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

Abstract

2624 Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) has a 5-year overall survival (OS) rate of less than 5% and remains a leading cause of cancer related mortality. Mitazalimab, a human CD40 agonistic IgG1 antibody, activates CD40 signaling in myeloid cells, enhancing tumor sensitivity to chemotherapy and licensing dendritic cells to prime and activate tumor-specific T cells. The OPTIMIZE-1 Phase 1b/2 trial evaluated the safety and efficacy of mitazalimab combined with mFOLFIRINOX (mFFX) in treatment naïve mPDAC patients (pts) (Van Laethem 2024). This combination therapy has shown promising clinical efficacy compared to historical controls with a median OS of 14.9 months, median duration of response of 12.6 months, median progression free survival of 7.7 months, and an overall response rate of 54.4 % (42.1% confirmed) (Geboes, 2024). 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. Associations between survival benefits and both baseline and on treatment biomarkers (RNAseq data from tumor biopsies and longitudinal circulating tumor KRAS (ctKRAS) data) were assessed in patients from the full analysis set (n = 57) treated with 900 µg/kg mitazalimab. Results: Differential gene expression analysis (DGEA) identified a fibrosis-related gene signature (including genes involved in extracellular matrix (ECM) remodeling) that correlated with improved OS (p = 0.002). Conversely, a distinct gene signature linked to chemoresistance mechanisms involved in the inactivation and secretion of mFFX components was associated with shorter OS. Comparing DGEA of three on-treatment biopsies from patients with partial response to baseline samples revealed treatment-induced tumor changes. These analyses identified upregulation of genes involved in myeloid cell biology and regulation of T cell responses, along with downregulation of immunosuppressive genes. Longitudinal data analyses revealed that ctKRAS clearance was reached by 72% of pts and was significantly associated with longer OS. Molecular response was also associated with longer OS and predicted radiological response with 76.7% accuracy (sensitivity 72.7%, specificity 81.0%). Further, molecular progression was significantly associated with OS and predicted radiological response with 62.8% accuracy (sensitivity 71.4%, specificity 58.6%). Conclusions: A potentially predictive fibrosis-related gene signature, directly linked to mitazalimab’s mode of action, was associated with improved OS. Biomarker correlations further suggest a mitazalimab-driven contribution to clinical benefits in the OPTIMIZE-1 trial. These encouraging results will inform the planned randomized confirmatory trial of mitazalimab in combination with mFFX in mPDAC. Clinical trial information: NCT04888312 .