Multicenter phase 2 study of motixafortide, cemiplimab, gemcitabine and nab-paclitaxel for metastatic PDAC

The C-X-C motif chemokine receptor 4 (CXCR4)/C-X-C motif chemokine ligand 12 (CXCL12) axis drives immune exclusion in pancreatic ductal adenocarcinoma (PDAC). A multicenter phase 2 trial in the US evaluated the combination of CXCR4 inhibition with motixafortide, PD-1 blockade with cemiplimab, and gemcitabine plus nab-paclitaxel (MCGN) in 11 treatment-naïve patients with metastatic PDAC. The primary endpoint, objective response rate, was 64% partial response and 55% confirmed partial response per RECIST. Secondary endpoints included median progression-free survival of 9.7 months (95% CI 5.9-NR), median overall survival of 10.1 months (9.3-NR), duration of response 8.2 months, and disease control rate of 91%. One patient achieved a pathological complete response after pancreatoduodenectomy and hepatectomy, remaining disease-free for 18 months without adjuvant therapy. Exploratory single-nucleus RNA-sequencing of serial biopsies showed reduced tumor heterogeneity, depletion of epithelial-to-mesenchymal transitional states, and enrichment of CXCL12+ cancer-associated fibroblasts in responders compared with resistant patients. MCGN als induced tumor inflammation as confirmed by tissue staining and T cell rescue. A multicenter phase 2 trial comparing MCGN to GN chemotherapy in patients with treatment-naïve metastatic PDAC is ongoing.