Gentry King, MD, Assistant Professor in the Division of Hematology and Oncology, University of Washington, and Assistant Professor in the Clinical Research Division of Fred Hutchinson Cancer Center, Seattle, offered his thoughts on the findings of NuTide:121.
“Only recently, with TOPAZ-1 [durvalumab]1 and KEYNOTE-966 [pembrolizumab],2 have studies been able to demonstrate a survival advantage with new agents in addition to gemcitabine and cisplatin chemotherapy for the first-line treatment of biliary tract cancers. However, the overall benefit of adding immune checkpoint inhibitors appears to be modest, and we currently lack validated biomarkers to predict benefit from this strategy. As such, there is a need to improve the efficacy of the chemotherapeutic agents that have been the standard backbone of treatment for more than a decade,” he said.
Gentry King, MD
Research Challenges
The NuTide:121 phase III trial investigators hoped to answer this need with a more potent novel formulation of gemcitabine but failed to demonstrate an overall survival advantage. In fact, the experimental arm of NUC-1031 plus cisplatin demonstrated inferior survival, despite showing a numerically higher objective response rate and a control arm having comparable survival vs historic controls, Dr. King noted.
“One of the potential reasons for the inferior outcome of the experimental arm is the higher rate of grade ≥ 3 transaminitis, a higher rate of treatment discontinuation, and consequently lower treatment exposure in patients who received NUC-1031,” he suggested. “As such, this study illustrates the challenges of translating promising new agents with good preclinical and early clinical data into a feasible treatment strategy that benefits a larger population of patients with biliary tract cancers.” He suggested that future research explore dose optimization of NUC-1031, to allow for more consistent drug delivery.
“The investigators should be commended for the massive undertaking of enrolling 773 patients across 15 countries, which demonstrates the feasibility of enrolling patients into phase III trials in biliary tract cancer and opening the possibility of conducting these studies in anatomic and biologically heterogeneous subtypes,” Dr. King added.
DISCLOSURE: Dr. King reported no conflicts of interest.
REFERENCES
1. Oh DY, He AR, Qin S, et al: A phase 3 randomized, double-blind, placebo-controlled study of durvalumab in combination with gemcitabine plus cisplatin in patients with advanced biliary tract cancer: TOPAZ-1. 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 378. Presented January 21, 2022.
2. Kelley RK, Ueno M, Yoo C, et al: Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 401:1853-1865, 2023.
