Results from the ongoing eNRGy trial, a single-arm, multicenter, international phase 2 clinical trial evaluating xenocutuzumab in neuregulin-1-positive solid tumors (NRG1) gene fusion, with manageable side effects and clinically meaningful efficacy (including nearly twice the progression-free survival compared to expected with standard therapy) reported in patients with previously treated advanced disease NRG1-Positive cholangiocarcinoma. Based on these results, the U.S. Food and Drug Administration has approved xenocutuzumab as a next treatment. NRG1-I tested positive for bile duct cancer on May 8th.
“Second-line chemotherapy is only marginally effective for most patients with this disease, and better treatment options are desperately needed,” says James Cleary, M.D., a gastrointestinal oncologist at Dana-Farber University who led the trial and published the results in an academic journal. Journal of Clinical Oncology. “Compared to what is typically observed with standard chemotherapy, xenocutuzumab doubles the duration of clinical effect. Furthermore, this treatment is well tolerated, making it a major advance in terms of quality of life.”
Cholangiocarcinoma is a rare and aggressive cancer that affects the bile ducts inside or outside the liver. Less than 1% of patients with cholangiocarcinoma have NRG1 Gene fusion. Twenty-five percent of patients with NRG-1-positive cholangiocarcinoma are younger than 40 years, and this pattern has also been observed in patients with: NRG1-Positive for pancreatic cancer.
Currently, patients usually receive chemotherapy as a second-line treatment. Only 5% of patients have an objective radiological response to standard second-line chemotherapy, and the median progression-free survival is approximately 4 months.
This single-arm study enrolled 22 patients with the following symptoms: NRG1– Positive cholangiocarcinoma that has progressed after initial chemotherapy or is not amenable to standard treatment. Among the 19 patients evaluated after treatment with xenocutuzumab, the objective radiological response rate was 36.8 percent. Additionally, 57.9 percent of patients experienced clinical benefit. Median progression-free survival was 9.2 months.
Additionally, xenocutuzumab was well tolerated. Patients experienced mild side effects such as diarrhea and infusion reactions, but these side effects were manageable.
This study is limited by its small cohort of 22 people and being a single-arm study, which precludes direct comparisons with other treatments. However, this is a very difficult patient population to study. NRG1 Fusion is very rare.
Zenocutuzumab is a bispecific antibody that targets human epidermal growth factor receptor (HER) 2 and 3. NRG1 Fusion-driven signaling promotes tumor growth. This drug is also approved to treat progressive diseases NRG1– Positive for non-small cell lung cancer, and class wild type NRG1-Positive for pancreatic cancer.
Gene fusions may be detectable by DNA-based next-generation sequencing tests, which are widely used to customize medical care for patients. of NRG1 However, gene fusions are complex and are more likely to be detected using RNA-based next-generation sequencing. In fact, in this study, all but one bile duct cancer patient NRG1 Fusion using RNA testing.
The number of genetic mutations and fusions that can be targeted with precision medicine in cholangiocarcinoma is increasing, highlighting the need for comprehensive DNA- and RNA-based molecular profiling of patients with this disease.
It is becoming increasingly important to perform appropriate tests on patients, such as RNA and DNA tests for patients with cholangiocarcinoma. We worry that patients will miss out on the benefits of new precision medicine. We are deeply grateful to the patients around the world who participated in this trial and hope that as many patients as possible can benefit from these discoveries in the future. ”
James Cleary, MD, Gastrointestinal Oncologist
sauce:
Dana-Farber Cancer Institute
Reference magazines:
Cleary, J.M.; Others. (2026). Efficacy and tolerability of Zenocutuzumab in advanced patients NRG1 Fusion-positive cholangiocarcinoma: results of the eNRGy phase II trial. Journal of Clinical Oncology. DOI: 10.1200/jco-25-03128. https://ascopubs.org/doi/10.1200/JCO-25-03128
