NUC-1031 Did Not Prolong Overall Survival for Patients With Advanced Biliary Tract Cancers

Phase 3 NuTide121 Trial of Phosphoramidate Transformation of Gemcitabine, NUC-1031

In a phase 3 study, the phosphoramidate transformation of gemcitabine, NUC-1031 plus cisplatin did not prolong the overall survival, compared with gemcitabine-cisplatin, among patients with advanced biliary tract cancer.

These data were presented by Jennifer Knox, MD, Princess Margaret Cancer Center, Toronto, Ontario, Canada, at the 2023 World Congress on Gastrointestinal Cancers on June 28, 2023,  in Barcelona, Spain.

The open label, phase 3 NuTide121 trial enrolled 773 patients with advanced biliary tract cancer who had received no prior systemic chemotherapy for locally advanced or metastatic disease. Patients were randomized on a 1-to-1 basis to receive cisplatin plus either NUC-1031 or gemcitabine. The primary end points were overall survival and objective response rate with progression-free survival and safety among the secondary end points. Enrollment for this study was stopped at the time of the first interim analysis, due to futility.

The median overall survival was 9.2 months in the experimental arm compared with 12.6 months in the gemcitabine-cisplatin arm. The objective response rate was 18.7% in the experimental arm and 12.4% for gemcitabine-cisplatin (odds ratio, 1.59; 99% confidence interval [CI], 0.86 to 2.94; P = .049. The progression-free survival was 4.9 months and 6.4 months, respectively (hazard ratio, 1.45; 95% CI, 1.18 to 1.7; P < .001).

There were similar rates of grade >3 treatment-emergent adverse events across the 2 arms, aside from liver-related events, hepatobiliary disorders, and hematological events. Liver-related events including increased ALT and increased AST were higher in the experimental group. Hepatobiliary disorders such as cholangitis and biliary obstruction were higher in the experimental group. Hematological events including anemia and neutropenia were both higher in the gemcitabine-cisplatin group. There was also a higher discontinuation rate due to treatment-emergent adverse events in the experimental arm (30%) vs the gemcitabine-cisplatin atm (16%). Dr Knox and coauthors added, “More patients discontinued during the first 30-days of treatment with NUC-1031 [plus cisplatin] (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.”

While there was a higher ORR in the experimental arm, the primary end point of OS was not met at the dose and scheduled utilized for NUC-1031. Dr Knox et al adding, in regards to the liver-related events, “while these early liver events were more frequent in [the experimental arm], 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.”

Source:

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). Presented at the World Congress on Gastrointestinal Cancers; June 28-July 1, 2023; Barcelona, Spain. Abstract O-2