Cleaning Out Cancer with New Targeted Bile Duct Treatment

Fluffy dust bunnies, fuzzy mold, or wild racoons can find refuge in the ductwork of any home, slowly sprawling out and quickly becoming a problem. And like any home, the tiny channels in our body can get blocked, sometimes by the dirtiest kind—cancer.  

Cholangiocarcinoma is a rare cancer that forms in the bile duct. The biliary tract is made up of a network of ducts that connect the liver, gallbladder, and small intestine. Fewer than 1% of patients with this rare cancer also have something else—an alteration of their neuregulin 1 (NRG1) gene, a gene that drives cell growth. Up until May 2026, there were no U.S. Food and Drug Administration (FDA)-approved treatments.  

Now, there is zenocutuzumab, an FDA-approved targeted drug for NRG1-positive cholangiocarcinoma, supported by research led by Dana-Farber’s James Cleary, MD, PhD, principal investigator and co-director of clinical trials in the Center for Gastrointestinal Oncology. 

“Compared to what we typically observe with standard chemotherapy, zenocutuzumab doubles the duration of clinical benefit,” says Cleary, senior author, who published the results in the Journal of Clinical Oncology. “This is a new option for patients and families who have this alteration.” 

New Alteration Alternatives 

NRG1 gene fusions can occur across many tumor types. About 25% of NRG1 fusion positive cancers occur in patients with bile duct and pancreatic cancers who are under the age of 40. The fusion occurs when the NRG1 gene merges with another gene, overencouraging cell growth.  

NRG1 proteins are highly controlled because they manage cell growth and replication. In healthy cells, NRG1 proteins bind to a cell surface receptor or communication “antenna” called HER3. This activates HER3 and causes it to pair up with a partner protein called HER2. This partnership triggers a chain reaction inside the cell that drives cell growth. 

“NRG1 is a fascinating gene fusion with unique biology,” Cleary says. “Most cancer-causing fusions create receptor proteins that directly drive cell growth. NRG1 fusions are different because they produce a persistently active messenger protein, known as a ligand, which keeps downstream signaling constantly turned on.” 

In NRG1-positive cholangiocarcinoma cases, chemotherapy was typically the mainstay of therapy for patients. When one chemotherapy stopped working, patients would then start another line of a different chemotherapy regimen. 

“Second-line chemotherapy is only modestly effective for most patients with this disease, and we urgently need better treatment options,” Cleary says. “Our goal is to develop more effective therapies that can improve quality of life for cholangiocarcinoma patients.”  

In this phase 2 study, patients with NRG1-positive cholangiocarcinoma were treated with zenocutuzumab. Zenocutuzumab is a bispecific antibody that “docks and blocks” the growth signals that result from the NRG1 gene fusion. The drug targets HER2 and 3, blocking the NRG1 fusion-driven signaling that fuels tumor growth. “This drug uses a clever mechanism to block signals created by this fusion,” Cleary says. 

Clinical outcomes with zenocutuzumab were substantially better than what is typically seen with chemotherapy. Impressively, 60% of patients on the trial derived clinical benefit from zenocutuzumab for at least 6 months. Importantly, the drug was well tolerated with minimal side effects. Notably, zenocutuzumab demonstrated similar results in NRG1 fusion positive pancreatic cancer and lung cancer and is FDA approved for those indications as well. 

Leveraging Advances in Molecular Testing 

A critical element to treating patients with targeted therapy is identifying patients with targetable mutations. Oncologists perform molecular testing to detect abnormalities in genes within the cancer. This molecular testing has been critical in finding druggable molecular targets like EGFR, IDH1, KRAS, and ALK. 

However, while many targetable alterations are easily found with DNA sequencing, the team has learned that catching NRG1 fusions through DNA sequencing is not enough. RNA sequencing of cancer cells is needed, too. “You will likely miss an NRG1 fusion with just DNA sequencing,” Cleary adds. “In the trial, nearly everyone had an NRG1 fusion using RNA testing.” 

The team hopes more patients can benefit from the advancement in precision medicines like zenocutuzumab and use it in other settings that build on this trial’s success.  

“We’re excited about these results because they add an additional targeted therapy for cholangiocarcinoma, and our goal is to continue finding precision treatments so that every patient with this disease has viable targeted options,” Cleary says. “We are profoundly grateful to the patients who participated in this trial and made this advance possible.” 

Written by: Maddi Langweil
Medically Reviewed By: James Cleary, MD, PhD