P-175 - Oncolytic Virus Therapy in Pancreatic Cancer: Clinical Efficacy and Pharmacodynamic Analysis of REOLYSIN in Combination with Gemcitabine in Patients...

Date 04 July 2015
Event WorldGI 2015
Session Posters
Topics Anti-Cancer Agents & Biologic Therapy
Pancreatic Cancer
Presenter D. Mahalingam
Citation Annals of Oncology (2015) 26 (suppl_4): 1-100. 10.1093/annonc/mdv233
Authors D. Mahalingam1, S. Goel2, M. Coffey3, N. Noronha3, G. Selvaggi3, S. Nawrocki1, G. Nuovo4, M. Mita5
  • 1San Antonio/US
  • 2New York/US
  • 3Oncolytics Biotech, Calgary/CA
  • 4Powell/US
  • 5Los Angeles/US

Abstract

Introduction

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 1-year survival rate of approximately 18% for all stages of the disease. Currently, FOLFIRINOX or gemcitabine in combination with nab-paclitaxel are standard treatment options for metastatic disease. However, both regimens are more toxic than gemcitabine alone, often limiting their use to patients with good performance status (PS). REOLYSIN® (proprietary isolate of reovirus Type 3 Dearing) has shown promising antitumor activity in preclinical models, attributed to the ability of reovirus to preferentially replicate in cells with activated RAS pathway. In addition to direct cytotoxic effects on cancer cells, REOLYSIN can also trigger an antitumor immune response. Due to the high frequency of RAS mutations in PDAC, we hypothesized REOLYSIN would promote selective reovirus replication in pancreatic tumors and enhance anticancer activity of gemcitabine.

Methods

Patients with chemotherapy-naïve, advanced or metastatic PDAC were eligible for this phase 2 study. The primary objective was to assess Clinical Benefit Rate (CBR) defined as Complete Response (CR) + Partial Response (PR) + Stable Disease (SD) ≥12 weeks. Secondary objectives included determination of progression-free survival (PFS), overall survival (OS), toxicity profile, and pharmacodynamic analysis of viral replication in patients consenting to on-treatment biopsy. Patients were treated every 3 weeks with 800mg/m2 gemcitabine on days 1 + 8 and REOLYSIN 1x1010 TCID50 REOLYSIN IV on days 1,2,8 + 9. Tumor assessment was performed every 6 weeks. A Simon-two stage design was used where at least 3/17 patients must achieve CBR in order to proceed to stage 2.

Results

34 patients were enrolled. Mean age was 66 years (range 48-85) with 53% of patients above 65 years. M/F: 53/47%, 71% Caucasian, and 94% with PS 0-1; 94% of patients had metastatic disease (62% with liver metastases, 18% with peritoneal involvement). Median number of cycles was 4 with 29 patients evaluable for response. One confirmed PR, 23 SD, and 5 had progressive disease as best response, with 70% of patients having a CA19.9 ≤20% from baseline. The treatment was well tolerated with manageable non-hematological toxicities, including grade 3-4 asthenia (38%), fever (12%), chills (3%), flu-like syndrome (3%), nausea/vomiting (3%), diarrhea (9%), neutropenia (18%). Median PFS was 4 months; 53% of patients received post-PD chemotherapy, including 12% nab-paclitaxel. The median OS was 10.2 months, with a 1- and 2-year survival rate of 45% and 24% respectively, with a median duration of follow-up of 2 years. One patient with KRAS G12D mutation displayed positive staining for reoviral protein and activated caspase 3 by immunohistochemistry (IHC) in tumor biopsies. Fluorescent in situ hybridization demonstrated co-expression of reoviral protein and caspase-3 consistent with a productive lytic infection. Further, we also reveal upregulation of immune markers including PD-L1 on IHC following Reolysin therapy.

Conclusion

REOLYSIN in combination with gemcitabine is tolerable and an effective alternative to single agent gemcitabine with a promising survival advantage that requires further validation in randomized trials. Pharmacodynamic analysis reveals reovirus replication within pancreatic tumor and associated apoptosis. Upregulation of immune checkpoint marker PD-L1, suggest future consideration of combining oncolytic virus therapy with anti-PD-L1 inhibitors.