As a first-line treatment for advanced biliary tract cancer, an experimental formulation of gemcitabine, NUC-1031, given with cisplatin failed to improve outcomes over standard gemcitabine/cisplatin in the global phase III NuTide:121 trial.¹

“NuTide:121 has not advanced the field in biliary tract cancer. Gemcitabine plus cisplatin had superior progression-free survival and overall survival in this first-line chemotherapy setting, and the data were consistent with prior trials of this standard regimen. While NUC-1031 plus cisplatin achieved higher objective response rates (by blinded independent central review), it demonstrated inferior durability,” said Jennifer Knox, MSc, MD, FRCPC, Professor of Medicine at Princess Margaret Cancer Centre in Toronto, who reported the findings at the 2023 World Congress on Gastrointestinal Cancer.

Jennifer Knox, MSc, MD, FRCPC

Need for Better Treatments in Biliary Tract Cancer

Advanced biliary tract cancer has few treatment options and therefore carries a poor prognosis. The accepted global standard-of-care chemotherapy backbone is gemcitabine plus cisplatin.

NUC-1031 is a phosphoramidate transformation of gemcitabine that was designed to enhance its function and overcome key shortcomings that limit gemcitabine’s clinical effectiveness. It enters cells independently of the hENT-1 nuclear transporter, is resistant to breakdown by cytidine deaminase and is already phosphorylated, and so not dependent on dCK phosphorylation. In comparison to gemcitabine, the drug has greater plasma stability and increased intracellular levels of the active anticancer metabolite, gemcitabine triphosphate. In a phase Ib study of 21 patients with biliary tract cancer, the response rate to NUC-1031 plus cisplatin was 44%, including complete responses in 6%, and no unusual toxicity was seen.²

About NuTide:121

Those encouraging results led to the phase III NuTide:121 open-label randomized trial, which compared NUC-1031 with gemcitabine/cisplatin as a first-line treatment in advanced biliary tract cancer. From 125 sites in 15 countries, the study enrolled 773 patients with confirmed biliary tract cancer—cholangiocarcinoma, gallbladder cancer, or ampullary cancer—who had received no prior systemic chemotherapy for locally advanced or metastatic disease.

Patients were randomly assigned 1:1 to receive NUC-1031 at 725 mg/m² or gemcitabine at 1,000 mg/m², both with cisplatin at 25 mg/m² on days 1 and 8 of a 21-day cycle. Baseline characteristics were well balanced across both arms. Median patient age was 65; 53% were male; 72% were White; 84% had metastatic disease; and primary tumor locations were intrahepatic (54%), extrahepatic (21%), gallbladder (21%), and ampullary (5%). The co-primary endpoints were overall survival and objective response rate.

Endpoints Not Met

“Enrollment was stopped at the first interim analysis (February 2022), per the independent data monitoring committee’s recommendation, as the futility boundary for overall survival was crossed,” Dr. Knox said. In addition to the final analysis, three interim analyses had been planned.

At final data cutoff (April 2022), median overall survival was 9.2 months with NUC-1031/cisplatin vs 12.6 months with gemcitabine/cisplatin (hazard ratio [HR] = 1.79; P < .001). Objective response rateby blinded independent central review was 18.7% with NUC-1031/cisplatin vs 12.4% with ­gemcitabine/cisplatin (odds ratio = 1.59; P = .049). Median duration of response was 6.4 months and 12.3 months, respectively. Median progression-free survival, a secondary endpoint, was 4.9 months with NUC-1031/cisplatin vs 6.4 months with gemcitabine/cisplatin (HR = 1.45; P < .001).

The grade ≥ 3 treatment-emergent adverse event profile was generally similar across the two arms, with a few exceptions. The NUC-1031/cisplatin-treated patients were more likely to have increased alanine aminotransferase (ALT; 18% vs 3%) and aspartate aminotransferase (AST; 9% vs 2%), cholangitis (3% vs 2%), and biliary obstruction (2% vs 0.3%). Gemcitabine/cisplatin–treated patients had more hematologic toxicity, including anemia (9% vs 18%) and neutropenia (14% vs 24%). Treatment exposure was lower in the NUC-1031/cisplatin arm, with a median number of cycles delivered of four vs six in the control arm, presumably because of the higher discontinuation rate because of treatment-emergent adverse events, predominantly in the first 30 days of drug exposure (14.6% vs 2.6%).

“NUC-1031 plus cisplatin was associated with more liver-related [treatment-emergent adverse events], leading to early discontinuation,” Dr. Knox said. “This was mainly due to grade ≥ 3 increases in ALT/AST, which were reversible…. The liver toxicity may be due to higher intracellular drug levels and could benefit from further dose optimization. The protocol prevented a dose-reduced rechallenge with grade 3 or 4 liver toxicity resolved early, and this led to undertreating some patients,” she added.

Signs of liver toxicity were actually observed early on in both arms, Dr. Knox stated. These findings are likely the result of a combination of drug-induced liver toxicity, disease progression, and underlying liver dysfunction in this patient population, she suggested. 

DISCLOSURE: Dr. Knox has served as a consultant for AstraZeneca, Merck, Roche, Eisai, Pfizer, Ibsen, and Incyte.

REFERENCES

1. Knox J, Bazin I, Oh D, et al: Phase III study of NUC-1031 + cisplatin vs gemcitabine + cisplatin for first-line treatment of patients with advanced biliary tract cancer (NuTide:121). 2023 World Congress on Gastrointestinal Cancer. Abstract O-2. Presented June 28, 2023.

2. McNamara MG, Bridgewater J, Palmer DH et al: A phase Ib study of NUC-1031 in combination with cisplatin for the first-line treatment of patients with advanced biliary tract cancer (ABC-08). Oncologist 226:e669-e678, 2020.