Evaluation of Molecular Determinants Related to Outcomes in Recurrent High Grade Glioma Treated With Hypofractionated Stereotactic Radiotherapy (HFSRT) and Immune Checkpoint Blockade

Abstract

Recurrent high-grade glioma (rHGG) continues to cause increased morbidity and mortality. To date, salvage therapy for rHGG remains ineffective, even with novel immune checkpoint blockade approaches. Here we evaluate molecular factors that may influence outcomes in rHGG patients treated with HFSRT and immunotherapy.This retrospective analysis identified 76 continuous rHGG patients treated with HFSRT and PD-1 inhibitors on or off trial protocol with > 3 months of follow-up from 2010 to 2020. Clinical characteristics, treatment, outcomes, and available molecular alterations in IDH1 (n = 74), PTEN (n = 54), EGFRvIII (n = 64) or amplification (n = 56), CDKN2A (n = 42), TERT (n = 42) and MGMT promoter methylation (n = 69) were collected. Time to recurrence (TTR) and overall survival (OS) were estimated from the end of HFSRT with univariable (UVA) Kaplan-Meier methods compared via log-rank test as well as Cox regression analyses.The median age at HFSRT was 55 years (range: 22-83) with a KPS of 80 (range: 50-100). The majority (63%) of patients were male, 35% had > 2 recurrences of HGG before HFSRT and 55% underwent salvage surgery. A total of 11 patients (15%) received bevacizumab (Bev) prior to HFSRT. The median HFSRT dose was 35 Gy (range: 30-40 Gy) given in 5-10 fractions. Sixty-six (87%) patients were treated with concurrent HFSRT and Bev followed by immunotherapy. At a median follow-up from HFSRT of 13.8 months (range: 8.7-18.9), 55 (72%) patients relapsed with a median TTR of 6.94 months (5.0-8.87) and OS of 10.1 months (7.4-12.9); this included Bev-naïve and -resistant patients. Bev vs no Bev with HFSRT improved TTR (13.7 vs 6.3 months, P < 0.001), though Bev with HFSRT was not associated with improved OS. Of interest, no Bev prior to HFSRT improved OS from HFSRT (12.0 vs 8.4 months, P = 0.01). No molecular factors were associated with TTR after HFSRT, though IDH1-mut (P = 0.001) and wild-type PTEN (P = 0.02) and EGFR (P = 0.02) were related with prolonged OS. Similarly, mutations in TERT were associated with inferior OS (26.7 vs 60.7 months, P < 0.001). MGMT methylation status was not associated with TTR of OS.Salvage treatments for rHGG remain a challenge. This study provides further insight into prognostic molecular determinants in the setting of HFSRT, PD-1 blockade and Bev.E. Guvenli: None. D. Grass: None. D.E. Oliver: None. A.B. Etame: None. N. Tran: None. R.J. Macaulay: None. P. Forsyth: Research Grant; NIH/NCI, CDMRP, Department of Defense, Pfizer, State of Florida - Bankhead Coley, Moffitt Center of Excellence Celgene project, NIH/NCI. Honoraria; BTG, NIH, Ziopharm, Tocagen, NCRI. Consultant; AbbVie, Inc, Ziopharm, Novellus, NCI Neuro-Oncology Branch Peer Review, Physical Sciences Oncology Network, Tocagen. Advisory Boar. S. Sahebjam: Research Grant; Merck, Bristol Myers Squibb, Brooklyn Immunotherapeutics. Advisory Board; Merck, Boehringer Ingelheim. Travel Expenses; Eli Lilly. H.M. Yu: Honoraria; UpToDate. Speaker's Bureau; BrainLab. Advisory Board; Novocure, AbbVie.