On December 4, 2024, the U.S. Food and Drug Administration (FDA) granted accelerated approval for Merus N.V.’s BIZENGRI® (zenocutuzumab-zbco), a breakthrough therapy for patients with advanced unresectable or metastatic pancreatic adenocarcinoma and non-small cell lung cancer (NSCLC), harboring a neuregulin 1 (NRG1) gene fusion. This fills an important unmet need for patients with advanced NRG1+ cancer who had limited treatment options and suboptimal responses to conventional systemic treatment.
The approval is based on the efficacy evaluated in the eNRGy study (NCT02912949), highlighting the clinical benefits and tolerability of BIZENGRI® for NRG1-driven cancers. The drug is formulated as a 20 mg/mL intravenous injection and is expected to be available to patients soon.
“The FDA approval of BIZENGRI® marks an important milestone for patients with pancreatic adenocarcinoma or NSCLC that is advanced unresectable or metastatic and harbors the NRG1 gene fusion. I have seen firsthand how treatment with BIZENGRI® can deliver clinically meaningful outcomes for patients,” said Dr. Alison Schram, oncologist and principal investigator for the eNRGy trial at Memorial Sloan Kettering Cancer Center.
Understanding NRG1 Gene Fusion
NRG1 gene fusions were identified as a novel oncogenic driver across cancer types in the 2000s but became clinically relevant only a decade later. NRG1 gene fusions are rare genomic alterations that drive tumor growth across various cancer types, including pancreatic, lung, and breast cancers. These fusions create altered proteins that activate HER3 and HER4 receptors, triggering downstream signalling pathways that promote tumor growth.
Targeted treatments for HER2/HER3 pathway inhibition offer a promising strategy for managing these cancers. Although NRG1 fusions have a low global incidence of about 0.2%, their presence is linked to resistance against chemotherapy and HER2-targeted therapies, particularly in invasive mucinous adenocarcinoma subtypes of NSCLC.
Early detection remains a challenge. RNA sequencing is the most reliable method for identifying NRG1 fusions, as DNA-based diagnostic methods are not sensitive enough. Initial screening can be done by immunohistochemistry, to detect HER3 phosphorylation and identify specific histological subtypes, such as invasive mucinous adenocarcinoma for NSCLC, and KRAS-wild-type tumors.
How BIZENGRI® Works
NRG1 fusions can create high NRG1 concentrations near HER2/HER3, resulting in constituent activation of HER2/HER3 tumor signaling. BIZENGRI® is a first-in-class IgG1 bispecific antibody that targets HER2 and HER3, inhibiting HER2:HER3 dimerization and preventing NRG1 binding to HER3.
Preclinical in-vitro studies demonstrated inhibition of cancer cell proliferation and signaling via the PI3K-AKT-mTOR pathway. Additionally, it was shown to induce antitumor effects via antibody-dependent cellular cytotoxicity in mouse models of NRG1+ lung and pancreatic cancers.
Clinical Success: The eNRGy Study
The eNRGy study (NCT02912949) was a multicenter, open-label, multicohort trial conducted across North America, Europe, Asia, and the Pacific islands. The trial evaluated the drug’s efficacy in 64 patients with advanced or metastatic NRG1+ NSCLC and 30 patients with pancreatic adenocarcinoma who had disease progression following standard of care treatment.
Key findings include:
- NSCLC Outcomes: An overall response rate (ORR) of 33%, with a median duration of response (DOR) of 7.4 months.
- Pancreatic Cancer Outcomes: An ORR of 40% with DOR ranging from 3.7 to 16.6 months.
The therapy demonstrated significant antitumor effects and was well tolerated. However, some common treatable side effects were reported, such as diarrhea, musculoskeletal pain, fatigue, and infusion-related reactions. A few patients (<2%) also reported laboratory abnormalities, including increased gamma-glutamyl transferase, decreased hemoglobin, decreased sodium, and decreased platelets.
Prescribing Information and Patient Support
BIZENGRI® is administered as a 750 mg intravenous infusion every two weeks. The prescribing guidelines include a boxed warning for embryo-fetal toxicity, prohibiting use during pregnancy and requiring contraceptive measures. Merus N.V., the manufacturing company, is committed to ensuring access and patient support through the PTx Assist™ program, which offers guidance on insurance, financial assistance, and treatment resources.
