Table 3 Examples of NRG1 targeting molecules and clinical trials and outcomes

Zenocutuzumab

IgG1 bispecific antibody with enhanced ADCC activity targeting HER2 and HER3 receptors

Phase 1/2, open-label, multi-center, multi-national, dose escalation, single agent study to assess the safety, tolerability, PK, PD, immunogenicity, and anti-tumor activity of zenocutuzumab (MCLA-128) in patients with solid tumors harboring an NRG1 fusion (eNRGy)

ORR 34% and median duration of response of 9.1 months across multiple NRG1 fusion-bearing solid tumors (e.g., NSCLC, pancreas cancer, breast cancer, cholangiocarcinoma)

Study ongoing

Patients with NRG1 fusions

[76]/NCT02912949

Seribantumab

Fully human anti-HER3 IgG2 monoclonal antibody

Phase 2, open-label, international, multi-center, study in adult patients with recurrent, locally-advanced or metastatic solid tumors, which harbor the NRG1 gene fusion (CRESTONE)

ORR was 30% (only 10 patients, with most having NSCLC)

Patients with NRG1 fusions

[77]/NCT04383210

Zenocutuzumab

Bispecific antibody with activity targeting HER2 and HER3 receptors

Phase 1/2 in advanced solid tumors

70% CBR in 10 patients with HER2+ metastatic breast cancer

NRG1 fusion not required for eligibility

[78]

GSK2849330

Anti-HER3 monoclonal antibody

Phase 1, first-in-human, open-label study assessed the safety, PK, PD, and preliminary activity of GSK2849330 in patients with HER3-expressing advanced solid tumors

Of 29 patients, 1 confirmed PR, for 19 months in a patient with CD74-NRG1-rearranged NSCLC

NRG1 fusion not required for eligibility

[79]

Tarloxotinib

Potent, covalent pan-HER tyrosine kinase inhibitor

Phase 2, open-label, single-treatment arm clinical trial in adult patients with NSCLC whose tumors test positive for EGFR exon 20 insertions (cohort A), HER2 mutations (cohort B), and NRG1 and HER fusions (cohort C)

No results for cohort C

Patients with a variety of alterations including NRG1 fusions

[81]

Afatinib

Irreversible pan-ERBB tyrosine kinase inhibitor

Novel, prospective real-world outcomes study based on single-patient protocol data in patients with advanced/metastatic solid tumors harboring NRG1 gene fusions

Study ongoing

Patients with NRG1 fusions

[80]

Zenocutuzumab

Bispecific antibody targeting HER2 and HER3 receptors

Phase 2, open-label, 2-arm, multicenter, international study designed to evaluate the efficacy of zenocutuzumab alone or in combination in patients with the following diagnoses: Group A: NRG1 fusion positive NSCLC

Group B: mCRPC

Study ongoing

Patients with NRG1 fusion bearing NSCLC or with mCRPC (no NRG1 fusion required for the latter)

NCT05588609