CheMo4METPANC: Combination chemotherapy (gemcitabine and nab-paclitaxel), chemokine (C-X-C) motif receptor 4 inhibitor (motixafortide), and immune checkpoint blockade (cemiplimab) in metastatic treatment-naïve pancreatic adenocarcinoma—Updated clinical and translational findings.

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4167 Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) is a uniformly fatal disease with an immunosuppressive tumor microenvironment (TME). In our KPC mouse model study, targeting the C-X-C motif chemokine receptor 4 (CXCR4)/C-X-C motif chemokine ligand 12 (CXCL12) axis in combination with αPD-1, and gemcitabine improved survival when compared to mice treated with gemcitabine or other combinations. The goal of this first-in-human study was to evaluate safety, radiologic response rate, and change in tumor microenvironment (TME) elicited by motixafortide (CXCR4i), cemiplimab (αPD1), gemcitabine, and nab-paclitaxel (MCGN) in treatment-naïve mPDAC. Methods: CheMo4METPANC is an open label, multicenter, investigator-initiated, study evaluating MCGN in mPDAC (NCT04543071). Here we report the updated results of the signal seeking phase of this study. The primary aim was to study the safety of MCGN. All patients received pre- on-treatment and optional on-progression biopsies. Single nucleus RNA sequencing (snRNAseq) and quantitative multiplex immunofluorescence (qmIF) were used to characterize the TME. Results: A total of 11 patients (1 over-enrolled) participated in the study at Columbia and Brown Universities (11/9/2020-3/3/2023). The median age was 58 years. As of 04/22/24 (median follow up 23 months), 7 (63%) and 3 (27%) patients experienced a partial response (PR) and stable disease, respectively. One patient experienced radiologic resolution of hepatic metastasis and underwent definitive radiation therapy to the primary tumor. A second had a sustained PR (11 months) and underwent pancreaticoduodenectomy and hepatic wedge resection which revealed a pathologic complete response within the hepatic and primary lesion. Median progression free survival (PFS) was 9.6 months. The most common adverse events experienced while on the study combination included skin hyperpigmentation (11/11), alopecia (10/11) and injection site reaction (9/11). The most common grade 3 or greater adverse events were anemia (5/11) and rash (3/11). Analysis of the TME revealed an increase in intratumoral CD8+ T-cells in all patients, and that patients achieving a PR were found to have higher proportions pre-treatment of CXCL12-producing cancer associated fibroblasts, a potential marker of response. Conclusions: Preliminary results from this pilot study of MCGN in mPDAC were promising, with a PR rate of 63% and disease control rate (DCR) of 91%. Based on these results, the study was amended to transition to a randomized phase 2 trial testing MCGN compared to GN (2:1; N = 108). The primary endpoint is PFS. The phase 2 study is actively enrolling patients and incorporates optional paired research tumor biopsies. Clinical trial information: NCT04543071 .

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