Motixafortide, cemiplimab, gemcitabine and nab-paclitaxel in metastatic pancreatic cancer: a single-arm phase 2 study with single-cell correlatives

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 (PDA). Building on our preclinical data, we conducted the first stage of an open-label, single-arm phase 2 clinical trial combining CXCR4 inhibition (motixafortide), PD-1 blockade (cemiplimab), and chemotherapy (gemcitabine/nab-paclitaxel [GN]; MCGN) in 11 treatment-naïve patients with metastatic PDA (NCT04543071). The primary endpoint, objective response rate, was 64% partial response and 55% confirmed partial response per Response Evaluation Criteria in Solid Tumors. Secondary endpoints include median progression-free survival of 9.7 months (95% confidence interval [CI]: 5.9-not reached [NR]), overall survival of 10.1 months (95% CI: 9.3-NR), duration of response of 8.2 months, and 91% disease control rate. 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 relative to resistant patients. MCGN also induced tumor inflammation as confirmed by tissue staining and T cell rescue. A multicenter randomized phase 2 trial comparing MCGN to GN in patients with treatment-naïve metastatic PDA is ongoing. The CXCR4-CXCL12 axis drives immune exclusion and immunosuppression in pancreatic cancer. Here, the authors report a single-arm phase 2 study of metastatic pancreatic cancer evaluating motixafortide (CXCR4 inhibitor), cemiplimab (PD-1 blockade) and chemotherapy, reporting a 64% response rate and 91% disease control, with CXCL12+ fibroblasts and T-cell changes linked to response.