| Abstrakt: |
Neuregulin 1 (NRG1) fusions are oncogenic drivers that have been detected in non-small-cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC) and other solid tumors. NRG1 fusions are rare, occurring in less than 1% of solid tumors. Patients with NRG1 fusion positive (NRG1+) cancer have limited therapeutic options. Zenocutuzumab is a novel, bispecific IgG1 antibody that targets both HER2 and HER3 proteins and inhibits NRG1 binding through a 'Dock & Block®' mechanism of action. Here, we describe the rationale and design of the phase II component of the eNRGy trial, part of the overall, open-label phase I/II, multicenter trial exploring the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity and antitumor activity of zenocutuzumab in patients with NRG1+ NSCLC, PDAC or other solid tumors. Plain language summary eNRGy: a clinical trial of zenocutuzumab for cancer caused by NRG1 gene fusions NRG1 gene fusions are rare mutations that cause cancer cells to grow. These fusions are found in many different types of cancer. Tumors with NRG1 gene fusions do not respond well to standard treatment options. Zenocutuzumab, or Zeno, is a treatment that is being tested to see if it can stop cancer that is growing because of NRG1 gene fusions. Here, we describe the reasoning for and design of an ongoing clinical trial (eNRGy) designed to study the efficacy (how well it works) and safety of Zeno in patients with cancer that has NRG1 gene fusions. The eNRGy trial is recruiting patients with cancer that has NRG1 gene fusions, including non-small-cell lung cancer, pancreatic cancer and others. Patients who join this trial will receive Zeno once every 2 weeks until their cancer grows. The main goal (primary end point) of this trial is to determine the percentage of patients whose tumors decrease in size by 30% or more. The eNRGy trial is currently enrolling patients. For more information, refer to ClinicalTrials.gov (Identifier: NCT02912949), visit https://nrg1.com/, or call 1-833-NRG-1234. Tweetable abstract eNRGy is a global phase I/II trial currently recruiting patients with NRG1+ NSCLC, PDAC or other solid tumors to assess zenocutuzumab, an investigational bispecific IgG1 antibody that inhibits NRG1-activated HER2/HER3 oncogenic signaling. Graphical abstract Executive summary Neuregulin 1 (NRG1) is a ligand for HER2/HER3 signaling, which can promote the growth and development of epithelial, glial and muscle cells; chromosomal rearrangements can result in NRG1 gene fusions, leading to dysregulated HER2/HER3 signaling. NRG1 fusions can function as oncogenic drivers and are typically mutually exclusive of other common oncogenic drivers. Background & rationale NRG1 fusions have been described in numerous cancers, including non-small-cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC). Although the incidence of cancers harboring NRG1 fusions is relatively low, these cancers have limited therapeutics options. It has been shown that inhibiting HER2/HER3 signaling could provide therapeutic benefits to patients with NRG1+ cancer. Zenocutuzumab is a novel, bispecific IgG1 antibody that targets both HER2 and HER3 proteins and inhibits NRG1 binding through a 'Dock & Block®' mechanism of action. eNRGy trial design & planned sample size The eNRGy trial is a phase I/II, open-label, multicenter trial exploring the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity and antitumor activity of zenocutuzumab in patients with NRG1+ NSCLC, PDAC, or other solid tumors. Planned enrollment in the eNRGy trial is approximately 100 patients with NRG1+ NSCLC, 50 patients with NRG1+ PDAC, and 100 patients with other NRG1+ solid tumors. The primary objective is to assess the magnitude of antitumor activity of zenocutuzumab, and the key secondary objective is to assess the durability of antitumor activity. Conclusion The eNRGy trial will investigate the efficacy and safety of zenocutuzumab, a potential first-in-class IgG1 bispecific antibody targeting HER2/HER3, in patients with NRG1+ cancer. Enrollment of patients with NRG1+ cancer began in September 2019 and, at the time of this publication, the eNRGy trial is actively recruiting participants. [ABSTRACT FROM AUTHOR] |
