Abstract A022: Combination benefit of treatment with focal adhesion kinase inhibitor narmafotinib and KRAS inhibitors

Abstract Narmafotinib (AMP945) is a potent and selective orally bioavailable inhibitor of Focal Adhesion Kinase (FAK). FAK is a non-receptor tyrosine kinase that acts through numerous signaling pathways to mediate communication between cells and their environment. Aberrant FAK signaling has been implicated in cancer progression and treatment resistance by promoting tumor growth and migration, immunosuppression and tumor fibrosis. FAK is frequently overexpressed in a variety of cancers, including pancreatic cancer (PCa), where high FAK expression correlates with poor prognosis. PCa is an aggressive malignancy, in which mutant KRAS is a key oncogenic driver in >90% of cases. Preclinically, narmafotinib improves responsiveness to standard-of-care (SOC) therapies. In PCa xenograft models, mice given narmafotinib combined with gemcitabine/nab-paclitaxel showed enhanced and prolonged sensitivity to chemotherapy, resulting in improved survival, compared to chemotherapy alone. Similarly ovarian cancer xenograft tumors treated with pegylated liposomal doxorubicin (PLD) combined with narmafotinib showed enhanced tumour reductions and expression profiling of these tumors (PLD combined with narmafotinib) identified enrichment of genes pertaining to the KRAS signalling pathways, suggesting that adding narmafotinib to standard therapy improves antitumor outcomes by disrupting the RAS/ERK/MAPK signalling axis and dampening the downstream c-Myc response. ACCENT clinical trial (NCT05355298) interim analysis of narmafotinib in combination with gemcitabine/nab-paclitaxel in first-line patients with metastatic PCa. shows a rapid and sustained reduction in tumor size, with a confirmed objective response rate of 33%, including 1 complete response. A mPFS of 7.6 months compares favorably to the historical mPFS of 5.5 months for gemcitabine/nab-paclitaxel alone in the benchmark MPACT trial. Narmafotinib is generally well tolerated with no evidence of increased Grade 3 and above adverse events compared to chemotherapy alone. The value of narmafotinib is not limited to combinations with chemotherapies. While KRAS inhibitors have shown efficacy in the clinic, issues with acquired drug resistance are evident. Studies show that treatment with KRASG12C inhibitors can result in excessive fibrogenesis and induce FAK hyperactivity ultimately leading to compromised drug responses. Recent approval of the beneficial combination of FAK inhibitor defactinib with Raf/MEK inhibitor avutometinib in KRAS mutant LGSOC further demonstrates the benefit of dual targeting FAK and RAS pathway signaling. Our preclinical studies show that narmafotinib inhibits cell growth across a range of PCa patient-derived organoids (PDOs) harboring different KRAS mutations with similar potency. Furthermore, co-treatment with narmafotinib increases tumor responsiveness to KRASG12C inhibitor adagrasib in xenograft tumor models. Further studies focused on the combination of narmafotinib with KRASG12D and pan-RAS inhibitors in both PDOs and in vivo models will be presented. Citation Format: Terrie-Anne Cock, Sarah Kinkel, Han Kyul Cho, Jiho Park, Braydon Meyer, Kendelle Murphy, Paul Timpson, Jason Lickliter, Christopher J. Burns, Sang Hyun Lee, Kyung Min Lee, Sang Hyub Lee. Combination benefit of treatment with focal adhesion kinase inhibitor narmafotinib and KRAS inhibitors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr A022.