Nanvuranlat Linked To Better PFS Compared With Placebo in Patients With Pretreated, Advanced BTC


Nanvuranlat inspired better progression-free survival in patients with advanced, pretreated refractory biliary tract cancer, meeting the primary end point of a phase 2 trial.

Nanvuranlat, (JPH203), a first-in-class LAT1 inhibitor, was associated with a superior progression-free survival rate in patients with advanced, pretreated refractory biliary tract cancer (BTC) compared with placebo, according to findings from a phase 2 trial (UMIN000034080).

Data presented at the 2023 Gastrointestinal Cancers Symposium showed that the hazard ratio (HR) for progression-free survival (PFS) by blinded independent central review was 0.557 (95% CI, 0.3435-0.9029; P = .0164) in favor of nanvuranlat. The disease control rate (DCR) across all BTC subtypes was 24.6% in the nanvuranlat group (n = 69) compared with 11.4% in the placebo group (n = 35).

The DCR achieved with nanvuranlat was higher in patients with extrahepatic cholangiocarcinoma (20.0% vs 0.0%), gallbladder cancer (31.3% vs 0.0%), and ampulla of Vater (27.3% vs 0.0%) who were assigned to the experimental arm vs the control arm. Conversely, the DCR was slightly worse for those with intrahepatic disease who received nanvuranlat compared with placebo (22.2% vs 23.5%).

“The forest plot of PFS demonstrated favor to nanvuranlat in every subgroup—especially in [those with] extrahepatic cholangiocarcinoma and gallbladder cancer,” Junji Furuse, MD, PhD, lead study author and a professor in the Department of Medical Oncology at Japan’s Kyorin University School of Medicine, said in his presentation of the data. “This is a first uncontrolled clinical trial in which nanvuranlat, [a] LAT1 inhibitor, demonstrated statistically significant PFS improvement over placebo.”

Overexpression of LAT1 in cancer cells supports aggressive proliferation and has been identified as a predictor of poor prognosis in patients with various cancer types, including BTC. Data from a dose-escalation phase 1 study of nanvuranlat done in patients with solid tumors showed that the investigative agent had the highest DCR in the 5 patients with BTC.

These data supported the launch of the phase 2 trial done specifically in those with BTC (n = 104). To be eligible for enrollment, patients were required to be 20 years of age or older and have intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer, or ampulla of Vater. All were refractory to, or intolerant of, standard chemotherapy and other investigational agents and had a performance status of 0 or 1. Patients with non-rapid acetylators via N-acetyltransferase 2 (NAT2) were selected to maximize the safety and efficacy of nanvuranlat.

Patients were randomly assigned 2:1 to nanvuranlat given at a daily dose of 25 mg/m2 for 5 consecutive days, followed by 9 days of rest (n = 69) vs placebo in the same cycle (n = 35).

Stratification factors included BTC subtype (intrahepatic cholangiocarcinoma vs extrahepatic cholangiocarcinoma vs gallbladder cancer vs ampulla of Vater) and whether patients underwent resection (yes vs no).

The primary end point of the trial was PFS as assessed by BICR using RECIST v1.1 criteria. DCR served as a key secondary end point.

The demographics and baseline characteristics were well balanced between the 2 groups, according to Furuse. Forty-five patients (65%) in the experimental group were aged 65 years or older compared with 16 patients (46%) in the placebo arm. Roughly half of patients in both groups (52% vs 51%) had undergone prior primary resection.

At baseline, 93% of patients in the experimental group had metastatic disease compared with 91% in the placebo group. Intrahepatic cholangiocarcinoma was the most common BTC subtype in the experimental group (40%), followed by gallbladder cancer (23%), extrahepatic cholangiocarcinoma (21%), and ampulla of Vater (16%); in the placebo group, these rates were 49%, 23%, 17%, and 11%, respectively. Twenty-seven patients (39%) in the experimental arm received 3 or more previous treatments compared with 14 patients (40%) in the placebo arm.

Nanvuranlat was generally well tolerated. Grade 3 or greater adverse effects (AEs) were rare, except for cholangitis. Nine patients (12.9%) who received nanvuranlat experienced grade 3 or higher cholangitis and 7 patients (10.0%) experienced the condition as a serious AE (SAE).

No more than 1 patient in the placebo arm experienced a given grade 3 or greater AE. Similarly, no more than 1 patient experienced a given SAE.

“Nanvuranlat demonstrated a cleaner safety profile comparable to that of the placebo group,” Furuse concluded.

Editor’s Note: Furuse received honoraria from Astellas Pharma; AstraZeneca; Bayer Yakuhin; Chugai Pharma; Daiichi Sankyo; EA Pharma; Eisai; Fujifilm; Kyowa Hakko Kirin; Lilly Japan; Merck; MSD; Mylan; Nihon Servier; Novartis; Ono Pharmaceutical; Pfizer; Sanofi; Taiho Pharmaceutical; Takeda; Teijin Pharma; Yakult Honsha. Furuse has a consulting or advisory role with Astellas Pharma; AstraZeneca; Chugai Pharma; Eisai; Fujifilm; J-Pharma; Merck; MSD; Mundipharma; OncoTherapy Science; Ono Pharmaceutical; Takara Bio; Yakult Honsha. He also received research funding from Astellas Pharma (Inst); AstraZeneca (Inst); Bayer (Inst); Chugai Pharma (Inst); Daiichi Sankyo (Inst); Eisai (Inst); Incyte (Inst); J-Pharma (Inst); Merck (Inst); MSD (Inst); Ono Pharmaceutical (Inst); Sanofi (Inst); Sumitomo Dainippon (Inst); Taiho Pharmaceutical (Inst); Takeda (Inst); Yakult Honsha (Inst).


Furse J, Ikeda M, Ueno M, et al. 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. J Clin Oncol. 2023;41(suppl 4):494. doi:10.1200/JCO.2023.41.4_suppl.494

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