Abstract B114: A Phase 1/1b study of KAZ954 alone and in combination with spartalizumab (PDR001) and taminadenant (NIR178) in patients with advanced gastrointestinal malignancies

Abstract Background:KAZ954 (KAZ), a humanized immunoglobulin G1 monoclonal antibody, is a potent, selective inhibitor of anti-ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2). Preclinical data show that KAZ blocks the hydrolysis of adenosine triphosphate, enhances immune activation in the tumor microenvironment, and augments the efficacy of PDR001 (PDR, anti-PD-1), and NIR178 (NIR, adenosine A2aR inhibitor). Methods: This is an open-label, multicenter, dose-escalation (ESC)/expansion study (NCT04237649). We present the dose-ESC results of KAZ single-agent (SA) and with PDR or NIR in patients (pts) with advanced gastrointestinal (GI) malignancies. Dose ESC was guided by Bayesian logistic regression models and comprised 3 arms: (1) SA KAZ administered intravenously (IV) at 30, 50, 100, and 150 mg biweekly (Q2W) flat dosing; KAZ 100 mg priming dose followed by 300, 600, and 1200 mg experimental dose; (2) KAZ 100 mg priming dose followed by 300, 600, and 1200 mg experimental dose with PDR 400 mg IV every 4 weeks; and (3) KAZ 100 mg priming dose followed by 300 and 600 mg experimental dose with NIR 160 and 240 mg twice daily orally. Primary objectives were to evaluate safety and tolerability and determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE). Secondary objectives were to assess antitumor activity and pharmacokinetics (PK). Tumor biopsies and blood samples were taken for biomarker analysis. Results: As of March 20, 2023, 77 pts were enrolled in ESC KAZ (n=43), KAZ+PDR (n=18), and KAZ+NIR (n=16) arms. Tumor types enrolled were microsatellite-stable colorectal cancer (37, 48%), pancreatic ductal adenocarcinoma (27, 35%), cholangiocarcinoma (10, 13%), and esophageal cancer (3, 4%). At data cutoff, 43 (100%), 15 (83.3%), and 11 (68.8%) pts discontinued treatment, and treatment-related adverse events (TRAEs) were reported in 37 (86%), 12 (66.7%), and 13 (81.3%) pts in KAZ, KAZ+PDR, and KAZ+NIR arms, respectively. KAZ had an acceptable and manageable safety profile. Given the occurrence of cytokine release syndrome (CRS) observed with cycle 1 day 1 (C1D1), prophylactic premedication with acetaminophen, antihistamine, and corticosteroid, together with a priming dose on C1D1, was established as the recommended regimen to administer KAZ. Grade ≥3 TRAEs were reported in 9 pts(20.9%) in KAZ, most commonly CRS and decreased lymphocyte count (n=2 each); 7 pts(38.9%) in KAZ+PDR, most commonly lymphopenia and increased aspartate aminotransferase (n=2 each); and 2 pts(12.5%) in KAZ+NIR (asthenia and lymphopenia [n=1 each]). No MTDs were reached in any treatment arm explored. Although no objective responses were observed, 12(27.9%), 2(11.1%), and 2(12.5%) pts showed stable disease in the KAZ, KAZ+PDR, and KAZ+NIR arms, respectively. Conclusions: KAZ was considered to be safe and well tolerated at all doses, and PK/PD analysis suggest effective ENTPD2 inhibition from a dose range of 150 to 1200 mg Q2W. Although a biologically active dose range was established, further dose-exploration studies are required to establish an RDE. Citation Format: Devalingam Mahalingam, Chia-Chi Lin, Philippe L. Bedard, Massimo Di Nicola, Zev Wainberg, Patricia LoRusso, Shubham Pant, Brigette B.Y. Ma, Wei-Peng Yong, Mia C. Weiss, Alessio Amatu, Kentaro Yamazaki, Lisa Nardi, Jong Bong Lee, Mike Roy, Anhthu Dang, Shu Yang, Bernard Pereira, Javier A. Otero, Teresa Macarulla. A Phase 1/1b study of KAZ954 alone and in combination with spartalizumab (PDR001) and taminadenant (NIR178) in patients with advanced gastrointestinal malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B114.