Phase 2 study to evaluate safety and efficacy of MEDI4736 (durvalumab [DUR]) in glioblastoma (GBM) patients: An update.

Abstract

2042 Background: DUR is a human IgG1 monoclonal Ab against PD-L1. PD-1/PD-L1 blockade has shown benefit in solid tumors. PD-L1 is expressed by many GBM tumors while cytotoxic lymphocytes infiltrating GBM tumors often express PD-1; thus, there is a rationale for exploring PD-1/PD-L1 blockade in GBM. Bevacizumab (BEV) is a VEGF-specific angiogenesis inhibitor approved for recurrent GBM. PD-L1 blockade and angiogenesis inhibition may be synergistic. Methods: This ongoing Phase 2, multicenter, open-label study (NCT02336165) evaluates safety/efficacy of DUR (10 mg/kg every 2 wks) in 5 GBM cohorts. Secondary endpoints are safety/tolerability, median PFS/OS, overall response rate and quality of life measures. Exploratory endpoints: neurologic function and immunocorrelative biomarkers. Results: Enrollment as of 16 Dec 2016: Cohort A = 35, B = 31, B2 = 34, B3 = 34, and C = 20 pts. Enrollment is ongoing for Cohorts A and C. This is an update to the interim analysis that was reported for Cohort B (male: 83.9%; mean age: 54.0 [24-77] years; baseline ECOG PS0: 51.6%, PS1: 48.4%; baseline measurable lesions: 77.4%). Incidences of treatment-related adverse events (TRAEs) by max CTCAE grade (Gr) were Gr1: 35.5%; Gr2: 41.9%; Gr3: 9.7%; and Gr4/5: 0%. Most common TRAEs (≥3 pts): fatigue, headache, hemiparesis, gait disturbance, increased AST, and decreased platelets/WBCs/lymphs. Six of 30 evaluable pts were progression free at 6 months (Kaplan-Meier, 20.0% [90% CI: 9.7, 33.0]); best overall response: partial response, 4 (13.3%) pts and stable disease, 14 (46.7%). At 1 year, 4 pts remained progression free (longest PFS ongoing at 80 wks, n=2). OS-6 and OS-12 are 59.0 and 44.4%, respectively. As of 16 Dec 2016, 7 pts remain alive (longest OS ongoing at 86 wks). Conclusions: DUR monotherapy appears to be well tolerated and shows durable activity in a subset of BEV-naïve recurrent GBM pts. Study is ongoing. Clinical trial information: NCT02336165. [Table: see text]

PD-L1 Expression in Glioblastoma, the Clinical and Prognostic Significance: A Systematic Literature Review and Meta-Analysis

“…However, early clinical trials on the effectiveness of PD-L1 blockade agents are still limited and elusive. A combination between Anti-PD-L1 mAb durvalumab and bevacizumab is now being tested in a phase 2 open label, non-randomized clinical trial for GBM (cohort B, NCT02336165) (65). Interim results of durvalumab monotherapy revealed low SAE (severe adverse events) rate of 10% and efficacy with OS-6 of 42% and PFS-6 (progression-free survival) of 20%.…”

Immune Checkpoints and Innovative Therapies in Glioblastoma

“…Finally, phase 2 trial NCT02336165, the PD-1 inhibitor Durvalumab was tested in combination with Bevacizumab and radiotherapy and showed partial response or disease stabilization in 60% of the patients after 6 months. Four patients remained progression free ( 64 ).…”

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors

“…There were five studies related to the efficacy of dur-valumab. 11 , 12 , 15 , 16 , 25 Study NCT02087423 measured the expression of PD-L1 on tumor cell (TC) membranes in NSCLC patients and chose 25% as the cutoff value. The PD-L1-positive subgroup had higher ORR (16.4% vs 7.5%), mPFS (3.3 vs 1.9 months), and mOS (10.9 vs 9.3 months) values than the PD-L1-negative subgroup.…”