NRG 1 Fusion Genes Can be Targeted with the Zenocutuzumab Bispecific Antibody
NRG1 fusion genes are present in several cancer types, and currently lack significant treatment options. When a NRG1 gene fusion protein is present in a cancer it increases the cancers growth by binding to human epidermal growth factor receptor 3 (HER3) receptors on the cell surface, which then recruit human epidermal growth factor receptor 2 (HER2). When both HER2/HER3 combine, this activates a signaling pathway that is crucial for cancer survival and causes cancer cells to grow.
Neuregulin 1 or NRG1 is a cell adhesion molecule that in humans is encoded by the NRG1 gene. NRG1 is one of four proteins in the neuregulin family that act on the EGFR family of receptors and can be targeted to decrease cancer cell growth.
About Zenocutuzumab (MCLA-128)
MCLA-128 is a precision cancer medicine bispecific antibody construct that represents an innovative immunotherapy approach to help the body’s immune system target the HER2 and HER3 protein on cancer cells. Upon intravenous administration, the bispecific antibody docks on HER2, and subsequently blocks heregulin-stimulated proliferation of tumor cells by binding HER3. In addition to inhibiting HER3-dependent signaling, simultaneous targeting of HER2 and HER3 by MCLA-128 may overcome a common way that cancers develop resistance. MCLA-128 eliminate cancer cells by activating the immune system to recruit natural killer (NK) cells to cancer cells coated with the MCLA-128 bispecific antibody.
Initial clinical data showed that patients treated with MCLA-128 responded to treatment with symptomatic improvement and MCLA-128 works across cancer types. Responses were reported in patients with pancreatic ductal adenocarcinoma and non-small cell lung cancer.
ASCO 2022 Update
Zenocutuzumab was found to produce durable responses in patients with previously treated advanced NRG1-positive cancers in several tumor types according to data from a phase 1/2 trial (NCT02912949) presented during the 2022 ASCO Annual Meeting.
The phase 1/2 clinical trial enrolled patients with locally advanced, unresectable or metastatic solid tumors that were NRG1 positive to receive treatment with intravenous zenocutuzumab at 750 mg, given every 2 weeks, until disease progression.
Zenocutuzumab - the first approved systemic therapy for patients with NRG1 fusion–positive NSCLC or pancreatic adenocarcinoma.
Zenocutuzumab targeted therapy approved for treatment of pancreatic ductal adenocarcinoma and non-small cell lung cancer with NRG1 fusions.
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- 42% of patients with pancreatic cancer responded to treatment.
- 35% of patients with NSCLC responded to treatment.
- Zenocutuzumab was reported to be very well tolerated, with less than 1% of patients discontinuing treatment because of side effects.
FDA Approval Dec 2024
The FDA granted accelerated approval to Bizengri (zenocutuzumab-zbco) for the treatment of advanced, non–small cell lung cancer (NSCLC) and pancreatic cancer harboring an NRG1 gene fusion with disease progression on or after prior systemic therapy.1
The approval was supported by data from the phase 2 eNRGy trial (NCT02912949), which showed that patients with NSCLC achieved an overall response rate of 33%, and a median duration of response of 7.4 months. In patients with pancreatic adenocarcinoma the ORR was 40% and the DOR ranged from 3.7 months to 16.6 months.
The company developing Zenocutuzumab is Merus and they are currently evaluating Bizengri in other phase 2 trials.
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References:
- Schram AM, Goto K, Kim DW, et al. Efficacy and safety of zenocutuzumab, a HER2 x HER3 bispecific antibody, across advanced NRG1 fusion (NRG1+) cancers. J Clin Oncol. 2022;40(suppl 16):105. doi:10.1200/JCO.2022.40.16_suppl.105
- Merus granted FDA fast track designation of zenocutuzumab for the treatment of patients with neuregulin 1 fusion cancers. News release. Merus NV. January 7, 2021. Accessed June 5, 2022. http://bit.ly/3bobmtY
- Merus announces FDA orphan drug designation of zenocutuzumab for the treatment of pancreatic cancer. Merus NV. July 27, 2020. Accessed June 5, 2022. https://bit.ly/3QeKlLN
