Flash Talk + Poster Presentation 37th Lorne Cancer Conference 2025

Pulsed priming with narmafotinib reduces fibrosis and enhances both gemcitabine/Abraxane & FOLFIRINOX response in pancreatic cancer (#218)

Kendelle J Murphy 1 2 , Cecilia R Chambers 1 2 , Daniel A Reed 1 , Lily M Channon 1 , Victoria Lee 1 , Anna E Howell 1 , Max Nobis 1 2 , Astrid Magenau 1 2 , Janett Stoehr 1 , Brooke A Pereira 1 2 , Sophie McKay 1 , Ruth J Lyons 1 , Anthony J Gill 1 2 3 , Andrew V Biankin 4 , Jaswinder Samra 5 , Elizabth C Caldon 1 2 , Thomas Jeffry R Evans 4 6 , Lorraine Chantrill 1 7 , Lisa G Horvath 1 2 , Owen J Sansom 4 6 , Jennifer P Morton 4 6 , Tri G Phan 1 2 , Yingxiao Wang 8 , Terrie-Anne Cock 9 , Anthony Bishop 9 , Mark Devlin 9 , John Lambert 9 , Christopher J Burns 9 , Thomas R Cox 1 2 , Marina Pajic 1 2 , David Herrmann 1 2 , Paul Timpson 1 2
  1. Garvan Institute of Medical Research, Darlinghurst, Sydney, NEW SOUTH WALES, Australia
  2. St Vincents Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW, Australia
  3. Department of Anatomical Pathology, NSW Health Pathology, Royal North Shore Hospital, NSW, Australia
  4. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
  5. Department of Surgery, Royal North Shore Hospital, Sydney, NSW, Australia
  6. Cancer Research UK, Beatson Institute, Glasgow, UK
  7. Department of Medical Oncology, NSW Health, Illawarra Shoalhaven Local Health District, NSW, Australia
  8. Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angles, California, USA
  9. Amplia Therapeutics Limited, Melbourne, VIC, Australia

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with few treatment options currently available for patients. Extensive remodeling of extracellular matrix (ECM) generates a highly fibrotic tumor landscape, which impairs therapeutic response. Polychemotherapy regimens including gemcitabine/Abraxane and FOLFIRINOX are the standard-of-care for PDAC patients to extend survival but can also affect ECM deposition and remodeling, which may further drive PDAC fibrosis. Focal Adhesion Kinase (FAK) is known to regulate ECM-feedback response and fibrosis in cancer, presenting multiple modalities to reduce fibrosis and enhance therapeutic efficacy in PDAC. Narmafotinib(AMP945) is a potent, orally bioavailable small molecule inhibitor of FAK, currently Narmafotinib is currently under clinical investigation in Phase Ib/IIa trials (AMP945-PC-201 [ACCENT, NCT05355298]) in combination with gemcitabine and Abraxane (nab-paclitaxel) in PDAC patients.

Here, we present pre-clinical data on the efficacy of narmafotinib, in mouse and patient-derived models of PDAC. Using(3D)-organotypic matrices we reveal that FAK inhibition via narmafotinib during stromal remodeling (or ‘priming’) reduces fibrosis, while also limiting subsequent PDAC invasion. Moreover, intravital imaging of a Fluorescence Resonance Energy Transfer (FRET) biosensor of FAK activity and a FUCCI cell cycle reporter confirms FAK inactivation in live PDAC in real time and an improvement in chemotherapeutic efficacy, respectively, upon narmafotinib administration in vivo. Lastly, long-term assessment of narmafotinib priming prior to gemcitabine/Abraxane or FOLFIRINOX chemotherapy in patient-derived (xenograft) models demonstrates that narmafotinib priming reduces PDAC metastasis, progression and extends survival in both settings. The potential utility of narmafotinib is further supported by Phase I safety data (ACTRN12620000894998) showing excellent safety, tolerability, and pharmacokinetic properties following oral administration in human volunteers. Collectively, our pre-clinical results using this Phase II drug combination, strongly support the clinical assessment of narmafotinib in combination with chemotherapy in pancreatic cancer, which is currently ongoing in Phase Ib/IIa clinical trials, assessing a pulse dosing regimen of narmafotinib in combination with gemcitabine and Abraxane as first-line therapy in patients with unresectable or metastatic pancreatic cancer and warrants future assessment of narmafotinib in human PDAC patients.