Neuregulin 1 (NRG1) is an epidermal growth factor (EGF) involved in the development of the nervous and cardiac systems, and homeostasis. Diverse cancers have been identified with recurrent chromosomal rearrangements in part of the NRG1 domain. Oncogenic fusions of NRG1 can occur in invasive mucinous lung adenocarcinoma and pancreatic Kirsten rat sarcoma (KRAS) wild-type adenocarcinoma. NRG fusions bind to human epidermal growth factor receptor 3 (HER3), using an EGF-like binding domain, resulting in HER2/HER3 heterodimerization. Downstream, growth and proliferation signaling pathways are activated resulting in worsening disease.
ZENOCUTUZUMAB-ZBCO (BIZENGRI)
Zenocutuzumab-zbco (Bizengri) is an immunoglobulin G1 (IgG1) bispecific HER2- and HER3-directed antibody that binds to the extracellular domains of HER2 and HER3 expressed on the surface of cells, including tumor cells, causing inhibition of HER2:HER3 dimerization and preventing NRG1 from binding to HER3. Zenocutuzumab-zbco (Bizengri) can decrease cell proliferation and signaling through the phosphoinositide 3-kinase (PI3K) v-akt murine thymoma viral oncogene homologue 1 (AKT)-mammalian target of rapamycin (mTOR) pathway. Zenocutuzumab-zbco (Bizengri) also mediates antibody-dependent cellular cytotoxicity (ADCC).
NON-SMALL CELL LUNG CANCER
Lung cancer caused close to 2 million deaths worldwide in 2020. In the United States, approximately 240,000 new cases are identified annually, and approximately 130,000 individuals die from lung cancer annually. Lung cancers are generally divided into two groups, based on the size of the cells that make up the tumor. Small-cell lung cancer makes up about 12 percent of lung cancers, and begin in neuroendocrine cells that line the inner airways. Non-small cell lung cancers make up most of the remainder of cancers, and can be further subdivided into two subtypes. Adenocarcinomas begin in the cells that line the alveoli and produce mucus. Squamous cell carcinomas begin in the cells that line the inside of the lungs. Each type of cancer responds differently to treatment, so must be differentiated via histology in order to determine a therapy regimen. With the development of therapies that are targeted at a specific biomarker, the prognosis for lung cancer has improved.
PANCREATIC CANCER
Pancreatic cancer is a highly deadly form of cancer, and is the fourth leading cause of cancer deaths in the United States. Because the initial symptoms are so generalized, pancreatic cancer is often not identified until the cancer is advanced and has spread to other organs. It is also difficult to treat. By the time the cancer is identified, curative surgery may not be possible. Common cancer therapies often only work for a short period of time, and may only add a few months to the individual’s lifespan. As with lung cancer, with the development of therapies that are targeted at a specific biomarker, the prognosis for pancreatic cancer has improved.
CLINICAL TRIAL
The efficacy and safety of zenocutuzumab-zbco (Bizengri) in the treatment of individuals with solid tumors harboring a neuregulin 1 (NRG1) fusion was evaluated in an open-label, multicenter Phase II clinical trial titled A Study of Zenocutuzumab (MCLA-128) in Patients With Solid Tumors Harboring an NRG1 Fusion (eNRGy) (NCT02912949). Enrolled individuals received zenocutuzumab-zbco (Bizengri) 750 mg intravenously (IV) every 2 weeks until they experienced disease progression or unacceptable toxicity. A total of 161 individuals were included in the primary efficacy set that consisted of 94 individuals with non-small cell lung cancer (NSCLC), 36 individuals with pancreatic adenocarcinoma, and 31 individuals with other solid tumor types. The co-primary endpoints were objective overall response rate (ORR) and duration of response (DOR).
At the time of data cutoff, the ORR, assessed by blinded independent central review (BICR), was 31 percent (29/94; 95 percent confidence interval [CI], 22–41 percent) for individuals with NSCLC and 44 percent (16/36; 95 percent CI, 28–62 percent) for individuals with pancreatic adenocarcinoma. The median DOR, assessed by BICR, was 13.4 months (range, 1.9–29.5 months) for individuals with NSCLC and 9.1 months (range, 1.9–16.6 months) for individuals with pancreatic adenocarcinoma. Of the total enrolled population, 95 percent of participants experienced at least one adverse event (AE), mostly grade 1 or 2. The most common grade 3 or grade 4 AEs, in the total enrolled population, were anemia (5 percent), gamma-glutamyl transferase (GGT) elevation (4 percent), and pneumonia (3 percent). Grade 3 or 4 AEs that were considered to be treatment-related occurred in 7 percent of the total enrolled population. Fatal AEs occurred in 4 percent of the total enrolled population, but none were considered to be treatment-related.
OFF-LABEL INDICATIONS
There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company's off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
