Pembrolizumab in combination with the oncolytic virus pelareorep in patients progressing on systemic chemotherapy for advanced pancreatic adenocarcinoma: A phase II study.

Abstract

e16789 Background: Pelareorep is an intravenously delivered oncolytic reovirus that can induce a T-cell-inflamed phenotype in pancreatic ductal adenocarcinoma (PDAC). Analysis of tumor tissue from patients treated with pelareorep have shown reovirus replication, T-cell infiltration, and upregulation of PD-L1. We hypothesized that pelareorep in combination pembrolizumab in patients with PDAC would lead to improved response, effective T-cell recognition of tumor antigens and expand peripheral T-cell repertoire. Methods: This investigator-initiated phase II study enrolled PDAC patients who progressed after first-line treatment. Patients received pelareorep at a dose of 4.5x1010TCID50IV on Days 1, 2, 3 & 8of Cycle (C) 1, and Days 1 & 8 with C2 onwards. Pembrolizumab was administered on Day 1 of each 21-day cycle at 200 mg IV. Primary objective was overall response rate (ORR) by RECIST v 1.1 criteria. Secondary objectives included evaluation for reovirus replication and immune analysis in peripheral blood and tumor biopsies. The study was designed using Simon’s two-stage design with 90% power and one-sided alpha = 0.025 to compare 10% vs. 35% ORR. A total of ≥2/11 responses were needed to proceed to stage 2. Results: Thirteen patients were enrolled. Disease control was achieved in 30% of the 12 efficacy-evaluable patients. One patient achieved partial response. Three additional patients achieved stable disease. Treatment was well tolerated, with mostly grade 1 or 2 treatment-related adverse events, including flu-like symptoms. Viral replication was observed in on-treatment tumor biopsies. T-cell receptor sequencing from peripheral blood revealed a high degree of peripheral repertoire turnover and creation of new T-cell clones during treatment. Immune correlation with efficacy analysis is ongoing. Conclusions: Pelareorep with pembrolizumab showed manageable safety profiles and modest efficacy in an unselected PDAC population. The study will not proceed to stage II, however further evaluation of anti-tumor activity of pelareorep and anti-PD-1 therapy is now planned in biomarker defined patients. Clinical trial information: NCT03723915 .