Murphy, K. J.; Chambers, C. R.; Reed, D. A.; Channon, L. M.; Mills, N. E.; McKay, S. E.; Lee, V.; Howell, A. E.; Tran, A. M.; Nobis, M.; Magenau, A.; Stoehr, J.; Pereira, B. A.; Kuepper, N.; Ritchie, S.; Gordon, K.; Trpceski, M.; Tyma, V. M.; Hafiz, S.; Johri, V.; Ang, A.; Barkauskas, D. S.; Vennin, C.; Wang, X. Q.; Naeini, M. M.; Meyer, B.; Parker, A. L.; Gummadi, S.; Chitti, S. V.; Chacon Fajardo, D.; Zaratzian, A.; Tayao, M.; Da Silva, A.; Australian Pancreatic Genome Initiative (APGI), ; Australian Pancreatic Matrix Atlas (APMA), ; Cesare, A. J.; Mathivanan, S.; Stirzaker, C.; Latham, S.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a particularly lethal malignancy with few treatment options available. Extensive remodelling of extracellular matrix (ECM) generates a highly fibrotic tumour landscape, which impairs therapeutic response. Objective: We investigated whether stromal priming via the highly specific Focal Adhesion Kinase (FAK) inhibitor narmafotinib (AMP945) in combination with the two major standard-of-care chemotherapies in PDAC, gemcitabine/Abraxane and FOLFIRINOX, reduces fibrosis and enhances treatment efficacy. Design: 3D organotypic matrices, intravital imaging, and in vivo subcutaneous and orthotopic PDAC models were used to provide a rationale for a first-line priming regimen of narmafotinib prior to chemotherapy. Results: Neoadjuvant chemotherapy induces fibrosis in PDAC indicating a need for upfront first-line priming of the ECM to normalise the stroma for optimal treatment response. Narmafotinib is a new potent small molecule FAK inhibitor. Phase I safety data shows excellent safety, tolerability, and pharmacokinetics following oral administration in humans. We reveal that narmafotinib treatment during early ECM remodelling (priming) reduces fibrosis, while limiting subsequent PDAC invasion. Moreover, intravital imaging demonstrates real-time FAK inactivation and cell cycle stalling, leading to improved chemotherapeutic efficacy upon narmafotinib priming in vivo. Long-term assessment in patient-derived models shows that narmafotinib priming prior to gemcitabine/Abraxane or FOLFIRINOX reduces PDAC progression and extends survival in both chemotherapy settings. Conclusions: Our results using these Phase II-ready drug combinations strongly support the clinical assessment of narmafotinib in PDAC. Narmafotinib is currently in Phase Ib/IIa trials, assessing a pulsed dosing regimen prior to gemcitabine/Abraxane, and warrants further clinical assessment in combination with FOLFIRINOX.