Treating NRG1 Fusion-Positive Non-Small Cell Lung Cancer

Alison Schram, MD, Memorial Sloan Kettering Cancer Center, New York, New York, discusses the treatment course taken for a case of a patient with non-small cell lung cancer (NSCLC) with a CD74-NRG1 gene fusion.

Dr Schram explained, “The 1 FDA-approved drug for NRG1 fusion-positive lung cancer patients is zenocutuzumab.”

Transcript:

Hi, my name is Alison Schram and I'm a medical oncologist at Memorial Sloan Kettering Cancer Center with a focus on early drug development.

Today we'll be talking about a case of NRG1 fusion-positive non-small cell lung cancer. And so the case that we presented had a gentleman who had non-small cell lung cancer that had progressed on standard frontline therapy and on genetic testing was found to have an NRG1 fusion. As some background NRG1 fusions are these rare oncogenic fusions that activate the HER2/HER3 signaling pathway. And recently there have been targeted therapies that have been investigated in patients with a specific genetic alteration.

The correct answer was that the patient should receive zenocutuzumab, which is a HER2/HER3 bispecific antibody and that is a drug that's given intravenously every 2 weeks until cancer progression. This is based on a recent publication in the New England Journal of Medicine in which patients with advanced NRG1 fusion-positive cancers, including non-small cell lung cancer, were treated with zenocutuzumab. And in this single arm phase 2 clinical trial, the overall response rate in that non-small cell lung cancer population was 29% with a median duration of response of 12.7 months. On the basis of this data, the FDA approved zenocutuzumab for patients with advanced NRG1 fusion-positive non-small cell lung cancer that had progressed on standard therapy.

Looking at the other possible answers we have listed some other targeted therapies and some chemotherapy. But importantly, there was another study looking retrospectively at patients with NRG1 fusion-positive non-small cell lung cancer called the eNRGy1 Registry Trial, published in the JCO [Journal of Clinical Oncology], and that showed that these patients tend to respond very poorly to chemotherapy and immunotherapy. And so we would expect that the response rate to docetaxel, for example, would be relatively low. And although it has not been compared to head-to-head with zenocutuzumab using cross-trial comparisons, which we hesitate to do, but looking at the overall numbers, it seems that the docetaxel would be less likely to be effective.

Repotrectinib is another targeted therapy, but that is for patients with NTRK fusion positive cancer and not for NRG1 fusion positive. So that is a different genetic alteration. And then afatinib is a tyrosine kinase inhibitor that targets the HER2/HER3 pathway. And that has been used off-label for patients with NRG1 fusion-positive cancers. But the retrospective data that we have suggests that the response rate and the durability of response is possibly less than zenocutuzumab. Again, they've never been compared head-to-head, but there is not an FDA approval for that indication.

The 1 FDA-approved drug for NRG1 fusion-positive lung cancer patients is zenocutuzumab.

Sources:

Schram AM, Goto K, Kim D-W, et al. Efficacy of zenocutuzumab in NRG1 Fusion-Positive Cancer. N Engl J Med. Published online: 2025;392(6):566-576. doi:10.1056/NEJMoa2405008.

Drilon A, Duruisseaux M, Han J-Y, et al. Clinicopathologic features and response to therapy of NRG1 fusion-driven lung cancers: The eNRGy1 Global Multicenter Registry. J Clin Oncol. 2021;39(25). doi:10.1200/JCO.20.03307