NRG1 Fusions Emerge as New Target of Interest in Lung, Pancreatic Cancers

Since it was first described in invasive mucinous lung adenocarcinoma in 2014, NRG1 fusion positivity has emerged as a therapeutic target of interest in several tumor types, the most notable of which are non–small cell lung cancer (NSCLC) and pancreatic adenocarcinoma.1 Over the course of a recent OncLive® News Network video series, experts in the fields of NSCLC and pancreatic cancer provided their perspectives on different testing approaches for NRG1 fusions, treatment strategies for patients with NRG1 fusion–positive disease, and ongoing research efforts in this area.

NRG1 is a gene that encodes the neuregulin 1 protein, which is involved in neural development, synaptic plasticity, myelination, and intercellular signaling in heart and breast tissues. The EGF-like domain of the NRG1 protein is primarily an activator of HER3 and activates heterodimerization of ErbB2-ErbB3 as well as downstream signaling of the MAPK and PI3K/AKT/mTOR pathways. NRG1 fusion proteins are abnormal activators of ErbB-mediated cell proliferation pathways, leading to the proliferation of molecularly altered cells.

“NRG1 fusions are a relatively novel advance in our armamentarium of targetable options for [patients with] lung cancer,” Mary B. Beasley, MD, a professor of pathology, molecular and cell based medicine, at The Mount Sinai Hospital in New York, New York, said during the series. “They’ve been described in a variety of tumor types, with pancreatic cancer [being an area] that has received a lot of focus. In regard to lung cancer, it’s particularly exciting that they are often found in the subtype of adenocarcinoma that we haven’t had a lot of treatment options for previously: invasive mucinous adenocarcinoma.”

Treatment and Testing Considerations for NRG1+ NSCLC

DNA and RNA testing play a key role in identifying patients with NRG1 fusion–positive NSCLC. RNA-based testing can be used to identify NRG1 fusions in-frame, which allows for the detection of transcription products produced by alternative splicing forms.1 Conversely, DNA-based next-generation sequencing (NGS) approaches enable the description of exact sequences of breakpoints but cannot identify if these sequences undergo translation.

“[To identify] NRG1 fusions, one can perform standard DNA testing, which is taking the genomic DNA from the tumor and looking to see if these 2 genes are joined together,” D. Ross Camidge, MD, PhD, the director of the Thoracic Oncology Clinical and Clinical Research Programs, as well as a professor of medicine-medical oncology, at the University of Colorado Anschutz Medical Campus in Aurora, said during the series. “The problem is, there may be a lot of junk in between them and your usual primers might miss it. One of the ways of increasing the sensitivity for NRG1 fusions is using an RNA-based extraction before you do the NGS in addition to the DNA [testing]. It’s not either/or, it’s in addition to the standard DNA NGS. You will likely double the detection rate if you do both a DNA and RNA extraction for your NGS.”

Depending on disease stage, frontline NRG1 fusion–positive NSCLC is treated with standard interventions such as surgery, adjuvant and neoadjuvant therapy, and standard chemotherapy in the advanced stage, according to Camidge. Off-label treatment with the pan-HER inhibitor afatinib (Gilotrif) is also an option. However, this agent has a low response rate and duration of response with high rates of toxicity, underscoring the need for NRG1-targeted and additional HER3-directed agents, Camidge added.

Treatment and Testing Considerations for NRG1+ Pancreatic Cancer

In pancreatic cancer, NRG1 fusions are rare occurring in approximately 0.5% of patients.1 “When we look at all of our patients in databases, presentations, and publications, we see that NRG1 fusions are enriched in [patients with] pancreatic cancers who have KRAS wild-type status,” E. Gabriela Chiorean, MD, noted during the series. The same DNA and RNA testing considerations as NSCLC should be applied to detecting NRG1 fusions in pancreatic cancer, with RNA sequencing being considered as more reliable in identifying fusions, Chiorean added.

Chiorean is the clinical director of the GI Medical Oncology Program, director of the Clinical Research GI Oncology Program, and an affiliate investigator in the Translational Science and Therapeutics Division, at Fred Hutch Cancer Center in Seattle, Washington. She is also a full professor of medicine at the University of Washington in Seattle.

Standard therapy for NRG1 fusion–positive pancreatic cancer is multi-agent chemotherapy for patients with an adequate performance status in the first- and second-line setting, Chiorean said. She also recommended enrolling patients with NRG1 fusion–positive disease in clinical trials of targeted therapeutics.

Zenocutuzumab Breaks New Ground in NRG1 Fusion+ Cancers

On December 4, 2024, the FDA granted accelerated approval to the HER2/HER3 bispecific antibody zenocutuzumab-zbco (Bizengri) for the treatment of adult patients with advanced, unresectable, or metastatic NRG1 fusion–positive NSCLC following disease progression on or after prior systemic therapy or advanced, unresectable; or metastatic pancreatic adenocarcinoma harboring an NRG1 gene fusion with disease progression on or after prior systemic therapy.2 The approval was supported by findings from the phase 2 eNRGy trial (NCT02912949). The regulatory decision marked the first FDA approval of a systemic therapy for patients with NRG1 fusion–positive NSCLC or pancreatic adenocarcinoma.

“[Zenocutuzumab] disrupts the signaling between the molecule that binds NRG1, [which is] HER3 and HER2, which then becomes the signaling [molecule],” Camidge explained.

Data from eNRGy demonstrated that patients with NSCLC (n = 64) achieved an objective response rate (ORR) of 33% (95% CI, 22%-46%), with a complete response (CR) rate of 1.6%, and a median duration of response (DOR) of 7.4 months (95% CI, 4.0-16.6).3 Forty-three percent of patients had a DOR of at least 6 months.

Patients with pancreatic adenocarcinoma (n = 30) experienced an ORR of 40% (95% CI, 23%-59%), including a CR rate of 3.3%, and a DOR that ranged from 3.7 to 16.6 months. Most patients (67%) had a DOR of at least 6 months.

“We do not yet know the progression-free and overall survival of these patients,” Chiorean said. “But the fact that [a significant portion] of patients sustained durable responses is an unprecedented [finding] for a refractory patient population, which speaks to incredible efficacy of this agent in this patient population.”

eNRGy was a global, multicenter, open-label study that enrolled adult patients with NRG1 fusion–positive locally advanced unresectable or metastatic solid tumors who were previously treated with or unable to receive standard therapy and had an ECOG performance status of 2 or less.4 All patients received zenocutuzumab at a dose of 750 mg once every 2 weeks until disease progression or unacceptable toxicity. The primary end point was ORR per RECIST 1.1. Secondary end points included ORR by central review, DOR, and safety.

Data from the NSCLC safety population (n = 99) revealed that patients who received zenocutuzumab experienced serious adverse effects (AEs) and fatal AEs at rates of 25% and 3%, respectively.3 Treatment discontinuation and dose interruptions occurred at rates of 3% and 29%, respectively. Any-grade AEs occurring in at least 10% of patients included diarrhea (25%), musculoskeletal pain (23%), and dyspnea (18%), among others.

In the pancreatic adenocarcinoma safety population (n = 39), patients experienced serious AEs at a rate of 23% and 2 patients died due to AEs. Thirty-three percent of patients experienced dose interruptions due to AEs. The most common any-grade AEs that were reported in at least 10% of patients included diarrhea (36%), musculoskeletal pain (28%), nausea (23%), and vomiting (23%).

“[An important message from this study] is that it was enriched for individuals with an NRG1 fusion, yet we are only getting a response rate of [approximately] 30%,” Camidge said. “Is that because there’s underlying heterogeneity in this population? We have to pull that apart and I suspect that this is the beginning of the story of NRG1 fusions not the end.”

References

1. Kucharczyk T, Nicoś M, Kucharczyk M, Kalinka E. NRG1 gene fusions-what promise remains behind these rare genetic alterations? A comprehensive review of biology, diagnostic approaches, and clinical implications. Cancers (Basel). 2024;16(15):2766. doi:10.3390/cancers16152766
2. FDA grants accelerated approval to zenocutuzumab-zbco for non-small cell lung cancer and pancreatic adenocarcinoma. FDA. December 4, 2024. Accessed December 13, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zenocutuzumab-zbco-non-small-cell-lung-cancer-and-pancreatic
3. Bizengri. Prescribing information. Merus; 2024. Accessed December 13, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761352s001lbl.pdf
4. Schram A, Goto K, Kim D-W, et al. Durable efficacy of zenocutuzumab, a HER2 x HER3 bispecific antibody, in advanced NRG1 fusion-positive (NRG1+) non-small cell lung cancer (NSCLC). Ann Oncol. 2023;34(suppl 2):S756-S757. doi:10.1016/j.annonc.2023.09.2349