Abstract
Background and Aims: The previous first-line standard of care for advanced biliary tract cancer (aBTC), gemcitabine/cisplatin, had modest efficacy. NUC-1031 is a phosphoramidate modification of gemcitabine. We 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 (ORR; 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: intra-hepatic cholangiocarcinoma (CCA) (54%), extra-hepatic CCA (21%), gallbladder (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 vs gemcitabine/cisplatin was 9.2 months (95%CI: 8.3–10.4) vs 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) vs 6.4 months (95%CI: 6.1–7.4) (HR 1.45). ORR 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.
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 (ORR; 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: intra-hepatic cholangiocarcinoma (CCA) (54%), extra-hepatic CCA (21%), gallbladder (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 vs gemcitabine/cisplatin was 9.2 months (95%CI: 8.3–10.4) vs 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) vs 6.4 months (95%CI: 6.1–7.4) (HR 1.45). ORR 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.
| Original language | English |
|---|---|
| Journal | Journal of Hepatology |
| Early online date | 18 Feb 2025 |
| DOIs | |
| Publication status | E-pub ahead of print - 18 Feb 2025 |
Keywords
- chemotherapy
- first-line
- biliary tract cancer
