Phase II study to evaluate safety and efficacy of MEDI4736 (durvalumab) + radiotherapy in patients with newly diagnosed unmethylated MGMT glioblastoma (new unmeth GBM).

Abstract

2032 Background: Durvalumab (durva), a human IgG1 monoclonal Ab against PD-L1, is FDA-approved for selected patients with bladder and non-small cell lung cancers. PD-L1 is expressed by some GBM tumors, while GBM infiltrating T lymphocytes often express PD-1. Radiation induced cell death releases tumor antigens and could potentiate anti-PD-(L)1 therapy. Methods: This ongoing Phase 2 open-label study (NCT02336165) evaluates the safety and efficacy of durva (10 mg/kg every 2 weeks) in 5 GBM cohorts. Results are presented for Cohort A, which evaluates durva + standard radiotherapy (RT, 60 Gy over 30 fractions) followed by durva monotherapy in patients with new unmeth GBM after maximum safe resection. The primary efficacy endpoint for Cohort A is overall survival at 12 months (OS12); secondary endpoints include safety/tolerability, tumor response rate, and progression-free survival (PFS). Historical benchmarks of median OS and OS12 for patients with new unmeth GBM following standard therapy are 12.7 months and 50%, respectively (EORTC 26981-22981/NCIC CE.3). Results: Median follow-up of 40 enrolled patients is 24.5 months (data cutoff = 05 Nov 2018). Baseline characteristics: male, 70%; median age, 57.0 [22 to 77] years; ECOG PS0, 60.0%; ECOG PS1, 40.0%; measurable disease, 80.0%; and dexamethasone use, 32.5%. Treatment-related adverse events with maximum CTCAE grade ≥ 3 occurred in 14 (35.0%) patients; the most common were asymptomatic increased lipase (n = 6) and increased amylase (n = 2). Twenty-four of 40 patients were alive at 12 months (Kaplan-Meier for OS12, 60.0% [90% CI: 46.1, 71.4]). Median OS was 15.1 (95% CI: 12.0, 18.4) months. As of 05 Nov 2018, 8 (20%) patients remain alive, with ongoing survival ranging from 15.7 to 34.9 months. Tumor immunocorrelative and systemic studies are pending. Conclusions: This is the first study report of anti-PD-L1 for new GBM. Durva was well tolerated when combined with RT and seemed to have efficacy among patients with new unmeth GBM. Further studies may be warranted. Clinical trial information: NCT02336165.

Deep immune profiling reveals targetable mechanisms of immune evasion in checkpoint blockade-refractory glioblastoma

“…Although PD-1 and PD-L1 checkpoint blockade therapies disrupt the same signaling axis, our results indicate that PD-L1 blockade is more effective than dual CTLA-4/PD-1 blockade in the SB28 model. This is in line with a recent report of a modest positive effect in interim data from a phase II clinical trial combining standard XRT and PD-L1 blockade in unmethylated GBM 35 . SB28 appears to be a faithful model of PD-L1 expression and myeloid infiltration in human GBM.…”

Checkpoint Inhibitors as High-Grade Gliomas Treatment: State of the Art and Future Perspectives

“…Cohort A included 40 patients receiving durvalumab combined with standard RT, followed by durvalumab monotherapy without TMZ in O 6 -methylguanine-DNA methyltransferase ( MGMT ) unmethylated newly diagnosed patients. At a median follow-up of 24.5 months, median OS was 15.1 months (95% confidence interval [CI]: 12.0, 18.4)), OS at 12 months (OS-12) was 60% (90% CI: 46.1, 71.4) [ 27 ]. Grade ≥ 3 adverse events (AE) occurred in fourteen (35%) patients, the most common being asymptomatic increased lipase ( n = 6) and increased amylase ( n = 2) [ 27 ].…”

Challenging Hurdles of Current Targeting in Glioblastoma: A Focus on Immunotherapeutic Strategies

“…A first study with recurrent GBM combined anti PD-L1 (avelumab) with axitinib, but did not meet its activity threshold of 50% PFS at 6 months [ 61 ]. The MEDI4736 study evaluated durvalumab, another anti-PD-L1 Ab, with SOC for primary MGMT unmethylated GBM, and showed OS improvement to 15.7 months, but only when compared with historical controls [ 62 ]. Multiple other immune checkpoints exist, such as GITR, TIGIT, CD27, LAG-3, CD137 (or 4-1BB), and CTLA-4, and their blockade was also tested, mostly in association with anti-PD-1, which showed efficacy in pre-clinical glioma mouse models [ 63 , 64 , 65 , 66 , 67 ], but clinical trials are still ongoing.…”