Hissim, Deanna

Abstract INTRODUCTION Immunotherapy has not improved survival in recurrent GBM (rGBM). Indoleamine 2,3 dioxygenase 1 (IDO1), highly expressed in ~90% of patients with malignant glioma, is a rate-limiting enzyme that catabolizes tryptophan (Trp) into kynurenine (Kyn) and enables immune escape. METHODS We hypothesized combining therapies targeting immunosuppressive pathways with cytotoxic and antiangiogenic therapies would overcome tumor-related immunosuppression. This was an open-label Phase II study of two regimens: Arm A consisted of retifanlimab (anti-PD1, 500mg IV Q4W) + bevacizumab (10mg/kg IV Q2W) + HFRT (3.5Gy/day x 10) in patients with IDH1/2-WT rGBM. Regimen B added the IDO inhibitor, epacadostat (400mg po BID), initiated prior to HFRT. Key inclusion criteria included dexamethasone ≤ 4 mg/day. The primary endpoint was overall survival (OS) at 9 months (OS-9). 24 evaluable patients were required to detect an OS-9 of 60% with 80% power, compared to 38% in historical controls (bevacizumab alone) by 1-sided 1-sample log rank test at alpha=0.1. RESULTS We previously reported Arm A. Here, we present results from Arm B. 25 of the 27 patients enrolled to regimen B were evaluable: median age 58years (23-71); 28% female; 23% MGMT promotor methylated; median KPS 90 (70 - 100); a median of 6 cycles of epacadostat as of May 2024 (1 - 13). 18 of 25 died with a median follow up 9.23 months. Median PFS was 7.52 months (95%CI: 5.52-9.43). Median OS was 9.5 months (95%CI 8.08-11.96). Regimen B met its primary endpoint with OS-9 of 61.07% (95%CI: 38.23-77.65%). There were 5 possible immune-related grade 3+ toxicities to date (2 ALT/AST increase; 3 rash). CONCLUSIONS Retifanlimab, epacadostat, HFRT, and bevacizumab in rGBM is well-tolerated, with encouraging OS and PFS at the time of submission. Arm B met its primary endpoint. Further studies are warranted to identify biomarkers to predict long-term responders.

Abstract INTRODUCTION Immunotherapies targeting PD-1 in recurrent glioblastoma (rGBM) have shown limited activity. We hypothesize combining therapies targeting immunosuppressive pathways with cytotoxic and antiangiogenic therapies will improve survival. This nonrandomized, noncomparative Phase II study examines safety and efficacy of an anti-PD-1 monoclonal antibody (retifanlimab), hypofractionated radiotherapy (HFRT), and bevacizumab, with or without an IDO1 inhibitor (epacadostat), in patients with rGBM. METHODS This is an open-label Phase II study of two regimens. Regimen A examines retifanlimab (500mg IV Q4W) + bevacizumab (10mg/kg IV Q2W) + HFRT (3.5Gy/day x 10) in patients with IDH1/2-WT rGBM. Regimen B adds epacadostat. Key inclusions include dexamethasone ≤ 4 mg/day and reirradiation candidacy. The primary endpoint is overall survival (OS) probability at 9 months (OS-9). An increase of OS-9 from 38% (bevacizumab alone) to 60% was considered clinically relevant and required 24 efficacy evaluable patients. RESULTS Regimen A accrual is complete; interim results are as follows: 26 rGBM enrolled, with 24 evaluable [median age 64.2 years (42.1-81.8); 29% female; 29% MGMT promotor methylated; 33.3% with multi-focal disease; median KPS 90 (70-100); median baseline dexamethasone 0 mg (0-4) and ALC 1,000 cells/µl (300-3,700)]. Patients received a median of 6 cycles as of May 2022 (2-24). Median follow-up is 16.0 months. Interim median PFS is 7.0 months (95%CI: 4.5~11.1) and median OS is 12.2 months (95%CI 7.1~18.0). Regimen A met primary endpoint with OS-9 of 67% (95%CI: 44~82%). Overall response rate is currently 58% (95%CI: 36.94~77.2%). There were five possible immune-related grade 3+ toxicities to date (n = 1 each colitis, vomiting, and seizure; n = 2 diarrhea). Regimen B is enrolling. CONCLUSIONS Interim analysis suggests combination retifanlimab, HFRT, and bevacizumab in rGBM is generally well-tolerated, with encouraging OS and PFS at the time of submission. Correlative analysis is ongoing and will be presented at the meeting.