancer ImmunosurveillanceRecurrent GbmImmune Checkpoint InhibitorMedicinePhase Iii Study
2008 Background: A Phase III study failed to demonstrate a therapeutic benefit of anti-PD-1 therapy in recurrent GBM. This study was initiated to ascertain tumor immune modulatory properties of pembrolizumab in these patients requiring surgery. The primary objectives were to evaluate immune effector function in resected GBM tissue after pembrolizumab treatment and to determine progression-free survival at 6 months (PFS6). Methods: In an open label, single-center, single-arm biomarker-driven Phase 2 trial, 15 patients with GBM, at first or second recurrence who required reoperation for tumor progression were enrolled (NCT02337686). Patients were treated with up to two doses of pembrolizumab prior to surgery and afterwards received pembrolizumab until disease progression or the development of unacceptable toxicities. Recurrent GBM patients receiving standard of care (SOC) were immunologically analyzed (n = 10) as a comparator. Results: 21 patients were screened. 15 were enrolled and received at least one dose of pembrolizumab. The most common adverse event was grade 1 or 2 fatigue in 40% of patients. There were no treatment-related deaths. The median follow-up time for all patients was 12 months (95% CI: 3-31). The longest ongoing duration of response exceeded 34 months in two patients (one IDH1 mutant, one wild-type). Median PFS was 7 months (95% CI: 4-16) and PFS6 was 53% (95% CI: 33%-86%). Median overall survival has not been reached (95% CI: 15 to not reached), with an estimated 1-year overall survival of 72% (95% CI: 52%–99.6%). Analysis with 35 immune markers by mass cytometry revealed that GBM tumors are poorly infiltrated with T cells but are enriched with distinct CD68+ populations. These CD68+ cells are less frequent in pembrolizumab-treated patients (n = 6) relative to those treated with SOC (n = 10; P= 0.01); however, GBM-infiltrating Tregs are more frequent in patients treated with pembrolizumab (P = 0.02). Conclusions: Although pembrolizumab was well tolerated, PFS6 data and immune analysis indicates that anti-PD-1 monotherapy is insufficient for a response in the majority of GBM patients, likely secondary to a marked scarcity of T cells within the tumor microenvironment and a preponderance of CD68+ cells. Clinical trial information: NCT02337686.