A First in Oncology! NRG1-Targeted Zenocutuzumab Receives FDA Approval for Lung and Pancreatic Cancer

On December 4, 2024, the US Food and Drug Administration (FDA) granted accelerated approval to zenocutuzumab-zbco (brand name Bizengri, manufactured by Merus N.V.) for the following conditions:

• Advanced, unresectable or metastatic neuregulin 1 (NRG1) gene fusion-positive non-small cell lung cancer (NSCLC) in patients previously treated with systemic therapy whose disease has progressed and
• advanced, unresectable or metastatic NRG1 gene fusion-positive pancreatic adenocarcinoma in patients previously treated with systemic therapy whose disease has progressed.

This is the first FDA approval of a systemic treatment for patients with NSCLC and pancreatic adenocarcinoma harboring an NRG1 gene fusion.

The Importance of NRG1 Gene Fusions

NRG1 gene fusions are genetic alterations that are rare in various cancer types but are considered important oncogenic drivers . NRG1 fusions have been identified as targetable oncogenic drivers, particularly in pancreatic cancers without a KRAS mutation.

These genetic alterations cause abnormal activation of the HER2 and HER3 receptors, supporting tumor cell growth and survival. Detecting NRG1 fusions therefore increases patients' potential to benefit from targeted treatments.

In non-small cell lung cancer (NSCLC), approximately 0.2% of cases have NRG1 gene fusions. In pancreatic adenocarcinoma, the rate is around 0.5% . These low prevalence rates show that NRG1 gene fusions are rare in both cancer types.

Nevertheless, approximately 2.3 million new cases of lung cancer are diagnosed worldwide each year. Approximately 80% of these cases are classified as non-small cell lung cancer (NSCLC). NRG1 gene fusions are identified in approximately 0.2% of NSCLC cases. Based on these data, approximately 4 thousand patients with NSCLC may have NRG1 gene fusions each year.

In Turkey, approximately 40 thousand people develop lung cancer each year. Assuming that 80% of these cases are NSCLC, there are approximately 32800 NSCLC cases. Given that NRG1 gene fusions are present in 0.2% of these cases, this genetic alteration could be identified in approximately 70 patients with NSCLC in Turkey each year.

FDA Approval Based on the eNRGy Study

The efficacy of zenocutuzumab-zbco was evaluated in a multicenter, open-label, multicohort clinical trial called the eNRGy study (NCT02912949). The study included 64 patients with advanced or metastatic NRG1 fusion-positive NSCLC and 30 patients with advanced or metastatic NRG1 fusion-positive pancreatic adenocarcinoma whose disease had progressed after standard treatment. NRG1 gene fusions were identified using next-generation sequencing tests.

The study's main efficacy measures were confirmed overall response rate and duration of response .

• In patients with NSCLC, the overall response rate was 33% (95% CI: 22%, 46%), and the median duration of response was 7.4 months (95% CI: 4.0, 16.6).
• In patients with pancreatic adenocarcinoma, the overall response rate was 40% (95% CI: 23%, 59%), and the duration of response ranged from 3.7 to 16.6 months.

Safety data showed that the most common adverse reactions (10% or more) were diarrhea, musculoskeletal pain, fatigue, nausea, infusion-related reactions, shortness of breath, rash, constipation, vomiting, abdominal pain and edema. The most common grade 3 or 4 laboratory abnormalities (10% or more) were increased gamma-glutamyl transferase, decreased hemoglobin, decreased sodium and decreased platelets. The prescribing information includes a warning about embryo-fetal toxicity.

Recommended Dose

The recommended dose of zenocutuzumab-zbco is 750 mg by intravenous infusion every 2 weeks until disease progression or unacceptable adverse reactions.

Conclusion and Future Perspectives

The FDA's accelerated approval of zenocutuzumab-zbco is an important milestone for patients with NRG1 gene fusion-positive NSCLC and pancreatic adenocarcinoma. This approval expands targeted treatment options for patients with this rare genetic alteration. However, accelerated approvals generally require additional clinical data; results from ongoing and future clinical trials are therefore awaited to learn more about the long-term efficacy and safety of zenocutuzumab-zbco.