Liver and Bile

J Hepatol. 2025;83(2):358-366

Knox JJ, McNamara MG, Bazin IS, Oh DY, Zubkov O, Breder V, Bai LY, Christie A, Goyal L, Cosgrove DP, Springfeld C, Sjoquist KM, Park JO, Verdaguer H, Braconi C, Ross PJ, De Gramont A, Shroff RT, Zalcberg JR, Palmer DH, Smith JR, Oelmann E, Bruce T, Valle JW

A phase 3 randomized study of first-line NUC-1031/cisplatin versus gemcitabine/cisplatin in advanced biliary tract cancer

Background and aims: The previous first-line standard of care for advanced biliary tract cancer (aBTC), gemcitabine/cisplatin, has modest efficacy. NUC-1031 is a phosphoramidate modification of gemcitabine. The authors report final analyses of the NuTide:121 study, designed to compare the efficacy of NUC-1031/cisplatin to gemcitabine/cisplatin in aBTC.
Methods: In this open-label, multicenter study, adult patients with treatment-naïve aBTC were randomized (1:1) to NUC-1031/cisplatin (n = 388) or gemcitabine/cisplatin (n = 385) on days 1 and 8 of 21-day cycles until disease progression or intolerance. Primary endpoints were overall survival (OS) and objective response rate (blinded independent central review). Three interim analyses (IA) and a final analysis were planned.
Results: Baseline characteristics were balanced; median age 65 years, 53% male, primary tumors: intrahepatic cholangiocarcinoma (CCA) (54%), extrahepatic CCA (21%), gallbladder cancer (21%) and ampullary cancer (5%). Enrollment stopped at IA1 as the OS futility boundary was crossed. At final data cut-off, median OS for NUC-1031/cisplatin versus gemcitabine/cisplatin was 9.2 months (95% CI: 8.3–10.4) versus 12.6 months (95% CI: 11.0–15.1) (HR = 1.79) and median PFS was 4.9 months (95% CI: 4.4–6.0) versus 6.4 months (95% CI: 6.1–7.4) (HR = 1.45). Objective response rate was higher for NUC-1031/cisplatin (18.7% vs. 12.4%; OR = 1.59; p = 0.049). The adverse event profile was similar between arms, except for hepatobiliary disorders (25% vs. 11%; higher with NUC-1031/cisplatin) and hematological events (48% vs. 65%; higher with gemcitabine/cisplatin). More patients met criteria for potential drug-induced liver injury (27% vs. 7%) and Hy’s law (1.6% vs. 0.5%) with NUC-1031/cisplatin. Treatment exposure was lower for NUC-1031/cisplatin, likely due to early discontinuation for AEs (30% vs. 18%).

Conclusions: NuTide:121 was terminated early due to futility. NUC-1031/cisplatin did not set a new standard in first-line aBTC.

DOI:  10.1016/j.jhep.2025.01.040