Safety and efficacy study of retifanlimab and epacadostat in combination with radiation and bevacizumab in patients with recurrent glioblastoma.

Abstract

TPS2070 Background: Recurrent glioblastoma (rGBM) after chemoradiotherapy has a dismal outcome with very limited treatment options. Addition of reirradiation to bevacizumab appears to improve progression-free survival (PFS) but does not improve overall survival (OS). Immune checkpoint inhibitors of programmed cell death-1 (PD-1) pathway appear to have limited single-agent activity for rGBM due to its immunesuppressive microenvironment. Indoleamine 2,3 dioxygenase 1 (IDO1) is an inducible and rate-limiting enzyme that catabolizes tryptophan (Trp) into kynurenine (Kyn). IDO1 is over-expressed in 50̃90% of GBM patients, and high IDO1 levels correlate with reduced OS. Epacadostat is a highly potent and selective oral inhibitor of IDO1 and may increase tumor sensitivity to anti-PD-1 blockade. Retifanlimab is a humanized anti-PD-1 monoclonal antibody directed against PD-1. The purpose of this study is to evaluate the safety and efficacy of combining retifanlimab plus or minus epacadostat with reirradiation and bevacizumab for rGBM patients. Methods: This is an open-label nonrandomized phase II study of two sequential cohorts for bevacizumab-naïve adults with rGBM: retifanlimab + bevacizumab+ radiation (cohort A), and retifanlimab + epacadostat + bevacizumab + radiation (cohort B). Each cohort will enroll 24 evaluable patients. Key eligibility criteria include candidates for reirradiation and bevacizumab, age ≥ 18 years, Karnofsky performance status ≥ 60%, and dexamethasone dose ≤ 4 mg/day. The primary endpoint is OS. Secondary endpoints include PFS, neurologic functions, and toxicity. The correlative endpoints include studies assess the anti-glioma immune response, serum Kyn/Trp ratio, and RNA expression of IDO1 and PD-L1 from available tissue. The trial is actively enrolling. At the time of abstract submission, 16 of the planned 24 patients in Cohort A have been enrolled. Clinical trial information: NCT03532295. [Table: see text]

The efficacy and adverse events of bevacizumab combined with temozolomide in the treatment of glioma: a systemic review and meta-analysis of randomized controlled trials

“…According to the WHO grading system, gliomas are divided into grades I-IV, grades I and II are low-grade gliomas, and slow tumor growth has a better prognosis through surgery; grades III (anaplastic astrocytoma) and IV (glioblastoma) are high-grade gliomas, of which glioblastoma patients with the highest degree of malignancy still have a median survival of less than 15 months even if the most aggressive treatment is used. The current standard of care for glioblastoma is to remove tumor cells as much as possible, followed by radiotherapy, chemotherapy, and adjuvant TMZ chemotherapy ( 25 ). Despite aggressive treatment, survival rates have not significantly improved, and most patients are prone to relapse, seriously affecting quality of life.…”

Interactions Between Anti-Angiogenic Therapy and Immunotherapy in Glioblastoma

“…In a second study, durvalumab in combination with bevacizumab and radiotherapy showed promise among a subgroup of patients with unmethylated MGMT tumors, however full results have yet to be posted ( 43 ). An intriguing study that is currently enrolling patients investigates the effect of retifanlimab, a PD-1 inhibitor, with or without epacadostat, an indoleamine 2,3-dioxygenase (IDO) inhibitor, in combination with bevacizumab and radiation in recurrent glioblastoma ( 150 ). IDO is an enzyme that catalyzes the rate limiting step of tryptophan (Trp) catabolism, converting Trp to kynurenine (Kyn).…”