A phase II single-arm study of CRS-207 with pembrolizumab (pembro) in previously treated malignant pleural mesothelioma (MPM).

Abstract

29 Background: CRS-207 is a live, attenuated, double-deleted Listeria monocytogenes (LADD) engineered to stimulate immune response to mesothelin. In a phase I trial of 60 MPM patients, 34% of subjects had tumor reduction (range -1 to -47%) following 2 doses of CRS-207 alone. In KEYNOTE-028 pembro showed activity in PDL1+ (≥1% by IHC) MPM, with an objective response rate (ORR) of 20% (5/25) and stable disease in 52% of subjects who had failed or did not receive chemotherapy. Subsequent studies of pembro have shown similar results in MPM. Results from a pre-clinical murine lung tumor model (CT26hMeso) showed anti-PD-1 enhanced LADD-induced tumor response. The study described here evaluated the efficacy of combination therapy of CRS-207/pembro. Methods: Adults with epithelial/biphasic MPM, ≤2 prior lines, progression on pemetrexed and platinum-based therapy, and no prior immunotherapies were enrolled. CRS-207/pembro were administered IV Q3W for 4 cycles, after which pembro continued Q3W and CRS-207 changed to Q6W. Response was assessed Q6W by modified RECIST for MPM (Byrne and Nowak, 2004). The primary endpoint was ORR; secondary endpoints included DOR, disease control rate (DCR), progression-free survival (PFS) and overall survival. Pre- and on-treatment blood and tumor samples were collected. Shedding and blood clearance of CRS-207 were evaluated. Results: 9/10 subjects were evaluable for response. No responses were observed; DCR was 11% (1/9 with SD) and PFS ranged from 3.4 to 8.9 weeks. Most common treatment related adverse events were chills, pyrexia and nausea. 3/10 subjects evaluated were PDL-1 negative by IHC. Of 6 subjects who underwent clearance and shedding evaluation, CRS-207 was detected in blood in 1 at 18-24 hrs after the first CRS-207 dose and cleared by the next evaluation at Day 4; shedding samples (urine, fecal, and saliva) tested negative. Conclusions: The toxicity profile of CRS-207/pembro combination was consistent with the safety profile of each component alone. No evidence of clinical activity was observed. Based on the results and an overall evaluation of the program, the clinical development of CRS-207 was discontinued. (NCT01675765) (NCT02054806). Clinical trial information: NCT03175172.