592 CD40 agonist mitazalimab combined with mFOLFIRINOX in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): updated efficacy and correlative biomarkers from the OPTIMIZE-1 trial

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Background Metastatic pancreatic ductal adenocarcinoma (mPDAC) has a 5-year overall survival (OS) rate of less than 5%, with limited efficacy from existing systemic therapies. OPTIMIZE-1 is an open-label, single-arm, multicenter phase 1b/2 study to evaluate efficacy and safety of mitazalimab, a human CD40 agonistic IgG1 antibody, in combination with modified (m) FOLFIRINOX in previously untreated patients with mPDAC.1 Methods Patients received mitazalimab on day 1 (priming dose), followed by a 2-week dosing regimen starting with mFOLFIRINOX on day 8 and mitazalimab on day 10 (figure 1). The primary endpoint was overall response rate (ORR), with secondary endpoints including safety, duration of response (DoR), progression-free survival (PFS) and OS. Whole blood samples were collected at baseline and during treatment for immunophenotyping, and ctDNA analysis. Tumor biopsies collected at baseline underwent TruSight Oncology 500 (TSO500) and RNA sequencing (figure 1). Results This updated efficacy and biomarker analysis included 57 evaluable patients treated with the 900 µg/kg mitazalimab dose (data cutoff on May 16, 2024). 19 patients (33%) remained in the study, with 9 still undergoing treatment. The confirmed ORR was 42.1%, with 23 partial responses (PR) and 1 complete response (CR) (table 1). The unconfirmed ORR was 54.4%. Disease control rate (DCR) including patients with stable disease, PR and CR was 79%. Median DoR was 12.6 months, median PFS was 7.7 months (6 and 12-month PFS of 61% and 35% respectively), and median OS was 14.9 months (12 and 18-month OS of 58% and 36% respectively). The pharmacodynamic biomarker profile was consistent with the mode of action of mitazalimab, including upregulation of MCP-1 and IFN-γ and transient decreases in B cells. The main immune phenotypic changes associated with clinical outcomes were observed at cycle 1 Day 8, after the mitazalimab priming dose, before the first dose of mFOLFIRINOX. Updated comprehensive biomarker results and pertinent correlations of immune profiles, genetic alterations and PDAC molecular subtyping with different efficacy outcomes will be presented. Conclusions Mitazalimab in combination with mFOLFIRINOX demonstrated a manageable safety profile and encouraging activity, including a promising DoR that contributes to a clinically meaningful survival benefit. Changes in immunological correlates observed after the priming dose and their association with efficacy outcomes suggest a mitazalimab-driven response in this novel regimen, and further strengthens this unique dosing schedule. These encouraging results from OPTIMIZE-1 form the basis of a future randomized confirmatory trial of mitazalimab in combination with mFOLFIRINOX in mPDAC. Acknowledgements We would like to show our gratitude to the patients, their families and the clinical research staff who are making this trial possible. Trial Registration NCT04888312. Reference Van Laethem JL, I Borbath, H Prenen, et al., Combining CD40 agonist mitazalimab with mFOLFIRINOX in previously untreated metastatic pancreatic ductal adenocarcinoma (OPTIMIZE-1): a single-arm, multicentre phase 1b/2 study. Lancet Oncol 2024. Ethics Approval The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines as defined by the International Conference on Harmonisation, in 14 European University Hospitals according to the study protocol and amendments, approved by local Institutional Review Boards and independent ethics committees: France:Comité de protection des personnes Est I, Centre hospitalier la Chartreuse - 1 Bld Chanoine Kir, BP 23314 21033 DIJON France Belgium: CHU UCL Namur, site Godinne, Comité d’éthique, Avenue Docteur G. Thérasse 1, 5530 YVOIR Spain: The CEIm of the Ramón y Cajal University Hospital, Madrid, Spain Patients provided written informed consent before enrolment.

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