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Treatment of <em>NRG1</em>-Positive Cancers
NRG1 Oncogenic Gene Fusions Across Solid Tumors: Emerging New Agents for an Important Target

Released: February 28, 2022

Expiration: February 27, 2023

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The identification of gene fusions such as NRG1, ROS1, NTRK, ALK, FGFR, and RET has changed the treatment landscape across a variety of solid tumor types. Of importance, targeted DNA-based and RNA-based next-generation sequencing (NGS) approaches are critical for the identification of actionable gene fusions to guide treatment decision-making with FDA-approved targeted therapies as well as for the appropriate selection and treatment of patients on a clinical trial. 

The NRG1 gene encodes a ligand for HER3. The fusion of the NRG1 gene with a specific fusion partner results in the formation of chimeric oncoproteins that retain the extracellular EGF-like domain of NRG1 and the transmembrane domain of the fusion partner. The resulting fusion protein serves as a ligand for HER3. The HER3 kinase domain is unable to catalytically activate other kinases because of the lack of critical residues. As a result, the clinical utility of HER3 was largely ignored previously. Recently, the HER3 kinase domain was found to have a specific allosteric activation function with the capability to form heterodimers, and thereby, activate other HER-family receptor kinases such as HER2 and HER4. The binding of NRG1 to HER3 can induce HER2/HER3 heterodimerization, which triggers the constitutive activation of downstream signaling pathways that regulate cell growth and cell proliferation. There are several NRG1 fusion partners, including SLC3A2, SDC4, and ATP1B1, with the most commonly reported fusion partner being CD74. Although DNA-based and RNA-based NGS platforms can be used to identify NRG1 fusions, the optimal approach for the detection of NRG1 fusions is targeted RNA-based NGS because often DNA-based NGS fails to detect all NRG1 oncogenic fusions that are present in a tumor sample. 

Emerging Data and Potential Treatment Options for NRG1 Fusion–Positive Cancers
NRG1 fusions are rare oncogenic driver alterations and have been identified in a broad array of solid tumors, including lung cancer, pancreatic cancer, gallbladder cancer, renal cell cancer, ovarian cancer, breast cancer, sarcoma, head and neck cancer, bladder cancer, and colorectal cancer. The incidence of NRG1 fusions across different types of solid tumors is 0.2%. However, the incidence varies by tumor type, with a reported incidence of 0.5% in gallbladder cancer, pancreatic cancer, and renal cell cancer; 0.4% in ovarian cancer; and 0.3% in non-small-cell lung cancer (NSCLC). NRG1 fusions are enriched in the invasive mucinous adenocarcinoma subtype of NSCLC, with a reported incidence of approximately 10% to 30%.

Data from the eNRGy1 global multicenter registry of 110 patients with NRG1 fusion–positive lung cancer demonstrated that 43% of the patients were previous or current smokers. This suggests that unlike other more common gene fusions such as ALK, ROS1, or RET, which occur more predominantly in never-smokers compared with previous/current smokers, NRG1 fusions seem to have a high prevalence regardless of smoking history. The eNRGy1 study demonstrated that NRG1 fusion–positive lung cancers are characterized by a low level of PD-L1 expression and low tumor mutational burden, suggesting that the currently approved immune checkpoint inhibitors will have minimal, if any, activity in this setting. An evaluation of the activity of systemic therapies in patients with metastatic lung cancer on the eNRGy1 study demonstrated that the response rates to standard of care therapies were dismal, ranging from 13% with platinum doublet–based chemotherapy to 20% with single-agent immunotherapy. No objective response was reported with the combination of chemotherapy and immunotherapy. The median progression-free survival with these systemic therapies ranged from approximately 3.0-5.8 months. From these results, it is clear that there is a need for the development of better targeted therapeutic strategies for patients with NRG1 fusion–positive solid tumors. 

Of note, the specific role and utility of immunotherapy, either as a single agent or in combination with chemotherapy, remains unclear among patients in this space. Afatinib is a second-generation pan-HER inhibitor. In the eNRGy1 study, the response rate to afatinib was low at 25%, and the median progression-free survival was only 2.8 months. However, afatinib is currently being investigated in the TAPUR multi-basket study, which is a prospective, nonrandomized, multiarm phase II study that matches genomic alterations in a patient to commercially available targeted therapies. In one of the arms of the TAPUR trial, patients with NRG1 fusion–positive cancers will receive afatinib (NCT02693535). This study will help to determine the efficacy of afatinib in this setting.

A proof-of-concept phase I study initially demonstrated that targeting HER3 in NRG1 fusion–positive cancers elicits durable clinical and radiographic responses (NCT01966445). Since then, multiple agents targeting HER3 have been in development and are under investigation in NRG1 fusion–positive solid tumors. Seribantumab is an investigational anti-HER3 IgG2 monoclonal antibody. It acts by blocking the NRG1 fusion protein from binding to HER3. By so doing, seribantumab is able to prevent ligand-dependent activation as well as HER3 phosphorylation and HER2/HER3 dimerization, thereby inhibiting cancer cell proliferation and cell growth. Seribantumab is currently being investigated in the prospective, multicohort, single-arm phase II CRESTONE trial for patients with recurrent, locally advanced, or metastatic solid tumors harboring NRG1 fusions (NCT04383210). Zenocutuzumab is another agent under investigation in NRG1 fusion–positive solid tumors. Zenocutuzumab is a bispecific antibody targeting HER2 and HER3, with enhanced antibody-dependent cellular cytotoxicity. It docks on HER2 and inhibits the interaction of NRG1 with HER3. In July 2020, zenocutuzumab received the FDA’s orphan drug designation for pancreatic cancer, and in January 2021, it was granted the FDA’s fast track designation for NRG1 fusion–positive cancers. It is being investigated in an ongoing nonrandomized phase I/II trial for patients with locally advanced, unresectable, or metastatic solid tumors harboring NRG1 fusions who have been previously treated with standard therapy or who have been unable to receive standard therapy (NCT02912949). Preliminary results from the phase I/II trial of zenocutuzumab demonstrated promising activity across multiple NRG1 fusion–positive tumor types with an overall response rate of 29%. In the subgroup of patients with pancreatic cancer, the response rate was 42%; response rate was 25% in the patient population with NSCLC. In addition, zenocutuzumab was reported to have a manageable safety profile.

Overall, NRG1 fusions are rare but actionable alterations that occur across different solid tumor types. The preliminary results from the ongoing prospective studies are promising, suggesting that antibody-based HER3-directed therapies offer promising activity and a tolerable safety profile in patients with solid tumors harboring NRG1 fusions

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