530 CD40 agonist mitazalimab + mFOLFIRINOX in patients with metastatic pancreatic ductal adenocarcinoma: dose characterization based on exposure response and biomarker analysis from the OPTIMIZE-1 study

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Background Mitazalimab, a human CD40 agonistic IgG1 antibody, has shown promising efficacy in combination with mFOLFIRINOX in treatment naïve mPDAC patients with a median overall survival (OS) of 14.9 months, median duration of response of 12.6 months, median progression free survival (PFS) of 7.7 months, overall response rate (ORR) of 54.4% (42.1% confirmed), and 24 month OS of 29.4% 1 2 (table 1). To address the Project Optimus initiative3 we characterized safety and efficacy at two dose levels.Methods Between September 2021 and December 2024, 29 patients were treated with 450 μg/kg mitazalimab and 65 patients with 900 μg/kg in combination with mFOLFIRINOX. All comparisons of efficacy and safety endpoints between dose levels were based on a seven-month restricted follow-up time enabling an unbiased comparison between doses. Exposure-Response (ER) (efficacy and safety), population PK and PK/PD analysis were performed.Results Based on the restricted follow-up time analysis, the ORR (unconfirmed) was approximately doubled in the 900 µg/kg group (50.9%) compared with the 450 µg/kg group (22.7%). Further, PFS and OS estimates at 6 months show more favorable outcomes for patients treated with 900 µg/kg (50.8% PFS and 89.5% OS) compared with 450 µg/kg (38.7% PFS and 69.4% OS). Mitazalimab in combination with mFOLFIRINOX demonstrated a manageable safety profile. A higher percentage of treatment emergent adverse events (TEAEs) and mitazalimab-related serious adverse events (SAEs) was observed in the 900 μg/kg group (80.0% vs 65.5% and 12.3% vs 3.4% respectively), however this may be related to exposure to the higher number of treatment cycles of both mitazalimab and mFOLFIRINOX in this group.Higher treatment-induced increases in immune populations, including Ki67+T cells, were observed following treatment with the 900 µg/kg dose compared with the 450 µg/kg dose. Furthermore, simulations with the exploratory PK/PD model showed a higher typical response for IP-10 at the higher dose level (figure 1A-C).ER analyses based on OPTIMIZE-1 data suggest that a mitazalimab 900 μg/kg dose is expected to offer higher clinical efficacy than 450 μg/kg (figure 1D). The analyses of safety endpoints suggest a higher probability of an event with higher exposure of mitazalimab, but this may be confounded by the combination treatment with mFOLFIRINOX.Conclusions The exposure-response data further supports mitazalimab contribution to the clinical benefits observed in OPTIMIZE-1. Based on available nonclinical and clinical mitazalimab data, a dose of 900 μg/kg is selected for the planned Phase 3 study.Ethics Approval OPTIMIZE-1 was single-arm, phase 1b/2 study conducted in 14 university hospitals in Belgium, France, and Spain according to the study protocol and amendments approved by local Institutional Review Boards and independent ethics committees, and in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines as defined by the International Conference on Harmonisation.References Van Laethem JL, 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.Geboes KP, et al. 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. Journal for ImmunoTherapy of Cancer 2024;12(Suppl 2):A677–A678.FDA. Optimizing the dose of human prescription drugs and biological products for the treatment of oncologic diseases. Guidance for industry, August 2024.Abstract 530 Table 1Outcomes from the 24 month readout of OPTMIZE-1 in patients treated with 900 µg/kg dose mitazalimab in combination with mFOLFIRINOXAbstract 530 Figure 1Pharmacokinetics, pharmacodynamics and exposure response for mitazalimab at two dose levels in OPTIMIZE-1. A) Population PK data B) Changes in IP-10 levels C) Treatment induced levels of IP10 in patients treated with 900 μg/kg mitazalimab D) Exposure response analysis

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