280MO - CD40 agonist mitazalimab combined with mFOLFIRINOX (mFFX) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): Primary analysis of the OPTIMIZE-1 phase Ib/II study

Background

With a 5-year overall survival (OS) rate <5%, systemic therapies for mPDAC are associated with poor outcomes. We assessed the safety and efficacy of mitazalimab, a human CD40 agonistic IgG1 antibody, combined with mFFX in mPDAC patients (pts).

Methods

OPTIMIZE-1, an open label, single arm, multicenter, phase 1b/2 study, enrolled newly diagnosed, chemotherapy naïve pts with mPDAC. Pts received mitazalimab on day 1 prior to beginning a 2-week dosing regimen starting with mFFX on day 8 and mitazalimab on day 10. Phase 1b determined 900 μg/kg mitazalimab as the recommended phase 2 dose. The phase 2 primary endpoint was overall response rate (ORR). Secondary endpoints included safety, duration of response (DoR), progression free survival (PFS) and OS.

Results

70 pts received 450 μg/kg (n=5) or 900 μg/kg (n=65) mitazalimab + mFFX. Common treatment emergent adverse events (TEAEs) Grade ≥3 were neutropenia (25.7%; 18 pts), hypokalemia (15.7%, 11 pts), anemia and thrombocytopenia (11.4%, 8 pts), consistent with mFFX safety profile. Four (5.7%) patients discontinued treatment due to TEAEs. Primary efficacy analysis included 57 evaluable pts treated with the 900 μg/kg mitazalimab dose. At data cutoff (14 Nov 2023), 29 pts (51%) remained on study, 18 on treatment. Median follow up was 12.7 months (mo). Confirmed ORR was 40.4% (22 partial responses, 1 complete response), 22 pts achieved stable disease (78.9% disease control rate). The unconfirmed ORR was 50.9%. Median DoR was 12.5 mo, mPFS was 7.7 mo (6 month PFS 62.4%) and mOS was 14.3 mo (1 year OS 59.3%). Increases in CD38+ NKT cells after the first mitazalimab infusion correlated significantly with depth of response. Similar trends were observed in CD38+ and Ki67+ CD8 T cell populations. Tumor mutational burden was not associated to any endpoints.

Conclusions

The OPTIMIZE-1 study met its primary endpoint, with a manageable safety profile and promising DoR associated with a clinically meaningful survival benefit. Furthermore, the NKT & T cell activation profile is strongly suggestive of mitazalimab’s contribution to deep anti-tumor responses. These encouraging results warrant continued development in a randomized phase 3 study.

Clinical trial identification

NCT04888312.

Legal entity responsible for the study

Alligator Bioscience AB.

Funding

Alligator Bioscience AB.

Disclosure

T. Macarulla Mercade: Financial Interests, Personal, Advisory Board: Ability Pharmaceutical, SL, AstraZeneca, Basilea Pharma, Batxer, BioLineRX Ltd., Celgene SLU, Eisai, Ipsen Pharma, Incyte; Financial Interests, Personal, Other, Direct research fund: Servier, Merck, Sharp and Dohme, Novocure, QED Therapeutics Inc, Roche, Sanofi-Aventis, Zymeworks; Financial Interests, Personal, Invited Speaker: Lilly, Janssen; Financial Interests, Institutional, Research Grant: Amc Medical Research, Armo Biosciences, Basilea, Biokeralty Research Institute, Merck Sharp & Dohme, Oncomed Pharmaceuticals, QED Therapeutics, VCN Biosciences, AbbVie Farmaceútica, Ability Pharmaceuticals, Agios, Amgen, Aslan, AstraZeneca, Bayer, BeiGene, Biolinerx, Blueprint Medicines, Boston Biomedical, Bristol Myers Squibb (BMS), Cantargia, Celgene, Eisai, Erytech Pharma, F. Hoffmann-la Roche, FibroGen, Genentech, Hallozyme, Immunomedics, Incyte, Ipsen, Lab. Menarini, Lilly, Loxo Oncology, MedImmune, Merimarck, Millenim, Nelum, Novartis, Novocure, Pfizer, Pharmacyclics, Roche, Zymeworks; Non-Financial Interests, Member: American Society of Clinical Oncology - ASCO, “Sociedad Española de Oncología Médica” – SEOM, Sociedad Europea de Oncología Médica - ESMO; Other, Editorial Board: GI Annals of Oncology. I. Borbath: Financial Interests, Institutional, Invited Speaker: Ipsen, Servier, AstraZeneca, Eisai; Financial Interests, Institutional, Advisory Board: Roche; Financial Interests, Institutional, Other, Travel Grant: Ipsen, Servier; Financial Interests, Institutional, Research Grant: Servier, Roche. K. Geboes: Financial Interests, Institutional, Advisory Board: BMS, MSD, Ipsen, Servier. P. Cassier: Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Advisory Board: Roche, Amgen, Boehringer Ingelheim; Financial Interests, Personal, Other, Advisor: OSE immunotherapeutics; Financial Interests, Institutional, Invited Speaker: AbbVie, Amgen, Blueprint, Boehringer Ingelheim, Bristol Meyer Squibb, Exelixis, GSK, Incyte, Janssen, Loxo/Eli Lilly, Novartis, Roche, Taiho, Toray Industries, Transgene; Non-Financial Interests, Institutional, Product Samples: Plexxikon, Novartis, MSD, AstraZeneca, GSK. H. Prenen: Financial Interests, Institutional, Advisory Board: Amgen, Roche, AstraZeneca; Financial Interests, Institutional, Invited Speaker: Bayer, Ipsen, Sanofi. E. Mitry: Financial Interests, Personal, Other, travel: MSD, Pierre Fabre; Financial Interests, Personal, Expert Testimony: Pierre Fabre, AstraZeneca/Daiichi Sankyo, Servier, Esteve, MSD, Bayer, Viatris. J.F. Blanc: Financial Interests, Personal, Advisory Role: Bristol Myers Squibb, Ipsen, Servier, Taiho Pharmaceutical; Financial Interests, Personal, Other, Travel: Roche, AstraZeneca, Ipsen; Financial Interests, Personal, Expert Testimony: Bayer Schering Pharma, Roche, Incyte, Eisai, AstraZeneca. J. Feliu: Financial Interests, Personal, Advisory Board, Expert testimony: Amgen, Novartis, Roche, Ipsen; Financial Interests, Personal, Advisory Board, Expert Testimony: Viatris, AstraZeneca; Financial Interests, Personal, Research Grant: Amgen; Financial Interests, Personal and Institutional, Invited Speaker: Ipsen, Bristol Myers Squibb, Sanofi. M. Rodriguez: Financial Interests, Personal, Expert Testimony: Servier. R.A. Pazo Cid: Financial Interests, Personal, Advisory Board: Roche, BMS, Servier, Ipsen; Financial Interests, Personal, Invited Speaker: Servier, BMS, Roche, Eisai; Financial Interests, Personal, Expert Testimony: Lilly, AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker, Support for manuscript presentation (funding, provision of study materials, medical writing, article processing charges): Ipsen, Astellas. D. Gomez Jimenez: Financial Interests, Personal, Full or part-time Employment: Alligator Bioscience AB; Financial Interests, Personal, Stocks/Shares: Pfizer. K.E. Smith: Financial Interests, Personal, Full or part-time Employment: Alligator Bioscience AB; Financial Interests, Personal, Stocks/Shares: Alligator Bioscience AB. K. Nordbladh: Financial Interests, Personal, Full or part-time Employment, Director Clinical Operations: Alligator Bioscience AB; Financial Interests, Personal, Member of Board of Directors, Employee representative member of BOD: Alligator Bioscience AB; Financial Interests, Personal, Stocks/Shares: Alligator Bioscience AB. P. Ellmark: Financial Interests, Personal, Full or part-time Employment: Alligator Bioscience; Financial Interests, Personal, Stocks/Shares: Alligator Bioscience. Y. Pico de Coaña: Financial Interests, Personal, Full or part-time Employment: Alligator Bioscience AB; Financial Interests, Personal, Stocks/Shares: Alligator Bioscience AB. S.V. Ambarkhane: Financial Interests, Personal, Full or part-time Employment: Alligator Bioscience AB; Financial Interests, Personal, Stocks/Shares: Alligator Bioscience AB. All other authors have declared no conflicts of interest.