Zenocutuzumab Shows Promise Among Patients With NRG1 Fusion-Positive Cancers

Alison Schram, MD, Memorial Sloan Kettering Cancer Center, New York, New York, discusses data from the phase 2 eNRGy study which evaluated zenocutuzumab among patients with NRG1 fusion-positive cancer of any tumor type.

Dr Schram highlighted the importance of genetic testing, particularly for patients who don't have additional drivers on next generation sequencing, commenting, “It's a rare patient population, but if you find a patient with an NRG1 fusion, this can change the course of their disease and really be a game-changer for them. So, remember this drug, remember this genetic alteration.”

Based on results from this trial, zenocutuzumab was granted accelerated approval by the US Food and Drug Administration (FDA) in December 2024 for patients with advanced, unresectable, or metastatic non-small cell lung cancer or pancreatic adenocarcinoma with NRG1 gene fusion following progression on or after prior systemic therapy.

Transcript:

Hi, my name is Alison Schram and I'm a medical oncologist from Memorial Sloan Kettering Cancer Center. I focus on developing genomically targeted therapies in patients with advanced cancer. And here, I'll be discussing the development of zenocutuzumab, a HER2/HER3 bispecific antibody, in patients with NRG1 fusion-positive cance.

As some background NRG1 is the ligand for HER3. Binding of NRG1, also known as neuregulin, to HER3 induces HER2/HER3 heterodimerization and activation of HER2 PI3 kinase signaling pathway. Oncogenic gene fusions involving NRG1 can be found across solid tumor types and are enriched in otherwise driver-negative tumors. That includes KRAS wild-type pancreatic cancer and driver-negative non-small cell lung cancer. Although NRG1 fusions can be detected on DNA or RNA sequencing, due to the large size of the NRG1 gene and its introns, RNA sequencing is more sensitive, and it can often be missed on DNA panel testing. NRG1 fusions lead to overactivation of the NRG1/HER3 pathway, leading to cancer cell growth and survival.

Zenocutuzumab is a HER2/HER3 bispecific antibody that is being studied for the treatment of NRG1 fusion-positive cancers. One arm binds to the HER2 on the cancer cell surface and another arm binds to HER3, directly blocking the chimeric oncogenic NRG1 fusion from interacting with HER3, preventing HER2/HER3 dimerization, and also causing antibody dependent cellular cytotoxicity or ADCC, which leads to the immune system recognizing the cancer.

We studied the efficacy of zenocutuzumab in the global registrational phase 2 eNRGy study. Zenocutuzumab was given to patients with advanced NRG1 fusion positive solid tumors at a dose of 750 mg intravenously every 2 weeks. The primary end point was the overall response rate according to the investigator assessment and secondary end points included the duration of response, progression-free survival and safety.

A total of 204 patients were treated across 12 different tumor types and, among 158 patients who had measurable disease and were enrolled at least 24 weeks before the data cut-off, the overall response rate was 30% and the median duration of response was 11.1 months. The median progression-free survival was 6.8 months. Responses were observed in multiple tumor types. In non-small cell lung cancer, the overall response rate was 29% and in pancreatic cancer the overall response rate was 42%.

Zenocutuzumab treatment was extremely well tolerated. The most common adverse events considered by the investigator to be related to zenocutuzumab were low-grade diarrhea, fatigue, and nausea, all in less than 20% of patients. Infusion-related reactions were observed in 14% of the patients.

Importantly, on December 4th, 2024, the FDA granted accelerated approval to zenocutuzumab for patients with advanced, unresectable or metastatic non-small cell lung cancer and pancreatic cancer harboring NRG fusions with disease progression on or after prior systemic therapy.

What are the key considerations for clinicians using this agent?

It really is very well tolerated. Truthfully, I think the most notable toxicity is the infusion reaction, which happens as I mentioned, in about 14% of patients. This is typically mild. The guidelines are to give pre-medication with antihistamines and for at least the first infusion, we've been giving pre-medication with steroids as well. In the patients that I have treated who had an infusion reaction, all have been able to, with pre-medication and supportive care, continue the infusion either that day or a subsequent day and have not come off of the trial.

I think the clinicians should know to pre-medicate, to pay careful attention to patients, particularly in the first couple of infusions. But also, if there is a mild infusion reaction, you don't necessarily have to abort the whole treatment plan and with supportive medication you can have them come back the next day or at a future date to again try to give this treatment.

How important is proper genetic testing to detect these gene fusions?

I think that's a really important point. Unlike many of the other genomic markers that we have that are easily detected on DNA, this is a more difficult fusion to detect on DNA-based panels. And so oftentimes when it is seen on a DNA based panel, it's actually because the fusion partner is tiled on the panel, not NRG1 itself. That happens more often in lung cancer because a lot of these commercial assays have enriched for fusion partners that are common in lung cancer because of ALK and ROS-1and NTRK. But for other diseases, where these common fusion partners are not necessarily tiled on the panel, it can be more challenging to detect these fusions.

RNA-based sequencing is superior to DNA-based sequencing, and that is something that not all institutions are doing. Not all clinicians are sending RNA-based testing. What we would recommend is, if not sending RNA in everybody, at least selecting patients who are otherwise driver negative, they are more likely to have an oncogenic driver found on RNA sequencing, either an NRG1 fusion or another fusion. In any patient with a solid tumor that's driver negative, particularly like a KRAS wild-type pancreatic cancer, we would recommend sending those additional tests for RNA.

What are the next steps for this research?

We're very excited to have the FDA approval for zenocutuzumab, and it is definitely an unmet need. Patients are now able to access this all over the United States, which is very exciting. At this point, we really are focusing on getting more information about those patients that have been enrolled on the trial, and I do think that the next steps from my perspective would be to understand, using larger numbers, whether other disease types could potentially benefit from this therapy.

The clinical trial enrolled patients with all different disease types, but just based on the numbers, the majority of patients had lung cancer and pancreatic cancer, and that is where the 2 FDA approvals were specifically given. Patients, for example, with breast cancer and cholangiocarcinoma were also clearly enriched to some degree on the trial and had patients that benefited, but we do need more patients and more data to understand what is the overall response rate in that population, the durability, et cetera.

Do you have anything else to add about this research?

Truthfully, my final remark would just be, as we discussed earlier, just the importance of genetic testing in patients and remembering to keep this in mind for patients who don't have additional drivers on next generation sequencing. It's a rare patient population, but if you find a patient with an NRG1 fusion, this can change the course of their disease and really be a game-changer for them. So, remember this drug, remember this genetic alteration. I hope there will be more to come.

Source:

Schram AM, Goto K, Kim D-W, et al. Efficacy of zenocutuzumab in NRG1 fusion-positive cancer. N Eng J Med. 2025;392(6). doi:10.1056/NEJMoa2405008