Stephen Liu, MD, Shares Insights on the eNRGy Trial

Stephen V. Liu, MD, of the Georgetown University School of Medicine and Georgetown’s Lombardi Comprehensive Cancer Center in Washington, DC, joined Lung Cancers Today to discuss the results of the phase 2 eNRGy study, which were recently published in The New England Journal of Medicine.

The study demonstrated that zenocutuzumab had efficacy in patients with advanced NRG1 fusion–positive cancer, including patients with non–small cell lung cancer (NSCLC).

This finding can help address critical unmet needs in this population of patients, Dr. Liu explained, noting that these tumors “do not respond well to standard treatment.”

“Having a targeted agent here that’s effective is long overdue,” said Dr. Liu, who was involved with the phase 2 trial.

The study enrolled and treated 204 patients with 12 tumor types, including NSCLC and pancreatic cancer, with responses seen in multiple tumor types and across multiple NRG1 fusion partners.  Responses occurred in 30% (95% CI, 23%-37%) of the 158 patients who had measurable disease and were enrolled at least 24 weeks before the data cutoff date. Among patients with NSCLC, responses occurred in 27 of 93 patients (29%; 95% CI, 20%-39%).

Dr. Liu explained that the 30% response rate across tumors was “much better than standard treatments in the setting,” showing a median response duration of 11.1 months. However, questions remain about predicting and optimizing responses.

“We’re still in the process of trying to identify which NRG1 fusions are more likely to respond [and asking] how important is fusion partner or fusion variants and breakpoints? Are there other factors that can help predict response? And importantly, are there other drugs that can be effective in this space?” he said.

The publication of the eNRGy trial results comes on the heels the FDA’s December 2024 action to grant accelerated approval to zenocutuzumab (Bizengri, Merus N.V.) for adults with advanced, unresectable, or metastatic NSCLC or pancreatic adenocarcinoma who have an NRG1 gene fusion with disease progression during or after prior systemic therapy, Dr. Liu explained, noting that this is an “an important approval and an important target, but a unique one.”

For example, NRG1 fusions are rare and can be difficult to detect through certain types of biomarker testing.

“The NRG1 gene is a very big gene,” Dr. Liu said. “It is almost entirely intronic, which means if you’re using DNA-based next-generation sequencing, it is very easy to miss these fusions…to find these, we want to use RNA sequencing, which generally is tissue based, not liquid based.”

In addition to Dr. Liu’s work on the eNRGy trial, he also published a retrospective review on NRG1 fusions that further illuminated the unmet needs for these patients.

“Patients receiving frontline chemoimmunotherapy with an NRG1 fusion, none of them had a response to treatment, very poor outcomes,” Dr. Liu said. “This is a tumor that often spreads along airways. Radiographically, it can look a lot like pneumonitis or a ground glass appearance. It’s very difficult to treat.”

Based on the data currently available, Dr. Liu said he considers zenocutuzumab as the “best option for patients whose tumors harbor an NRG1 fusion,” and that the drug was “very well-tolerated.”

“This is an effective drug for a disease that doesn’t respond well to standard treatments,” he said. “But again, it’s only an option if we take the time to find these [NRG1 fusions] and we do need to look a little more closely at how we’re running this biomarker testing. RNA sequencing is really the way to go.”