Phase III study of NUC-1031 + cisplatin vs gemcitabine + cisplatin for first-line treatment of patients with advanced biliary tract cancer (NuTide:121)

Biliary tract cancer (BTC) carries a poor prognosis with limited treatment options. The accepted global standard of care chemotherapy backbone is gemcitabine + cisplatin (GemCis). NUC-1031 is a phosphoramidate transformation of gemcitabine, designed to overcome key shortcomings that limit its clinical effectiveness. NUC-1031 + cisplatin (NUC-1031+cis) was evaluated in a phase Ib study of 21 patients with advanced BTC. This study informed the recommended phase III dose demonstrating an encouraging ORR of 33%. NuTide:121 was a phase III, open-label, randomised study of NUC-1031+cis vs GemCis for first-line treatment of advanced BTC.

Patients ≥18 years with confirmed BTC (cholangiocarcinoma, gallbladder, ampullary), who had received no prior systemic chemotherapy for locally advanced/metastatic disease, were eligible. 828 patients were planned to be randomised (1:1) to either 725 mg/m 2 NUC-1031 or 1000 mg/m 2 gemcitabine, both with 25 mg/m 2 cisplatin (Day 1 & 8; 21-day cycle). Primary endpoints were OS and ORR. Secondary endpoints included PFS and safety. In addition to the final analysis, three interim analyses (IAs), were planned.

From Dec-2019 to Mar-2022, 773 patients were enrolled (ITT) with 761 patients comprising the safety population. NuTide:121 was conducted at 125 sites across 15 countries (North America, Europe and Asia Pacific). Demographic/baseline characteristics were well balanced across both arms; median age 65 years, 53.4% male and primary tumour locations of intra-hepatic (53.9%), extra-hepatic (21.0%), gallbladder (20.4%), and ampullary (4.7%). Prior to IA1, the IDMC reviewed safety on four occasions and recommended the study continue. Enrollment was stopped at IA1 (28-Feb-2022, per IDMC recommendation), as the futility boundary for OS was crossed. At final data cut-off (5-Apr-2022), median OS was 9.2 months (95% CI: 8.3-10.4) with NUC-1031+cis vs 12.6 months (11.0-15.1) with GemCis; HR 1.79. ORR by Blinded Independent Central Review (BICR) was 18.7% for NUC-1031+cis vs 12.4% for GemCis (odds ratio:1.59; 99%CI:0.86-2.94; p=0.049). PFS (BICR) was 4.9 months with NUC-1031+cis vs 6.4 months with GemCis (HR:1.45; 95% CI:1.18-1.7; p < 0.001). The Grade 3 or higher TEAE profile was similar across the two arms, with exception of: liver-related events [increased ALT (17.8% vs 3.4%) and AST (9.1% vs 2.4%), both higher in NUC-1031+cis], hepatobiliary disorders [cholangitis (3.4% vs 1.6%) and biliary obstruction (1.8% vs 0.3%), both higher in NUC-1031+cis]; and haematological [anaemia (9.4% vs 18.0%) and neutropenia (14.1% vs 24.1%), both higher in GemCis]. Treatment exposure was lower in NUC-1031+cis, which can be explained by a higher discontinuation rate due to TEAEs (30% vs 16%). More patients discontinued during the first 30-days of treatment with NUC-1031+cis (22% vs 10%), mainly due to Grade 3 ALT/AST increases, which were reversible, leading to a late protocol amendment allowing rechallenge of NUC-1031 at dose minus 1.

At the dose and schedule utilised for NUC-1031 in this study, the primary endpoint was not met with a longer OS with GemCis, despite a higher ORR with NUC-1031+cis. NUC-1031+cis was associated with more liver-related TEAEs, leading to early discontinuation. While these early liver events were more frequent in NUC-1031+cis, they were observed in both arms and are likely a combination of drug-induced liver toxicity, disease progression, and underlying liver dysfunction in this patient population.

NCT04163900.

NuCana.

Has not received any funding.

V. Breder: Speaker Bureau / Expert testimony: AstraZeneca, Pfizer, EISAI. L. Goyal: Advisory / Consultancy: Alentis Therapeutics AG, Black Diamond, H3Biomedicine, Incyte Corp., QED Therapeutics, Servier, Sirtex Medical Ltd., Taiho Oncology; Research grant / Funding (self): AstraZeneca (DMSC); Research grant / Funding (institution): Adaptimmune, Bayer, Eisai, Merck, Macrogenics, Genentech, Novartis, Incyte, Eli Lilly, Loxo Oncology, Relay Therapeutics, QED Therapeutics Inc, Servier, Taiho Oncology, Bristol Meyers Squibb, Nucana, Alentis, Exelixis; Full / Part-time employment: Massachusetts General Brigham, Mass General Hospital Cancer Center. C. Braconi: Advisory / Consultancy: Boehringer-Ingelheim, Servier, Incyte; Speaker Bureau / Expert testimony: Astrazeneca, Incyte; Research grant / Funding (institution): Avacta, Medannex, Servier; Spouse / Financial dependant: Astrazeneca. R. Shroff: Advisory / Consultancy: AstraZeneca, Clovis, Genentech, Incyte, Merck, QED Therapeutics, Servier, Boehringer Ingelheim, Taiho, Zymeworks Biopharm, CAMI, Servier, SYROS; Research grant / Funding (institution): Bayer, BMS, Bristol-Myers Squibb, Exelixis Pharm., IMV Inc., LOXO, Novocure, NUCANA, Pieris, Rafael Pharm., Seagen, Taiho, QED. D. Palmer: Advisory / Consultancy: Servier, Celgene, Nucana; Research grant / Funding (institution): Nucana, BMS, Sirtex; Travel / Accommodation / Expenses: Nucana. All other authors have declared no conflicts of interest.