Circulating Immune Cell and Outcome Analysis from the Phase II Study of PD-L1 Blockade with Durvalumab for Newly Diagnosed and Recurrent Glioblastoma

Purpose: PD-L1 is upregulated in glioblastoma and supports immunosuppression. We evaluated PD-L1 blockade with durvalumab among glioblastoma cohorts and investigated potential biomarkers. Patients and Methods: MGMT unmethylated newly diagnosed patients received radiotherapy plus durvalumab (cohort A; n = 40). Bevacizumab-naive, recurrent patients received durvalumab alone (cohort B; n = 31) or in combination with standard bevacizumab (cohort B2; n = 33) or low-dose bevacizumab (cohort B3; n = 33). Bevacizumab-refractory patients received durvalumab plus beva-cizumab (cohort C; n = 22). Primary endpoints were: OS-12 (A), PFS-6 (B, B2, B3), and OS-6 (C). Exploratory biomarkers included: a systematic, quantitative, and phenotypic evaluation of circulating immune cells; tumor mutational burden (TMB); and tumor immune activation signature (IAS). Results: No cohort achieved the primary efficacy endpoint. Outcome was comparable among recurrent, bevacizumab-naive cohorts. No unexpected toxicities were observed. A widespread reduction of effector immune cell subsets was noted among recur-rent patients compared with newly diagnosed patients that was partially due to dexamethasone use. A trend of increased CD8 +/- Ki67 +/- T cells at day 15 was noted among patients who achieved the primary endpoint and were not on dexamethasone. Neither TMB nor IAS predicted outcome. Conclusions: Patients with recurrent glioblastoma have markedly lower baseline levels of multiple circulating immune cell subsets compared with newly diagnosed patients. An early increase in systemic Ki67 +/- CD8 +/- cells may warrant further evaluation as a potential biomarker of therapeutic benefit among patients with glioblastoma undergoing checkpoint therapy. Dexamethasone decreased immune cell subsets. PD-L1 blockade and combination with standard or reduced dose bevacizumab was ineffective.