Immunotherapies targeting the PD-1 pathway in recurrent glioblastoma (rGBM) have failed. We hypothesize that combining therapies targeting multiple immunosuppressive pathways with cytotoxic and antiangiogenic therapies will improve survival. Here, we evaluate the safety and efficacy of an anti-PD-1 monoclonal antibody (retifanlimab), hypofractionated radiotherapy (HFRT), and bevacizumab, with or without an oral IDO1 inhibitor (epacadostat), in patients with rGBM in a nonrandomized, noncomparative sequential two-arm phase II study.
This is an open-label phase II study of 2 sequential cohorts. Cohort A first examines retifanlimab (500mg IV Q4W)+ bevacizumab (10mg/kg IV Q2W) + HFRT (3.5Gy/day x10) in patients with IDH1/2-WT rGBM. After a toxicity monitoring period, Cohort B, which adds epacadostat (600mg PO BID), starts enrolling. Key inclusions include dexamethasone ≤ 4 mg/day and candidacy for reirradiation. The primary endpoint is OS probability at 9 months (OS-9). An increase of OS-9 from 38% (bevacizumab alone) to 60% is considered clinically relevant.
We have completed accrual for cohort A and the interim analysis results are presented here: 25 rGBM enrolled, with 23 evaluable. Median age is 64.3 years (42.1-81.8), 30.4% female, 30.4% MGMT promotor methylated, median KPS 90 (range 70-100), baseline dexamethasone 0 mg (range 0-4), median baseline ALC 1,000 cells/μl (range 300-3,700). Patients received a median of 6 cycles to date (range 2-20). Median follow-up is 11.97 months per the reverse Kaplan-Meier method. Interim analysis shows a median PFS of 9.9 months (95%CI: 5.5 to not reached (NR)) and median OS of 12.2 months (95%CI 7.3-NR). Notably, Cohort A met the primary endpoint with an OS-9 of 71.4% (95%CI: 46.7% -86.1%). No dose limiting toxicities have been observed. Two treatment-related grade 3 toxicities have occurred (myositis, hypertension).
Interim analysis suggests retifanlimab combined with HFRT and bevacizumab in patients with rGBM is well-tolerated and had encouraging OS and PFS at the time of data cutoff. Cohort B, which adds epacadostat, is currently enrolling.
Clinical trial identification
Legal entity responsible for the study
J.L. Campian: Non-Financial Interests, Institutional, Principal Investigator: Merck. A. Kim: Non-Financial Interests, Institutional, Funding: Monteris. M. Ciorba: Non-Financial Interests, Institutional, Funding: Incyte. M. Chheda: Non-Financial Interests, Institutional, Research Grant, PI for Orbus, Incyte and Merck trials: NeoImmuneTech. All other authors have declared no conflicts of interest.