Until May 2026, patients with NRG1-positive cholangiocarcinoma had no FDA-approved treatment aimed at their cancer. Now they have zenocutuzumab, a targeted drug backed by research led by Dr. James Cleary at Dana-Farber, who published the results in the Journal of Clinical Oncology.
The group is tiny. Cholangiocarcinoma is a rare cancer of the bile ducts, and fewer than 1% of those patients also carry an alteration in the NRG1 gene, which drives cell growth.
What the trial found
In the phase 2 study, patients with NRG1-positive cholangiocarcinoma received zenocutuzumab. Sixty percent of them got clinical benefit from the drug for at least six months. Cleary said it “doubles the duration of clinical benefit” compared with standard chemotherapy. The drug was well tolerated, with minimal side effects.
Chemotherapy had been the mainstay for these patients, and when one regimen failed they moved to another. “Second-line chemotherapy is only modestly effective for most patients with this disease, and we urgently need better treatment options,” Cleary said.
How it works
An NRG1 fusion happens when the NRG1 gene merges with another gene. The fusion produces a messenger protein that stays switched on, which keeps telling cells to grow. In healthy cells, NRG1 proteins bind a surface receptor called HER3, which pairs with a partner protein, HER2, and starts a chain reaction that drives growth.
Zenocutuzumab is a bispecific antibody that targets HER2 and HER3. It docks onto them and blocks the signals the fusion creates. The drug showed similar results in NRG1 fusion-positive pancreatic and lung cancer and is FDA approved for those uses as well.
Testing is the catch
Finding these patients takes more than standard DNA sequencing. “You will likely miss an NRG1 fusion with just DNA sequencing,” Cleary said. RNA sequencing of the cancer cells is also needed. In the trial, nearly everyone had an NRG1 fusion detected by RNA testing.
“This is a new option for patients and families who have this alteration,” Cleary said.
