Targeted therapy doubles progression-free survival in rare bile duct cancer

Results of the ongoing eNRGy trial, a single-arm, multicenter, global phase 2 clinical trial evaluating zenocutuzumab in solid tumors positive for Neuregulin 1 (NRG1) gene fusions, reported manageable side effects and clinically meaningful efficacy – including a near doubling of progression-free survival compared to expectations with standard of care – in previously treated patients with advanced NRG1-positive cholangiocarcinoma. Based on these results, the U.S. Food and Drug Administration approved zenocutuzumab as second-line therapy for NRG1-positive cholangiocarcinoma on May 8.

"Second-line chemotherapy is only modestly effective for most patients with this disease, and we greatly need better treatment options," says gastrointestinal oncologist James Cleary, MD, PhD, who led the trial at Dana-Farber and published the results in the Journal of Clinical Oncology. "Compared to what we typically observe with standard chemotherapy, zenocutuzumab doubles the duration of clinical benefit. In addition, since the therapy is well tolerated, it is a significant step forward in terms of quality of life."

Cholangiocarcinoma is a rare and aggressive form of cancer that affects bile ducts inside or outside of the liver. Fewer than one percent of patients with cholangiocarcinoma have the NRG1 gene fusion. Twenty-five percent of patients with NRG-1 positive cholangiocarcinoma are under the age of 40, a pattern which has also been observed in patients with NRG1-positive pancreatic cancer.

Currently, patients typically receive chemotherapy as second-line treatment. Only five percent of patients have an objective radiological response to standard second-line chemotherapy, with a median progression-free survival of about four months.

The single-arm study recruited 22 patients with NRG1-positive cholangiocarcinoma that had progressed after initial chemotherapy or were unsuitable for standard therapy. Of 19 patients evaluated after treatment with zenocutuzumab, the objective radiological response rate was 36.8 percent. Further, 57.9 percent of patients experienced clinical benefit. The median progression-free survival was 9.2 months.

In addition, zenocutuzumab was well tolerated. Patients experienced low-grade side effects, including diarrhea or infusion reactions, but these side effects were manageable.

This study is limited in that a 22-person cohort is small, and that it is a single-arm study, so no direct comparison to other therapies is possible. However, this is a very challenging patient population to study because NRG1 fusions are so rare.

Zenocutuzumab is a bispecific antibody that targets the human epidermal growth factor receptor (HER) 2 and 3, blocking the NRG1 fusion-driven signaling that fuels tumor growth. The drug is also approved for the treatment of advanced NRG1-positive non-small cell lung cancer and KRAS wild-type NRG1-positive pancreatic cancer.

Gene fusions can sometimes be detected through DNA-based next-generation sequencing tests, which are widely used to personalize medicine for patients. The NRG1 gene fusion is complex, however, and is more likely to be detected using RNA-based next-generation sequencing. In fact, all but one patient with cholangiocarcinoma in this study was confirmed to have an NRG1 fusion using RNA testing.

There are a growing number of gene mutations and fusions that are targetable using precision medicines for cholangiocarcinoma, underscoring a need for comprehensive DNA- and RNA-based molecular profiling of patients with this disease.

It is increasingly important that we do the right tests for our patients, which includes doing RNA and DNA testing for patients with cholangiocarcinoma. We are worried that patients might miss out on a chance to benefit from novel precision medicines. We are so grateful to the patients from around the world who participated in this trial and want as many patients as possible to benefit from these findings in the future."

James Cleary, MD, PhD, gastrointestinal oncologist