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.
Junji Furuse, Masafumi Ikeda, Makoto Ueno, Masayuki Furukawa, Chigusa Morizane, Tetsuo Takehara, Tomohiro Nishina, Akiko Todaka, Naohiro Okano, Kazuo Hara, Yousuke Nakai, Kazuyoshi Ohkawa, Takashi Sasaki, Kazuya Sugimori, Naoyuki Yokoyama, Kouji Yamamoto
Abstract
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 .