Abstract PR06: CD40 agonist mitazalimab in combination with mFOLFIRINOX in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): Interim efficacy results of the OPTIMIZE-1 phase 1b/2 study
Authors: Van Laethem Jean-Luc , Geboes Karen P. , Cassier Philippe A. , Borbath Ivan , Lambert Aurélien , Mitry Emmanuel , Prenen Hans , Blanc Jean-Frédéric , Pilla Lorenzo , Garrote Mercedes Rodriguez , Cid Roberto A. Pazo , Gallego Inmaculada , Feliú Jaime , Nordbladh Karin , Ellmark Peter , Carlsson Malin , de Coaña Yago Pico , Ambarkhane Sumeet V. , Macarulla Teresa 
Published: January 2024

Abstract
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 sensitizing the tumor to chemotherapeutic agents. 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 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). In the first 21-day treatment cycle, mitazalimab is administered IV at RP2D on day 1 and 10 and mFOLFIRINOX infusion started on day 8. In subsequent cycles, treatment follows a 14-day cycle where mitazalimab is 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 duration of response, progression free and overall survival, safety, PK and PD biomarker assessments. As of May 24, 2023, study enrolment was complete, 65 patients were treated with mFOLFIRINOX and mitazalimab 900 µg/kg (RP2D). Interim efficacy analysis comprised of 57 evaluable patients. Median follow up was 6.5 months and median exposure to treatment was 5 months. 28 patients (49%) remain on treatment, 18 (32%) continued treatment beyond 6 months, the longest being 17 months (ongoing). ORR was 43.9% (25 patients with partial response), an additional 19 patients achieved stable disease, resulting in a 77.2% disease control rate. Median time to response was 2.2 months and median duration of response was 8.7 months. The most common grade (Gr) ≥3 TEAEs were neutropenia (21.5%), anemia (12.3%), thrombocytopenia (12.3%) and hypokalemia (12.3%). Mitazalimab related Gr &gt;3 AEs occurring in more than one patient were fatigue in 3 (4.6%) patients, increased ALT in 3 (4.6%) patients, diarrhea in 2 (3.1%) patients, asthenia in 2 (3.1%) patients, increased AST in 2 (3.1%) patients, and hypokalemia in 2 (3.1%) patients. 25 patients (38.5%) experienced infusion reactions (all Gr 1-2, managed with symptomatic treatment, none amounting to cytokine release syndrome) and 7 (10.8%) patients discontinued treatment due to TEAEs (pneumonia, gastric obstruction, neuropathy, bacteremia, ileal obstruction, stroke, skin reaction). In this ongoing phase 1b/2 trial, 900 µg/kg mitazalimab has shown no evidence of additive toxicity when administered in combination with mFOLFIRINOX, allowing extended treatment until progression. Interim efficacy results demonstrate encouraging antitumor activity in mPDAC with good durability of responses, meriting continued development.
Citation Format: Jean-Luc Van Laethem, Karen P. Geboes, Philippe A. Cassier, Ivan Borbath, Aurélien Lambert, Emmanuel Mitry, Hans Prenen, Jean-Frédéric Blanc, Lorenzo Pilla, Mercedes Rodriguez Garrote, Roberto A. Pazo Cid, Inmaculada Gallego, Jaime Feliú, Karin Nordbladh, Peter Ellmark, Malin Carlsson, Yago Pico de Coaña, Sumeet V. Ambarkhane, Teresa Macarulla. CD40 agonist mitazalimab in combination with mFOLFIRINOX in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): Interim efficacy results of the OPTIMIZE-1 phase 1b/2 study [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr PR06.