Abraham, Christopher

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 PURPOSE Hippocampal volume (HV) is a predictor of neurocognitive function (NCF) in neurodegenerative disease. The role of patient-specific anatomic variables has not been well investigated in patients with brain metastases. This work aimed to evaluate HV at baseline and 6 months as a predictor of NCF and differential benefit from HA-WBRT for patients enrolled on CC001. MATERIALS HV was calculated at baseline and 6 months. HV at baseline and 6 months were correlated with baseline and 2, 4, and 6-month NCF scores (HVLT-R Total and Delayed Recall, Delayed Recognition, TMT Parts A and B, and COWA) using Pearson correlation. Correlation was defined as weak if ρ ≤0.35. A cox proportional hazards model was used to determine the impact of baseline HV on time to NCF failure. RESULTS Of 518 patients randomized on CC001, 277 had baseline imaging, and 135 had 6-month imaging. However, only 87 patients were analyzable at both baseline and 6-month periods. At baseline, HV was not significantly associated with NCF score for any measure (p-value range: 0.06-0.72). Additionally, there was no association between baseline HV and time to NCF failure (p = 0.16). Additionally, the impact of treatment arm allocation on HV was examined but found to be non-significant (p = 0.06). Lastly, baseline HV and NCF scores were noted to have weak correlation at 2, 4, 6, and 12 month timepoints (ρ: range, -0.17-0.15; P-value range, 0.04-0.98). At 6 months, the correlation between HV, baseline NCF change, and 6 month standardized NCF change were also noted to be weak (ρ: range, 0.05-0.16; P-value range, 0.06-0.76). CONCLUSIONS Radiotherapy is known to have deleterious effects on neurocognition. In neurodegenerative disease, HV and rate of HV change are known predictors for NCF. However, baseline HV is not an independent predictor of neurocognitive changes after WBRT or HA-WBRT for patients with brain metastases.

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.

2058 Background: Immunotherapies targeting the programmed cell death-1 (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. Methods: This is an open-label Phase II study of 2 sequential cohorts (Table). Cohort A first examines retifanlimab + bevacizumab + HFRT in patients with IDH1/2-WT rGBM. After a toxicity monitoring period, Cohort B, which adds epacadostat, starts enrolling. Key inclusion criteria includes dexamethasone ≤ 4 mg/day at registration and candidacy for reirradiation. Previous bevacizumab use for radiation necrosis is permitted. The primary endpoint is OS probability at 9 months (OS-9). Secondary endpoints include PFS, OS, and toxicity. Exploratory endpoints include immunological phenotyping of blood and tissue. An increase of OS-9 from 38% (bevacizumab alone) to 60% is considered clinically relevant. Results: From 6/2020 to 12/2021, we have completed accrual for cohort A and the interim analysis results are presented here: 25 patients with 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) with 52.2% of patients on dexamethasone during the first 3 cycles, 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 yet observed. Two treatment-related grade 3 toxicities have occurred (myositis, hypertension). Cohort B enrollment is ongoing, and correlative studies pending. Conclusions: 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 information: NCT03532295. [Table: see text]

OBJECTIVE The internal high-dose volume varies widely for a given prescribed dose during stereotactic radiosurgery (SRS) to treat brain metastases (BMs). This may be altered during treatment planning, and the authors have previously shown that this improves local control (LC) for non–small cell lung cancer BMs without increasing toxicity. Here, they seek to identify potentially actionable dosimetric predictors of LC after SRS for melanoma BM. METHODS The records of patients with unresected melanoma BM treated with single-fraction Gamma Knife RS between 2006 and 2017 were reviewed. LC was assessed on a per-lesion basis, defined as stability or a decrease in lesion size. Outcome-oriented approaches were utilized to determine optimal dichotomization for dosimetric variables relative to LC. Univariable and multivariable Cox regression analysis was implemented to evaluate the impact of collected parameters on LC. RESULTS Two hundred eighty-seven melanoma BMs in 79 patients were identified. The median age was 56 years (range 31–86 years). The median follow-up was 7.6 months (range 0.5–81.6 months), and the median survival was 9.3 months (range 1.3–81.6 months). Lesions were optimally stratified by volume receiving at least 30 Gy (V30) greater than or equal to versus less than 25%. V30 was ≥ and < 25% in 147 and 140 lesions, respectively. For all patients, 1-year LC was 83% versus 66% for V30 ≥ and < 25%, respectively (p = 0.001). Stratifying by volume, lesions 2 cm or less (n = 215) had 1-year LC of 82% versus 70% (p = 0.013) for V30 ≥ and < 25%, respectively. Lesions > 2 to 3 cm (n = 32) had 1-year LC of 100% versus 43% (p = 0.214) for V30 ≥ and < 25%, respectively. V30 was still predictive of LC even after controlling for the use of immunotherapy and targeted therapy. Radionecrosis occurred in 2.8% of lesions and was not significantly associated with V30. CONCLUSIONS For a given prescription dose, an increased internal high-dose volume, as indicated by measures such as V30 ≥ 25%, is associated with improved LC but not increased toxicity in single-fraction SRS for melanoma BM. Internal dose escalation is an independent predictor of improved LC even in patients receiving immunotherapy and/or targeted therapy. This represents a dosimetric parameter that is actionable at the time of treatment planning and warrants further evaluation.