Zenocutuzumab is a novel bispecific antibody targeting NRG1+ cancer, which is driven by rare chromosomal rearrangements involving NRG1 in various solid tumors, including NSCLC. It works by blocking NRG1:HER3 binding and HER2 HER3 dimerization, inhibiting tumor growth through the PI3K-AKT-mTOR pathway. Zenocutuzumab also demonstrates antibody-dependent cellular cytotoxicity (ADCC) in eliminating tumor cells. It has received Breakthrough Therapy Designations for NRG1+ NSCLC and NRG1+ pancreatic cancer.

In Phase I/II eNRGy trial, evaluating the efficacy of zenocutuzumab, a HER2 x HER3 bispecific antibody, in NRG1+ cancers, significant and durable responses were observed in both NRG1+ non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC). In NRG1+ NSCLC, an overall response rate (ORR) of 37.2% and a clinical benefit rate of 61.5% were achieved, with a median duration of response (DOR) of 14.9 months, and 20 patients continuing treatment. Similarly, in NRG1+ PDAC, a 42.4% ORR was observed, including one complete response and 13 partial responses, along with a clinical benefit rate of 72.7%. Tumor reduction was experienced by 82% of patients, and in those with evaluable CA 19-9 levels, 78% showed a ≥50% decrease. The median DOR in NRG1+ PDAC was 9.1 months, with 6 patients continuing treatment. These findings underscore the durable efficacy of zenocutuzumab in NRG1+ NSCLC and PDAC, representing a promising therapeutic option for these patients.

Zenocutuzumab, when administered at a dose of 750 mg every two weeks as a standalone treatment, showed good tolerability among 189 patients with NRG1-positive cancer. Only 6% of these patients experienced severe (Grade 3-4) adverse events related to the treatment, and none of the patients had to discontinue the treatment due to treatment-related adverse events. Infusion-related reactions were observed in 12% of the patients, but there were no severe (Grade 3 or greater) events among them.

KOL insights: “Zenocutuzumab exhibits a strong 37.2% response rate and a 61.5% clinical benefit rate in NRG1-positive NSCLC. With a rapid 1.8-month median time to response and a durable 14.9-month median response duration, along with a favorable safety profile and no treatment-related discontinuations, it could potentially become the first approved NRG1 agent for this condition.” - Director, Thoracic Oncology & Developmental Therapeutics, Georgetown Lombardi, US

Conclusion: Zenocutuzumab, a novel bispecific antibody targeting NRG1+ cancers, has shown remarkable promise as a therapeutic option for patients with NRG1+ non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC). In clinical trials, it demonstrated significant and durable responses, with impressive overall response rates and clinical benefit rates in both cancer types. Furthermore, the medication exhibited good tolerability, with a low incidence of severe adverse events, making it a well-tolerated treatment option for NRG1-positive cancer patients. These findings highlight Zenocutuzumab's potential to bring hope and improved outcomes to individuals with these challenging and rare cancer subtypes. The drug has received two breakthrough therapy designations by the US FDA and it is expected that the company will have sufficient data for both NRG1+ NSCLC and NRG1+ PDAC in the first half of 2024 to support biologics license application submissions.

NSCLC accounts for up to 85% of lung cancer. DelveInsight estimates that the total incident population of NSCLC in the 7MM will reach nearly 590,000 in 2032. Estimates show the highest contribution in the market size of mNSCLC is from the United States followed by Japan, Germany, and the UK.

For more insight into the patient's burden/epidemiology, treatment, and changing market landscape-related advancements, refer to the Non-Small Cell Lung Cancer Market Insight and Market Forecast Report and Non-Small Cell Lung Cancer Epidemiology Forecast