Narmafotinib (AMP945) in combination with gemcitabine and nab-paclitaxel as first-line treatment for patients with metastatic pancreatic cancer (ACCENT trial): Phase 2a results.

Abstract

735 Background: Narmafotinib is a potent and selective, orally bioavailable inhibitor of Focal Adhesion Kinase (FAK), a non-receptor tyrosine kinase over-expressed in pancreatic cancer (PCa) where it contributes to cell survival, proliferation, migration and chemoresistance playing a key role in tumor growth. FAK also contributes to multiple mechanisms underlying fibrosis and immunosuppression in the tumor microenvironment. Pre-clinically, narmafotinib combines with gemcitabine and nab-paclitaxel to reduce tumor burden, prolong sensitivity to chemotherapy and improve overall survival of treated animals. ACCENT is a Phase (P) 1b/2a trial of narmafotinib in combination with first-line gemcitabine and nab-paclitaxel (Gem/NabP), in metastatic PCa patients. P1b narmafotinib dose escalation was completed and 400 mg po mane was identified as the recommended P2 dose. We report the initial findings from the P2a study. Methods: Gem (1000 mg/m 2 ) and NabP (125 mg/m 2 ) were given on days 1, 8 and 15 of a conventional 28-day cycle. Patients also received narmafotinib (400 mg, p.o. mane) priming on days -8 to -2 of cycle 1 and then combined as 4-day pulses beginning on days 3, 10 and 24 of each 28-day chemotherapy cycle. The primary endpoint was investigator assessed objective response rate (ORR) by RECIST v1.1. Key secondary endpoints included adverse events (AEs, using NCI CTCAEv5.0), progression free survival (PFS) and overall survival (OS). A 2 stage Simon design was used, with null hypothesis that the true confirmed ORR is ≤23%. > 5/26 responses in stage I led to target recruitment of 50 patients, with type I error rate of 0.1 and power of 80% to identify a true response rate of 37%. Tumor imaging assessments were conducted every 2 months and evaluated using RECIST 1.1. Results: Between 16 Jan 2024 and 17 Feb 2025, 55 patients were enrolled in the P2a trial (7 sites in Australia, 5 in South Korea), all ECOG 0-1; median age 63.9; male: 51%. At data cut-off 20 July 2025, the confirmed ORR was 31%, including 1 complete remission. Combining all patients treated with 400 mg narmafotinib (P1b and 2a cohorts, N = 64), median PFS was 7.6 months. Most common AEs related to narmafotinib were nausea (29%), diarrhea (16%), vomiting (15%), fatigue (11%), gastroesophageal reflux (7%) and constipation (6%), which were predominantly grade 1-2 in severity. Only 2 patients (3.6%) had narmafotinib withdrawn due to a related AE. Toxicity was otherwise similar to that reported for chemotherapy alone. Conclusions: Narmafotinib combined with Gem/NabP was associated with manageable toxicity and the P2a study met its primary efficacy endpoint. OS data is awaited and further studies are planned. Clinical trial information: NCT05355298 .