Pembrolizumab in combination with the oncolytic virus pelareorep and chemotherapy in patients with advanced pancreatic adenocarcinoma: a Phase 1b study
Mené sur 11 patients atteints d'un adénocarcinome pancréatique de stade avancé, cet essai de phase IB évalue la dose maximale tolérée et l'efficacité, du point de vue du taux de réponse, du pélaréorep (un réovirus oncolytique) en combinaison avec le pembrolizumab et une chimiothérapie (5-Fluorouracile, gemcitabine ou irinotécan)
Purpose: Pelareorep is an intravenously delivered oncolytic reovirus that can induce a T cell-inflamed phenotype in pancreatic ductal adenocarcinoma (PDAC). Tumor tissues from patients treated with pelareorep have shown reovirus replication, T-cell infiltration, and upregulation of PD-L1. We hypothesized that pelareorep in combination with pembrolizumab and chemotherapy in patients with PDAC would be safe and effective. Experimental Design: A phase 1b single arm study enrolled PDAC patients who progressed after first-line treatment. Patients received pelareorep, pembrolizumab, and either 5-Fluorouracil, gemcitabine, or irinotecan until disease progression or unacceptable toxicity. Study objectives included: safety and dose-limiting toxicities, tumor response, evaluation for reovirus replication, and immune analysis in peripheral blood and tumor biopsies. Results: Eleven patients were enrolled. Disease control was achieved in three of the 10 efficacy-evaluable patients. One patient achieved partial response for 17.4 months. Two additional patients achieved stable disease, lasting 9 and 4 months, respectively. 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 the creation of new T-cell clones during treatment. High peripheral clonality and changes in the expression of immune genes were observed in patients with clinical benefit. Conclusions: Pelareorep and pembrolizumab added to chemotherapy did not add significant toxicity and showed encouraging efficacy. Further evaluation of pelareorep and anti-PD-1 therapy is ongoing in follow-up studies. This research highlights the potential utility of several pre-treatment and on-treatment biomarkers for pelareorep therapy warranting further investigation.