CD40 agonist mitazalimab + mFOLFIRINOX (mFFX) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): Final efficacy analysis of the OPTIMIZE-1 study.

Abstract

e16380 Background: With a 5-year overall survival (OS) rate <5%, PDAC is a major cause of cancer-related mortality. 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 mFFX in untreated patients with mPDAC. The study met its primary endpoint with promising clinical efficacy vs. historical controls resulting in an overall response rate (ORR) of 54.4 % (unconfirmed; 42.1% confirmed) (Van Laethem 2024). We report the final efficacy analysis for patients treated with 450 and 900 µg/kg mitazalimab. Methods: Patients received mitazalimab on day 1 (priming dose), followed by a 2-week regimen starting with mFFX on day 8 and mitazalimab on day 10. The primary endpoint was ORR compared to 30% ORR for FFX alone. Secondary and exploratory endpoints include Duration of Response (DoR), Progression Free Survival (PFS), OS, safety, PK and PD biomarker assessments. Results: Between 2021 and 2025 94 patients with mPDAC were treated with mFFX + mitazalimab (29 at 450 µg/kg and 65 at 900 µg/kg). 22 patients at 450 µg/kg and 57 at 900 µg/kg received ≥2 treatment cycles and were efficacy evaluable. Efficacy outcomes for both dose levels are summarized in Table 1. The 900 µg/kg dose presented higher ORR, DoR, mPFS and mOS and has been selected for Phase 3 development. The primary efficacy analysis comprised 57 evaluable patients treated with 900 µg/kg mitazalimab + mFFX. Median follow up was 36 months and median exposure to treatment was 7 months. Eighteen patients remained treatment for more than 12 months, including seven who continued beyond 24 months. One patient remains on treatment. ORR was 54.4% (42.1% confirmed) and 22 patients achieved stable disease, for a disease control rate of 78.9%. Three patients achieved complete responses (CR) in target lesions, including one with CR in target and non-target lesions. Median DoR was 12.6 months, mPFS was 7.7 months and mOS was 14.9 months (12, 18, 24 and 30-mo OS rates of 58%, 37%, 26% and 21% respectively). Conclusions: Mitazalimab (900 µg/kg) in combination with mFFX continues to demonstrate clinically meaningful survival benefits compared with historical controls. The robust duration of response and encouraging long-term survival—six patients surviving >36 months—support continued development of mitazalimab in a confirmatory Phase 3 study. Clinical trial information: NCT04888312 . 450 µg/kg(N=22) 900 µg/kg(N=57) Median follow up (95% CI) 13.1 (12.1 - 13.9) 36.2 (30.9 - 36.7) ORR n % (90% CI) 5 (22.7) 24 (42.1) DoR (95% CI) NE (3.7 - NE) 12.6 (7.5 - 22.0) mPFS (95% CI) 5.3 (2.0 - 9.2) 7.8 (5.8 - 11.5) mOS (95% CI) 9.7 (5.9 - NE) 14.9 (10.0 - 17.3) 12-month OS, % (95% CI) 42.9 (21.9 - 62.3) 57.8 (43.9 - 69.4) 18-month OS, % (95% CI) 32.1 (11.1 – 55.7) 37.3 (24.8 - 49.9) 24-month OS, % (95% CI) - 26.1 (15.4 - 38.2) 30-month OS, % (95% CI) - 20.5 (11.0 - 32.1)