Predictive Markers of Response to and Treatment Effects of Motixafortide, Cemiplimab, Gemcitabine and Nab-Paclitaxel in Treatment Naïve Metastatic Pancreatic Cancer - PROJECT SUMMARY/ABSTRACT Combination chemotherapy is the standard of care in treatment-naïve metastatic pancreatic adenocarcinoma (mPDA), and the addition of immune checkpoint blockade has failed to improve outcomes. The C-X-C motif chemokine receptor 4 (CXCR4)/C-X-C motif chemokine ligand 12 (CXCL12) axis contributes to the exclusion of anti-tumor immune cells from the tumor microenvironment (TME) in mPDA. We recently conducted a phase I study of motixafortide (CXCR4 inhibitor), cemiplimab (anti-PD1), gemcitabine and nab-paclitaxel (MCGN) in 11 patients with treatment-naïve mPDA, demonstrating promising, durable clinical efficacy with an objective response rate of 64% (7/11). Using single nucleus RNA sequencing (snRNAseq) analyses of pre-treatment biopsy samples, we demonstrated that CXCL12-producing cancer associated fibroblasts (CAFs) were more abundant in patients with a better response to therapy. These CXCL12-producing CAFs belonged to a CAF subtype displaying a ‘pro-axonogenic’ gene expression signature, enriched in axon guidance and axonogenic programs. We are now conducting a phase II, investigator-initiated, multicenter, randomized controlled trial (RCT) to evaluate this novel immunotherapeutic approach. This trial compares MCGN (N=72) with gemcitabine and nab-paclitaxel (GN, N=36) in treatment-naïve mPDA. The primary endpoint of the trial is progression free survival and secondary endpoints include response rate, disease control rate, duration of clinical benefit and overall survival. We also seek mechanistic insight into response and resistance to these novel therapies. All patients will undergo pre-treatment biopsies which will be analyzed using quantitative multiplex immunofluorescence (qmIF) to categorize the abundance and spatial relationships of CAF, tumor and immune cell populations. This panel will categorize CXCL12-producing pro-axonogenic CAF populations, the drivers of CXCR4/CXCL12 pathway- mediated immunosuppression, to validate their abundance as a potential marker of preferential benefit from MCGN. A subset of patients in each arm of this trial will undergo on-treatment biopsies which will be used to characterize the impact of MCGN (N=21) and GN (N=10) on the TME. qmIF and snRNAseq will be performed on paired pre- and on-treatment biopsy specimens. The goal of this investigation is to evaluate for mechanisms of response and resistance. GN is one of the most commonly used regimens in mPDA, but its impact on the TME has not been evaluated prospectively. This study could lead to a better understanding of response and resistance mechanisms to GN and lead to promising therapeutic combinations. We hope to elucidate why immunotherapy has so far been ineffective in mPDA and whether there are patients for whom adding PD1 and CXCR4 inhibition to chemotherapy can improve outcomes.
