Durvalumab and oleclumab in resectable pancreatic ductal adenocarcinoma: A window of opportunity trial (DORA).

Abstract

TPS4268 Background: Resectable pancreatic ductal adenocarcinoma (PDAC) comprises < 20% of cases and remains associated with poor outcomes despite surgery and adjuvant chemotherapy. PDAC features a hypoxic, immunosuppressive and “cold” tumor microenvironment (TME). CD73 has emerged as a prognostic biomarker in PDAC, with high expression linked to poor survival. CD73 on tumor cells impairs antitumor T-cell responses and results in tumor immune escape. Inhibition of CD73 could reverse immune suppression by the TME. Preliminary data from the phase I combination trial of durvalumab (anti-PD-L1 antibody) and oleclumab (anti-CD73 antibody) has shown modest antitumor activity in patients in PDAC, colon cancer, and non-small cell lung cancer. A window-of-opportunity (WOO) study allows for rapid early identification of biological activity. We therefore designed a WOO trial to assess the impact of CD73 and PD-L1 blockade in resectable PDAC to test the hypothesis that this strategy would increase CD8+ T cell infiltration and reduce suppressive immune cells as assessed by digital spatial profiling and image mass cytometry. Methods: DORA (NCT06060405) is a prospective phase II multicentre WOO trial evaluating the immune activity of combined CD73 and PD-L1 blockade in upfront resectable PDAC. Eligible patients must have ECOG 0–1, histologically confirmed NCCN resectable PDAC, and be immunotherapy-naïve. Patients undergo an upfront EUS for histological diagnosis and for correlative studies, and then receive a single dose of durvalumab 1500 mg IV and oleclumab 3000 mg IV x 2 doses every two weeks prior to surgical resection. Patients receive standard-of-care adjuvant systemic therapy following surgery. The primary objective is to determine the increase in immune cell infiltration, specifically CD8+ T cells, between the paired pre-treatment and surgical resection specimens. Secondary objectives include the percent change in other immune cell populations (CD3/CD45RA/RO T cells, M1 vs. M2 macrophage), and the dynamic changes in immune cell populations as measured by flow cytometry/CyTOF. A total of 22 patients will be enrolled to ensure 20 evaluable subjects who undergo surgical resection. With 20 patients, this provides 80% power to detect an effect size of 0.66 using a two-sided alpha of 0.05. Planned correlatives include serial ctDNA analysis and whole genome and transcriptome sequencing of all surgical resections. This study was activated in January 2024. Clinical trial information: NCT06060405 .