A phase III randomised study of first-line NUC-1031/cisplatin vs. gemcitabine/cisplatin in advanced biliary tract cancer

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.

Trial Registration

ClinicalTrials.gov Identifier: NCT04163900

Impact and Implications

Advanced biliary tract cancers remain in need of substantial therapeutic improvement. Although clinical practice guidelines identified gemcitabine plus cisplatin as the standard of care on the basis of clinical studies, the modest efficacy observed with this regimen highlighted the urgent need for more effective therapies. NuTide:121, one of the largest randomized interventional studies conducted in the first-line aBTC population to date, compared the combination of cisplatin with NUC-1031, a phosphoramidate form of gemcitabine, with the standard of care regimen. Despite a higher response rate in the NUC-1031/cisplatin arm, the study was terminated early based on a futility assessment of OS. Early toxicity and in particular liver injury likely contributed to the regimen's failure. This study emphasized some important challenges in study design and further confirmed the difficulties of advancing treatment options in this vulnerable patient population.