Abstract

BACKGROUND

GBM patients who progress on BEV, an approved angiogenesis inhibitor for recurrent GBM, have a dismal outcome with a median survival of < 6 months. DUR is a human IgG1 monoclonal Ab against PD-L1.

METHODS

This ongoing Phase 2 open-label study (NCT02336165) evaluates safety and efficacy of DUR (10 mg/kg every 2 weeks [Q2W]) in 5 GBM cohorts. Results are presented for Cohort C (DUR + continuing BEV 10 mg/kg Q2W in BEV-refractory recurrent GBM). The primary efficacy endpoint for Cohort C is overall survival at 6 months (OS-6), based on modified RANO criteria by investigator assessment; secondary endpoints include safety/tolerability and progression-free survival (PFS). The Intent-to-treat population includes patients receiving any dose of DUR and having at least baseline and 1 post-baseline tumor assessment.

RESULTS

First patient treated: 24 Mar 2015; data cutoff: 15 Mar 2017. Cohort C completed enrollment of 22 patients (male: 63.6%; mean age: 54.8 [37–77] years; baseline ECOG PS0: 27.3%, PS1: 68.2%; baseline measurable lesions: 81.8%). Treatment-emergent adverse events (TEAEs) occurred in 19 (86.4%) patients and most commonly included neurologic events associated with GBM. Treatment-related AEs (TRAEs) occurred in 10 (45.5%) patients, and incidences by maximum CTCAE grade (Gr) were Gr1: 5 (22.7%); Gr2: 4 (18.2%); Gr3: 1 (4.5%; fatigue); and Gr4/5: 0 patients. Most common TRAEs (≥2 [9.1%] patients) were fatigue, increased ALT, constipation, and headache. All patients (n=22) were evaluable for efficacy: OS range, 0.9 - 51.6 weeks; 8 patients (36%) had OS ≥ 22 weeks; PFS range, 0.9 -24.4 weeks; 11 patients (50%) had PFS ≥ 8 weeks; 3 patients were still alive at cutoff date; OS-6 to follow.

CONCLUSIONS

DUR + continuing BEV therapy appears to be well tolerated and shows preliminary activity in BEV-refractory recurrent GBM. Further studies are warranted.

Abstract

BACKGROUND

Durva is a human IgG1 mAb against PD-L1. Blockade of PD-1/PD-L1 has shown benefit among solid tumors; data implicate PD-1/PD-L1 signaling as a significant contributor to immunosuppression in GBM. BEV is an approved angiogenesis inhibitor for recurrent GBM; angiogenesis inhibition may promote antitumor benefit of immunotherapies. A review showed that lower dose BEV resulted in longer PFS/OS than the standard.

METHODS

Ongoing Phase 2 open-label study (NCT02336165) evaluates safety and efficacy of durva (10mg/kg Q2W) in 5 GBM cohorts. Results are presented for Cohorts B2 (durva + BEV 10mg/kg Q2W) and B3 (durva +BEV 3mg/kg Q2W) in BEV-naïve recurrent GBM. Primary efficacy endpoint for Cohorts B2/B3 is 6-month progression-free survival (PFS6), by modified RANO per investigator assessment; secondary endpoints include safety/tolerability. Comparative benchmark for BEV in recurrent GBM is PFS6 of 42%. The null hypothesis (PFS6 ≤42%) was tested in Intent-to-Treat (ITT) population against the alternative hypothesis (PFS6 ≥62%). ITT includes patients receiving any dose of durva and having at least baseline and 1 post-baseline tumor assessment. Durva alone in Cohort B of this study demonstrated PFS6 of 20% (90% CI: 9.7, 33.0).

RESULTS

As of 02Apr2018, 33 patients were treated in each cohort (B2, male: 54.5%, median age: 57.0 [40–74] years; B3, male: 60.6%, median age: 54.0 [23–73] years). Most common treatment-related adverse events (TRAEs, in ≥4 [12.1%] patients in either cohort): fatigue, dysphonia, increased ALT, AST, amylase, or lipase, diarrhea, hypertension, arthralgia, headache, and proteinuria. Incidences of TRAEs by maximum CTCAE grade (Gr) ≥3 for Cohorts B2/B3 were Gr3: 24.2/6.1%; Gr4: 0/6.1%; and Gr5: 0/0%. Kaplan-Meier estimate for PFS6 (n=33 each): B2, 15.2% (80% CI: 8.2, 24.0); B3, 21.1% (80% CI: 12.4, 31.4); 3 patients in each cohort showed partial response.

CONCLUSIONS

The addition of durva to BEV did not improve on the outcome of durva alone.

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.