Efficacy and safety of mitazalimab in combination with mFOLFIRINOX in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): An interim analysis of the optimize-1 phase 1b/2 study

4139 Background: Mitazalimab is a human CD40 agonistic IgG1antibody. Targeting CD40 kickstarts the cancer immunity cycle by licensing dendritic cells leading to tumor specific T cell priming and activation. Furthermore, in PDAC CD40 agonists on myeloid cells promote degradation of the desmoplastic tumor stroma, improving influx of T cells and chemotherapeutic agents into the tumor. OPTIMIZE-1 (NCT04888312) is a Phase 1b/2, open label, multicenter study designed to evaluate safety, tolerability, and efficacy of mitazalimab in combination with mFOLFIRINOX (Oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2, 5-FU 2.4 g/m2) in patients (pts) with previously untreated mPDAC. In the first part of the study (phase 1b), 900 µg/kg mitazalimab was selected as the recommended phase 2 dose (RP2D). Methods: In the first 21 day treatment cycle, mitazalimab was administered IV at RP2D on day 1 and 10 and mFOLFIRINOX infusion started on day 8. In subsequent cycles, treatment followed a 14 day cycle where mitazalimab was always administered 2 days after mFOLFIRINOX. The primary endpoint of this ongoing study is overall response rate (ORR) per RECIST v1.1. Secondary and exploratory endpoints include progression free and overall survival, safety, PK and PD biomarker assessments. Futility was prespecified as ORR≤30% in pts treated at RP2D, based on historical data with FOLFIRINOX (Conroy, 2011). Results: As of December 8, 2022, 43 pts with untreated mPDAC were treated with mFOLFIRINOX and 450 µg/kg (N = 5) or 900 µg/kg (N = 38) mitazalimab and evaluated for safety. The most common grade (Gr) ≥3 TEAEs were neutropenia (16%), fatigue (12%) and hypokalemia (12%). Mitazalimab related Gr >3 AEs were fatigue in 3 (7.9%) pts, hypokalemia in 2 (5.3%) pts, diarrhea in 1 (2.6%) pt, pneumonia in 1 (2.6%) pt, increased ALT in 1 (2.6%) pt, headache in 1 (2.6%) pt, acute kidney injury in 1 (2.6%) pt. 10 pts (23%) experienced infusion reactions (all Gr 1-2) and 5 (12%) pts discontinued treatment due to TEAEs (pneumonia, gastric obstruction, neuropathy, bacteremia). At cutoff, 23 pts were evaluable for futility. Median follow up was 170 days and median exposure was 163 days. 18 pts (78%) remain on treatment, 6 (26%) beyond the 6 month treatment period. ORR was 52.2% (12 partial responses), an additional 8 pts achieved stable disease, resulting in a 91.3% disease control rate. Combination with mFOLFIRINOX had no impact on mitazalimab PK. The PD biomarker profile was consistent with the mode of action of mitazalimab, including upregulation of MCP-1 and IFN-γ. Conclusions: Mitazalimab + mFOLFIRINOX is a feasible regimen with a manageable safety profile. Mitazalimab administered at 900 µg/kg in combination with mFOLFIRINOX shows encouraging antitumor activity in mPDAC, meriting continued development. The study passes futility and continues to full accrual. Clinical trial information: NCT04888312 .