A phase III randomized study of first-line NUC-1031/cisplatin vs. gemcitabine/cisplatin in advanced biliary tract cancer
- PMID: 39978598
- DOI: 10.1016/j.jhep.2025.01.040
A phase III randomized study of first-line NUC-1031/cisplatin vs. gemcitabine/cisplatin in advanced biliary tract cancer
Abstract
Background & 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. 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 (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 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). 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.
Impact and implications: Although clinical practice guidelines identified gemcitabine plus cisplatin as standard of care for advanced biliary tract cancer (aBTC) based on 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 for 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.
Trial registration: ClinicalTrials.gov Identifier: NCT04163900.
Keywords: biliary tract cancer; chemotherapy; first-line.
Copyright © 2025 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Conflict of interest statement
Conflict of interest MMN: Received research grant support from Servier, NuCana and Astra Zeneca and travel and accommodation support from Ipsen. JRS: Received consulting fees from NuCana. JJK: Received research grant support from Ipsen and Roche and consulting fees from Astra Zeneca, Ibsen, Roche, and Incyte. Has leadership roles at the Cholangiocarcinoma Foundation and the Canadian Clinical Trials Group. JWV: Consulting or Advisory role for AstraZeneca, Incyte, Taiho, Servier, Jazz, RedX Pharma, and Cogent. Payment for expert testimony from Oncosil. Participation on a DSMB/advisory board for Incyte and Servier. Received grants to his institution from AstraZeneca. Has a leadership role at the Cholangiocarcinoma Foundation (CMO). DYO: Received research grant support from AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD and Handok. Served on advisory boards for AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA, MSD, LG Chem, Astellas, Abbvie, J-Pharma, Mirati Therapeutics, Eutilex, Moderna and Idience. CB: Received honoraria as speaker (AstraZeneca, Incyte) and consultant (Servier, Boehringer Ingelheim, AstraZeneca, Jazz Therapeutics, Taiho, Molecular partners). Received research funds (Avacta, Medannex, Servier) and her spouse is an employee of AstraZeneca. CS: Served on advisory boards for AstraZeneca, Bayer, BMS, Incyte, MSD, Roche, Servier, and Taiho. DHP: Received research grant support, drugs for research, and travel and accommodation support from NuCana. AC: Received consulting fees from Incyte and AstraZeneca. PJR: Received grant support from Sanofi, travel and accommodation support from Merck Serono, Servier and Takeda, consulting fees from Amgen, and honoraria from Merck Serono. Served on advisory boards for AstraZeneca, BMS, Eisai, Taiho and Takeda and owns stock in Perci Health. KMS: Received honoraria as a member of advisory boards for BMS, Servier, and Astellas Pharma, as chair of an educational session (MSD), and membership of IDSMC (Novotech) within the last 36 months. She received consulting fees from Glenmark Specialty SA. Her institution has received untied educational grants for unrelated work from Bayer, Lisata and Amgen within the same time period. LG: reports consulting roles with AbbVie, AstraZeneca (DSMB), Boehringer Ingelheim, Compass Therapeutics, Exelixis, Kinnate Biopharma, Merck, Relay Therapeutics, Servier, Taiho, TransThera Biosciences, and Tyra Biosciences, and contracted work with her institution for Alyssum Therapeutics, AstraZeneca, Boehringer Ingelheim, and Genentech. HV served on a speakers’ bureau for AstraZeneca and received support for attending meetings from Merck. VB received consulting fees/honoraria from, and participated on a DSMB/advisory board for, AstraZeneca, Bayer, Eisai, and Roche. JOP received research support from BMS (Celgene), MediRama, MedPacto, and Servier and meeting attendance support from Minneamrita Therapeutics. Received consulting fees from AstraZeneca, Daiichi Sankyo, MediRama, Servier, BMS, ImmuneOncia, and MSD. Participated on a DSMB/advisory board for Adicet Bio and Arcus Biosciences. RTS received consulting fees from Syros, Hookipa Pharma, AbbVie, and Elevar Therapeutics. Participated on advisory boards for AstraZeneca, BI, Clovis, Genentech, Merck, QED Therapeutics, Zymeworks, Astellas, Duo Oncology, FOG pharma, and Servier. Has research interests in Bayer, BMS, Exelixis pharma, IMV Inc, LOXO, Novocure, Pieris, Rafael pharma, and Seagen. JZ received research funding to his institution from AstraZeneca, BMS, Pfizer, IQVIA, Mylan, Ipsen, Eisai, Medtronic, MSD oncology, Servier, Astellas pharma, and Taiho Oncology. Received consulting fees from MSD, Specialized Therapeutics, Deciphera, Revolution Medicine, FivePHusion, Genorbio, 1Global, Novotech, Alloplex Biotherapeutics, NOUS Consulting, and Oncology Republic. Recevied support for meeting attendance from MSD Oncology, ICON Group and Praxis. Owns stock in Biomarin, Ophthea, Amarin, Frequency Therapeutics, Gilead, UniQure, Orphazyme, Moderna Therapeutics, Novovax, CSL, and Korro. All remaining authors have declared no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details.
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