A phase 2 study of botensilimab and AGEN1423, an anti-CD73-TGFβ-trap bifunctional antibody, in subjects with advanced pancreatic cancer.

Abstract

702 Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly immunosuppressive tumor microenvironment resistant to traditional immune checkpoint inhibitors. AGEN1423 (also known as dalutrafusp alfa and GS-1423) is a bifunctional, humanized, aglycosylated immunoglobulin G1 kappa antibody that selectively inhibits CD73-adenosine production and neutralizes active TGF-β signaling, two major immunoregulatory and pro-tumorigenic pathways in PDAC. Botensilimab (BOT) is an Fc-enhanced multifunctional anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody. This study evaluated the combination of AGEN1423 with BOT in advanced PDAC. Methods: A single-arm phase II study was conducted to evaluate the safety, tolerability, and initial efficacy of BOT + AGEN1423 +/- chemotherapy in patients with metastatic PDAC (NCT05632328). In Cohort 1, eligible patients with metastatic PDAC with measurable disease by RECISTv1.1, ECOG PS ≤ 1, and disease progression on ≥ 1 line of treatment received AGEN1423 30mg/kg IV Q2W for 4 doses + BOT IV Q6W ongoing for up to 2 years. The first 3 patients in the safety lead-in received BOT 50mg IV Q6W, and subsequent patients received BOT 150mg IV Q6W. Pre-treatment and on-treatment tumor biopsies were obtained for translational studies. The primary endpoint was objective response rate (ORR) according to RECISTv1.1 criteria. Secondary endpoints were the incidence of adverse events according to CTCAE v5, disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). We are reporting the results of the preplanned interim analysis completed after enrollment of Cohort 1. Results: A total of 10 participants were enrolled in Cohort 1 of the trial. Among 8 patients with response assessment, two patients experienced partial responses, yielding ORR of 25% (95% CI: 3%-65%). An additional patient had stable disease, for a DCR of 38% (95% CI: 9%-76%). Grade ≥3 treatment-related adverse events occurred in 3 patients (anemia, colitis, and nephritis.) Median PFS was 1.5 months (95% CI: 0.7-3.3). Median OS was 7.8 months (95% CI: 0.7-not reached). Paired biopsies were obtained for 6 patients. Translational endpoints are underway, including the characterization of transcriptional signatures and changes in the cell composition of the tumor microenvironment (TME) using multiplexed immunofluorescence spatial technology. Conclusions: The combination of AGEN1423 and botensilimab showed two partial responses and one stable disease, yielding a disease control rate of 38%. The regimen was overall tolerable with Grade ≥3 treatment-related adverse events in 3 patients. Translational endpoints on paired biopsies are underway to assess changes in the TME after treatment. Clinical trial information: NCT05632328 .