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. 2024;20(16):1057-1067.
doi: 10.2217/fon-2023-0824. Epub 2024 Feb 13.

The phase I/II eNRGy trial: Zenocutuzumab in patients with cancers harboring NRG1 gene fusions

Dong-Wan Kim  1 , Alison M Schram  2 , Antoine Hollebecque  3 , Kazumi Nishino  4 , Teresa Macarulla  5 , Sun Young Rha  6 , Michaël Duruisseaux  7   8   9 , Stephen V Liu  10 , Mohammed Najeeb Al Hallak  11 , Kumiko Umemoto  12 , Claas Wesseler  13 , James M Cleary  14   15 , Christoph Springfeld  16 , Cindy Neuzillet  17 , Andrew Joe  18 , Shekeab Jauhari  18 , Jim Ford  19 , Koichi Goto  20
Affiliations

The phase I/II eNRGy trial: Zenocutuzumab in patients with cancers harboring NRG1 gene fusions

Dong-Wan Kim et al. Future Oncol. 2024.

Abstract

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.

Trial registration: ClinicalTrials.gov NCT02912949.

Keywords: HER2; HER3; NRG1 fusion; NRG1+; NSCLC; PDAC; Zeno; Zenocutuzumab; eNRGy trial; recruiting.

Plain language summary

eNRGy: a clinical trial of zenocutuzumab for cancer caused by NRG1 gene fusionsNRG1 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.

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Conflict of interest statement

D-W Kim reports uncompensated consultation or advisory role at Amgen, AstraZeneca, BMS/ONO Pharmaceutical, Daiichi Sankyo, GSK, Janssen, Merck, MSD, Oncobix, Pfizer, SK Biopharm, and Takeda. AM Schram reports serving on a Merus advisory board. All other authors have no other competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript apart from those disclosed.

Figures

Figure 1.
Figure 1.
Zeno mechanism of action. (A) NRG1 fusion proteins function as ligands for HER3 (similar to NRG1) and bind to HER3 with high affinity to promote HER2/HER3 dimerization and downstream signaling. (B) Zeno inhibits the NRG1/HER3 interaction via its ‘Dock & Block®' mechanism, whereby one arm of the antibody binds to the HER2 receptor, optimally positioning the anti-HER3 arm to block the ligand/receptor interaction and prevent HER2/HER3 dimerization. EGF: Epidermal growth factor; HER2: Human epidermal growth factor receptor 2; HER3: Human epidermal growth factor receptor 3; NRG1: Neuregulin 1; Zeno: Zenocutuzumab. Reproduced with permission from [27], © Elsevier (2018).
Figure 2.
Figure 2.
eNRGy trial design. ECOG PS: Eastern Cooperative Oncology Group performance status; iv.: Intravenous; NRG1: Neuregulin 1; NSCLC: Non-small-cell lung cancer; ORR: Overall response rate; PD: Progressive disease; PDAC: Pancreatic ductal adenocarcinoma; RECIST: Response Evaluation Criteria in Solid Tumors; Q2W: Every 2 weeks; Q8W: Every 8 weeks; Zeno: Zenocutuzumab.
Figure 3.
Figure 3.
eNRGy trial sites. Active sites include Memorial Sloan-Kettering Cancer Center, National Cancer Center Hospital (NCCH) East, Seoul National University Hospital, Gustave Roussy, Hospital Universitario Vall d'Hebron, Hospices Civils de Lyon Cancer Institute – Louis Pradel Hospital, St. Marianna University Hospital, Institut Curie – René-Huguenin Hospital, Karmanos Cancer Institute, Princess Margaret Cancer Centre, Osaka International Cancer Institute, Netherlands Cancer Institute, Deutsches Krebsforschungszentrum, Dana-Farber Cancer Institute, Georgetown University Department of Medicine, University of California Irvine Medical Center (UCIMC) – Chao Family Comprehensive Cancer Center, Mayo Clinic Hospital – Phoenix, Samsung Medical Center, Severance Hospital – Yonsei Cancer Center, A.O. Niguarda Cà Granda Farmacia Ospedaliera – U.O. di Cardiología, Universitair Medisch Centrum Utrecht, Hospital Clinico Universitario de Valencia, The University of Texas MD Anderson Cancer Center, Mayo Clinic Cancer Center (MCCC) – Rochester, Emory Clinic, National Cancer Center Hospital (NCCH), Centro Integral Oncológico Clara Campal (CIOCC), National Cancer Centre of Singapore Pte Ltd, Hospital Universitario 12 de Octubre, Istituti Fisioterapici Ospitalieri, Mayo Clinic Hospital – Florida, Northwest Medical Specialties, Medical Oncology Associates, P.S., University of Pennsylvania – Penn Memory Center, St. James Healthcare, Hematology-Oncology Associates of Fredericksburg, Cancer Specialists of North Florida, Utah Cancer Specialists, and Billings, Montana. TTD: Treatment of digestive tumors.
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