The effect of adding a selective FAK inhibitor AMP945 to FOLFIRINOX in a model of pancreatic cancer.

Abstract

e15128 Background: Pancreatic Cancer (PC) is a one of the leading causes of cancer-related death in the world, with a five-year survival rate of ~11%. The majority of patients present with advanced metastatic disease and are treated with chemotherapy. FOLFIRINOX is the standard-of-care treatment for patients in many countries and has been shown to result in a median overall survival of 11.1 months. Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase which transduces signaling from integrin receptors, activated through interactions with the extracellular matrix, to regulate cell survival, proliferation and migration, and is often highly expressed in PC. Inhibition of FAK in preclinical models of PC has been shown to sensitize cells to radiotherapy, immunotherapy and chemotherapy. AMP945 is a potent and selective FAK inhibitor currently undergoing a Phase Ib/IIa trial in PC in combination with gemcitabine and nab-paclitaxel (NCT05355298). We now demonstrate that AMP945, in combination with FOLFIRINOX, can significantly improve survival in mouse models of PC, providing strong rationale for clinical testing of this novel treatment combination. Methods: Patient Derived Xenograft (PDX) models of PC in NOGIL2 mice using TKCC10lo patient derived cells were conducted in both subcutaneous and orthotopic formats. Once the tumor was palpable, AMP945 (10 mg/kg, b.i.d.) was administered for four days. On day 8 oxaliplatin (5 mg/kg) and irinotecan (25 mg/kg) were administered, with leucovorin calcium (100 mg/kg) and fluorouracil (25 mg/kg) being dosed on day 9. The mice were monitored until day 12 and the treatment regimen was repeated for up to 20 cycles, or until the experimental endpoint was reached. At the experimental endpoint the mice were sacrificed, the tumor harvested and analyzed. Results: In the subcutaneous model the combination of AMP945 and FOLFIRINOX increased survival by ~35% compared to FOLFIRINOX alone. In the orthotopic model, median survival was extended by ~30% when using the AMP945/FOLFIRINOX combination, compared to FOLFIRINOX alone. In both models there was a significant reduction in tumor size and clear evidence of on-target FAK inhibition in tumors (reduction in pY397FAK levels) in the combination therapy groups. Notably, a significant increase in cleaved caspase-3, a marker of apoptosis, was also apparent in the combination therapy groups. Conclusions: The FAK inhibitor AMP945, given in a pulsed-dosing regimen in combination with FOLFIRINOX, significantly enhances survival in a mouse model of pancreatic cancer by increasing apoptosis and reducing tumor burden, highlighting the potential of this combination in clinical treatment of PC. A clinical study of the combination of AMP945 with FOLFIRINOX is now in planning.