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

Abstract

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-naïve, 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 bevacizumab (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-naïve cohorts. No unexpected toxicities were observed. A widespread reduction of effector immune cell subsets was noted among recurrent 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.

Figure 1.. Progression-Free and Overall Survival in All Patients

Efficacy for all patients including Kaplan-Meier plots and tabular PFS and OS data by cohort. Outcome for newly diagnosed, MGMT unmethylated patients (cohort A), bevacizumab naïve, recurrent patients (cohorts B, B2 and B3) and bevacizumab refractory, recurrent patients (cohort C) are summarized in panels A, B and C, respectively including Kaplan-Meier plots of PFS (upper) and OS (lower).

Figure 1.. Progression-Free and Overall Survival in All Patients

Efficacy for all patients including Kaplan-Meier plots and tabular PFS and OS data by cohort. Outcome for newly diagnosed, MGMT unmethylated patients (cohort A), bevacizumab naïve, recurrent patients (cohorts B, B2 and B3) and bevacizumab refractory, recurrent patients (cohort C) are summarized in panels A, B and C, respectively including Kaplan-Meier plots of PFS (upper) and OS (lower).

Figure 1.. Progression-Free and Overall Survival in All Patients

Efficacy for all patients including Kaplan-Meier plots and tabular PFS and OS data by cohort. Outcome for newly diagnosed, MGMT unmethylated patients (cohort A), bevacizumab naïve, recurrent patients (cohorts B, B2 and B3) and bevacizumab refractory, recurrent patients (cohort C) are summarized in panels A, B and C, respectively including Kaplan-Meier plots of PFS (upper) and OS (lower).

Figure 2.. Circulating Immune Cell Subsets Comparing Newly Diagnosed and Recurrent Patients

Measurement of baseline immune cell subsets detected by flow cytometry among newly diagnosed patients (cohort A; open bars and symbols) compared to bevacizumab-naïve, recurrent patients (cohorts B, B2 and B3; gray bars and symbols) including major immune cell subsets (panel A), and CD4+ and CD8+ T cells distinguished by memory or naïve (panel B), activation (panel C) or proliferation (panel D) markers. Asterisks indicate p<0.01 by Mann-Whitney U test comparing cohort A to cohorts B, B2 and B3. Panel E: Change in baseline CD8+Ki67+ T cells at day 15 for newly diagnosed (cohort A, open symbols) and bevacizumab-naïve, recurrent patients (cohorts B, B2 and B3, gray symbols) on baseline dexamethasone use (right side triangles) compared to those not on dexamethasone (left side circles). Bars indicate median value and error bars denote 25^th and 75^th percentiles. Asterisk indicates p ≤ 0.01. P value was determined by Wilcoxon Signed Rank test.