A Novel Immunotherapy Strategy Incorporating Epacadostat, Intralesional SD-101, and Radiotherapy Demonstrating Activity in Checkpoint Refractory Patients

Abstract

We have previously demonstrated, in mouse models and canines with spontaneous malignancies, the efficacy of a tri-modality immunotherapy strategy incorporating intralesional TLR9 agonist, local radiotherapy, and IDO blockade. Published clinical studies suggest a strong in-situ vaccination effect of combining TLR agonists and radiotherapy. Our data suggests that adding IDO inhibition significantly increases the efficacy of this in-situ vaccination by preventing “rebound immune suppression” and facilitating a robust systemic response. IRB approved protocol (NCT03322384) a phase I/II clinical trial of epacadostat, intralesional SD-101 (4mg x 5 weekly injections), and local radiotherapy (2Gy x 2, 4Gy x 5, or 8Gy x 3) for patients with advanced refractory solid tumors (cohort 1) and lymphomas (cohort 2) opened to accrual in 4/2018. The trial was designed as a phase I 3+3 dose de-escalation starting at 300 mg po bid of epacadostat. The phase II was designed as a Simon-two stage expansion for each cohort. Twenty total patients were enrolled. Using an intention-to-treat analysis we report the outcome for 7 patients refractory to prior therapy with PD-(L)1 checkpoint inhibition. In these patients, DCR and abscopal DCR was 86% (6/7) and 100% (7/7), response rate was 43% (3/7), and abscopal response rate was 29% (2/7) including 2 patients with long term durable complete responses. Patients had serial biopsies and serial blood samplings and results of intensive correlative analysis will also be reported. This is the first in human report of this novel triple therapy strategy and the first in human report of visceral intralesional injections of SD-101. This strategy appears to rescue some patients resistant to PD-(L)1 checkpoint blockade.