Nanvuranlat, an L-type amino acid transporter (LAT1) inhibitor for patients with pretreated advanced refractory biliary tract cancer (BTC): Primary endpoint results of a randomized, double-blind, placebo-controlled phase 2 study.

494 Background: LAT1 is a transporter ( SLC7A5) of L-type amino acid. Overexpression in cancer cells supports aggressive proliferation. High expression of LAT1 in tumor specimens has been identified as a predictor of poor prognosis in patients with various cancer types, including BTC. The efficacy and safety of nanvuranlat (JPH203), a first-in-class, single agent that selectively inhibits LAT1, was evaluated in patients with pretreated, advanced, refractory BTC in a placebo-controlled randomized trial. Methods: Patients with four different subtypes of advanced BTC were enrolled: intrahepatic (IHC), extrahepatic (EHC), gallbladder (GBC) and ampulla of Vater (AVC). All were refractory to or intolerant of standard chemotherapy and other investigational medicines. Patients were pre-classified as non-rapid acetylators via N-acetyltransferase 2 ( NAT2), to maximize efficacy/safety by minimizing the metabolism of nanvuranlat. The primary endpoint was progression-free survival (PFS), assessed by blinded independent center review (BICR), using RECIST 1.1. Results: At data cut-off (February 28, 2022), 211 BTC patients were consented at 14 centers in Japan. Using NAT2 testing for classification, a total of 106 patients were randomized (2:1) to nanvuranlat (n = 70) or placebo (n = 36). Nanvuranlat met its primary endpoint and demonstrated a statistically significant improvement in PFS by BICR in comparison with the placebo group (Hazard Ratio = 0.557; 95% CI, 0.3435 – 0.9029; one-sided p = 0.0164). The disease control rate (DCR) in the nanvuranlat group was approximately 25% (average = 24.6%) across all BTC subtypes, while it was 11.4% in the placebo group. Grade 3 adverse events were reported in 30.0% for nanvuranlat vs 22.9% for placebo. Treatment-related adverse event rates were respectively 41.4% and 57.1% in the nanvuranlat and placebo groups. No patient had adverse events leading to nanvuranlat treatment discontinuation, dose reduction, or death. Conclusions: The study met the primary endpoint. LAT1 inhibitor monotherapy with nanvuranlat demonstrated useful clinical efficacy in patients with four different subtypes of pre-treated, advanced, refractory BTC. Safe and highly tolerated profile was also documented. Clinical trial information: UMIN000034080 .