First-line NUC-1031/cisplatin trial for advanced BTC cut short due to futility

A recent phase III trial of NUC-1031/cisplatin has been terminated early due to ineffectiveness as first-line treatment for advanced biliary tract cancer (BTC).

The study randomly allocated adult patients with treatment-naïve advanced BTC 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. Overall survival (OS) and objective response rate (ORR) were the primary endpoints. The investigators also planned three interim analyses (IA) and a final analysis.

The participants had a median age of 65 years, and 53 percent were male. Baseline characteristics were comparable between groups. Of the patients, 54 percent had intrahepatic cholangiocarcinoma (CCA), 21 percent had extrahepatic CCA, 21 percent had gallbladder cancer, and 5 percent ampullary cancer.

Enrolment was terminated at IA1 when the OS futility boundary was crossed.

At the final data cutoff, the median OS for NUC-1031/cisplatin was 9.2 months (95 percent confidence interval [CI], 8.3‒10.4) vs 12.6 months (95 percent CI, 11.0‒15.1) for gemcitabine/cisplatin (hazard ratio [HR], 1.79), while the median progression-free survival was 4.9 (95 percent CI, 4.4‒6.0) vs 6.4 months (95 percent CI, 6.1‒7.4; HR, 1.45).

The ORR was higher for NUC-1031/cisplatin than gemcitabine/cisplatin (18.7 percent vs 12.4 percent; odds ratio, 1.59; p=0.049).

The adverse event profile did not significantly differ between arms, with the exception of hepatobiliary disorders (25 percent vs 11 percent; higher with NUC-1031/cisplatin) and haematological events (48 percent vs 65 percent; higher with gemcitabine/cisplatin).

More patients on NUC-1031/cisplatin met the criteria for potential drug-induced liver injury (27 percent vs 7 percent) and Hy’s law (1.6 percent vs 0.5 percent). On the other hand, treatment exposure was lower for NUC-1031/cisplatin, potentially due to early discontinuation for adverse events (30 percent vs 18 percent).

“NUC-1031 is a phosphoramidate modification of gemcitabine,” the investigators said.