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CD40 agonist mitazalimab with mFOLFIRINOX in untreated metastatic pancreatic cancer : Biomarkers associated with outcomes from OPTIMIZE-1

Van Laethem, Jean-Luc ; Geboes, Karen ; Borbath, Ivan ; Macarulla Mercade, Teresa ; Lambert, Aurélien ; Cassier, Philippe ; Prenen, Hans ; Mitry, Emmanuel ; Blanc, Jean-Frédéric and Pilla, Lorenzo , et al. (2025) In Cell Reports Medicine 6(10).
Abstract

Response determinants to immunotherapy in metastatic pancreatic ductal adenocarcinoma (mPDAC) remain unclear, limiting treatment advancements. We report a single-arm phase 1b/2 study (OPTIMIZE-1) evaluating the safety and efficacy of the cluster of differentiation 40 (CD40) agonist mitazalimab combined with modified FOLFIRINOX (mFOLFIRINOX), in chemotherapy-naive patients with mPDAC. Patients receive an initial dose of mitazalimab one week before starting biweekly cycles of mFOLFIRINOX plus mitazalimab. The study meets its pre-specified primary endpoint, achieving a confirmed objective response rate (ORR) of 42.1%. Median duration of response, progression-free survival, and overall survival was 12.6 months, 7.7 months, and 14.9 months,... (More)

Response determinants to immunotherapy in metastatic pancreatic ductal adenocarcinoma (mPDAC) remain unclear, limiting treatment advancements. We report a single-arm phase 1b/2 study (OPTIMIZE-1) evaluating the safety and efficacy of the cluster of differentiation 40 (CD40) agonist mitazalimab combined with modified FOLFIRINOX (mFOLFIRINOX), in chemotherapy-naive patients with mPDAC. Patients receive an initial dose of mitazalimab one week before starting biweekly cycles of mFOLFIRINOX plus mitazalimab. The study meets its pre-specified primary endpoint, achieving a confirmed objective response rate (ORR) of 42.1%. Median duration of response, progression-free survival, and overall survival was 12.6 months, 7.7 months, and 14.9 months, respectively. Multi-omic analyses of tumor and blood specimens identify a baseline tumor-intrinsic gene signature related to fibrosis associated with improved survival. Additionally, mitazalimab-induced increases in activated circulating myeloid, B cell, and T cell frequencies correlate with better outcomes. These results may inform future patient stratification strategies supporting a planned randomized confirmatory trial of mitazalimab with mFOLFIRINOX in mPDAC. This study was registered at ClinicalTrials.gov (NCT04888312).

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
biomarker, CD40 agonist, chemotherapy, classical mPDAC, ctKRAS, immunotherapy, mFOLFIRINOX, mitazalimab, mPDAC, tumor microenvironment
in
Cell Reports Medicine
volume
6
issue
10
article number
102407
publisher
Cell Press
external identifiers
  • scopus:105019822120
  • pmid:41061701
  • pmid:41061701
ISSN
2666-3791
DOI
10.1016/j.xcrm.2025.102407
language
English
LU publication?
yes
id
606b1b76-8b80-4249-af39-4ad5a7293c68
date added to LUP
2025-10-13 09:15:44
date last changed
2025-11-06 14:22:51
@article{606b1b76-8b80-4249-af39-4ad5a7293c68,
  abstract     = {{<p>Response determinants to immunotherapy in metastatic pancreatic ductal adenocarcinoma (mPDAC) remain unclear, limiting treatment advancements. We report a single-arm phase 1b/2 study (OPTIMIZE-1) evaluating the safety and efficacy of the cluster of differentiation 40 (CD40) agonist mitazalimab combined with modified FOLFIRINOX (mFOLFIRINOX), in chemotherapy-naive patients with mPDAC. Patients receive an initial dose of mitazalimab one week before starting biweekly cycles of mFOLFIRINOX plus mitazalimab. The study meets its pre-specified primary endpoint, achieving a confirmed objective response rate (ORR) of 42.1%. Median duration of response, progression-free survival, and overall survival was 12.6 months, 7.7 months, and 14.9 months, respectively. Multi-omic analyses of tumor and blood specimens identify a baseline tumor-intrinsic gene signature related to fibrosis associated with improved survival. Additionally, mitazalimab-induced increases in activated circulating myeloid, B cell, and T cell frequencies correlate with better outcomes. These results may inform future patient stratification strategies supporting a planned randomized confirmatory trial of mitazalimab with mFOLFIRINOX in mPDAC. This study was registered at ClinicalTrials.gov (NCT04888312).</p>}},
  author       = {{Van Laethem, Jean-Luc and Geboes, Karen and Borbath, Ivan and Macarulla Mercade, Teresa and Lambert, Aurélien and Cassier, Philippe and Prenen, Hans and Mitry, Emmanuel and Blanc, Jean-Frédéric and Pilla, Lorenzo and Feliu, Jaime and Rodriguez Garrote, Mercedes and Pazo-Cid, Roberto Antonio and Gallego, Inmaculada and Smith, Karin Enell and Nordbladh, Karin and Jimenez, David Gomez and Ellmark, Peter and Pico de Coaña, Yago and Ambarkhane, Sumeet Vijay and Beatty, Gregory L and O'Reilly, Eileen M}},
  issn         = {{2666-3791}},
  keywords     = {{biomarker; CD40 agonist; chemotherapy; classical mPDAC; ctKRAS; immunotherapy; mFOLFIRINOX; mitazalimab; mPDAC; tumor microenvironment}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{10}},
  publisher    = {{Cell Press}},
  series       = {{Cell Reports Medicine}},
  title        = {{CD40 agonist mitazalimab with mFOLFIRINOX in untreated metastatic pancreatic cancer : Biomarkers associated with outcomes from OPTIMIZE-1}},
  url          = {{http://dx.doi.org/10.1016/j.xcrm.2025.102407}},
  doi          = {{10.1016/j.xcrm.2025.102407}},
  volume       = {{6}},
  year         = {{2025}},
}