Background: L-type amino acid transporter 1 (LAT1, SLC7A5) is overexpressed in cancer cells, leading to aggressive proliferation and lymphatic metastases. In a placebo-controlled, randomized phase 2 trial involving patients with pre-treated, advanced, refractory biliary tract cancer (BTC), monotherapy with nanvuranlat (JPH203), a selective LAT1 inhibitor, demonstrated a significant improvement in progression free survival (PFS) as the primary endpoint compared to placebo. The safety profile was comparable between nanvuranlat and placebo treated patients, except for a higher rate of cholangitis in the nanvuranlat group. Nanvuranlat is metabolized to its main inactive, off-target metabolite, Nac-JPH203 by N-acetyl transferase 2 (NAT2). Since the NAT2 unknown patients mislead the benefit and risk ratio of nanvuranlat treatment, an ad-hoc analysis was conducted in enriched NAT2 non-rapid (NR) phenotype patients who slowly produced Nac-JPH203 in plasma. Methods: Among 104 (full analytical set (FAS) - nanvuranlat:69 & placebo:35) enrolled patients, 25 with unknown NAT2 phenotype were enrolled prior to an amendment to only enroll NAT2-NR phenotype. Subsequently, further analysis was conducted to determine the NAT2 phenotypes of these 25 patients. Results: Among the 25 NAT2 unknown patients, 16 and 9 patients were assigned to nanvuranlat or placebo, respectively. NAT2ad hoc analysis recorded those 9 patients in nanvuranlat and 5 in placebo as NAT2 NR, and 7 patients in nanvuranlat and 4 in placebo were NAT2 rapid (R). As a result, number of NAT2 NR patients was increased from 81 to 94. Efficacy analysis of this enriched population (FAS-NR-nanvuranlat:63 & placebo:31) revealed a significant improvement in PFS. With respect to cholangitis, 8 all-grade (12.7%) and 7 over grade 3 (11.1%) were documented in the FAS-NR population. In the FAS-R population, 2 all grades (28.5%) and 2 over grade 3 (28.5%) were observed (Table). Conclusions: By classifying BTC patients by NAT2 phenotype in this ad hoc analysis, the LAT1 inhibitor nanvuranlat further improved its clinical efficacy and safety in the NAT2 NR population. Therefore, selecting NAT2 NR for nanvuranlat treatment may improve the risk -benefit ratio. Clinical trial information: UMIN000034080.

*One-sided p value.