Conference Correspondent

Mechanism of Action of Neratinib: An Irreversible Pan-HER Inhibitor in Late-Stage Clinical Development

Conference Correspondent 

Breast cancer is the second leading cause of death in women. HER2 protein is a tyrosine kinase overexpressed in approximately 15% of breast cancer cases, and is shown to play a significant role in tumor development and progression. The poor prognosis associated with HER2-positive breast cancer has been dramatically improved with the development of HER2-targeted therapies.

Trastuzumab is an HER2-targeted monoclonal antibody that improves survival in the adjuvant setting. Despite the reduction of disease recurrence with trastuzumab, up to 24% of patients will experience disease recurrence within 8 to 11 years after receiving adjuvant therapy with trastuzumab. Efforts to improve outcomes, either by extending the duration of trastuzumab therapy or adding another HER2-targeted therapy such as lapatinib, have proved unsuccessful.

Neratinib is a potent, irreversible tyrosine kinase inhibitor (TKI) of HER1, HER2, and HER4, and is currently under development. Neratinib irreversibly binds to the intercellular signaling domain of HER1, HER2, HER3, and epithelial growth factor receptor, and inhibits phosphorylation and several HER downstream signaling pathways. The result is decreased proliferation and increased cell death. Clinical studies have shown that intracellular inhibition of HER signaling by neratinib is a more effective means of suppressing HER-mediated tumor growth and overcoming tumor escape mechanisms experienced with current HER2-targeted therapies and chemotherapeutic agents.

ExteNET is an ongoing, phase 3, international, randomized, double-blind study examining the efficacy and safety of neratinib in the extended adjuvant setting in patients with early-stage HER2-positive breast cancer. In this study, 2840 women with early-stage HER2-positive breast cancer were randomly assigned to receive a 1-year course of neratinib 280 mg daily or placebo after trastuzumab-based adjuvant therapy.

In this extended adjuvant treatment setting, patients experienced significantly improved invasive disease-free survival, and 50% of patients experienced no disease recurrence 2 years after study randomization. Neratinib was also shown to have a manageable and tolerable safety profile. Common grade 1 or 2 adverse events in this study were diarrhea, nausea, fatigue, vomiting, abdominal pain, headache, and rash. Grade 3 diarrhea occurred in up to 40% of patients when no antidiarrheal prophylaxis was used. When loperamide, a prophylaxis regimen, was used in the first cycle of neratinib, the incidence, severity, and frequency of diarrhea were reduced, thereby enabling patients to stay on therapy. Cardiac events were rare, with grade 3 or 4 decreases in left-ventricular ejection fraction reported in 1% of neratinib-treated patients.

Neratinib has also proved to be efficacious in first-line treatment of HER2-positive, metastatic breast cancer (MBC). In patients with previously treated HER2-positive MBC, overall response rates (ORRs) with single-agent neratinib 240 mg daily ranged from 29% to 40%. When used in combination with paclitaxel, neratinib showed an ORR of 73%. When combined with capecitabine, another chemotherapeutic agent, the ORR was 63%. In addition to HER2-positive MBC, neratinib was also efficacious in patients with HER2-mutated breast cancer. In the phase 2 SUMMIT trial, patients with HER2-mutated breast cancer experienced a 33% ORR at 8 weeks.

Neratinib is the first TKI proved to reduce the risk for disease recurrence in patients with early-stage HER2-positive breast cancer. Based on the efficacy of neratinib in early-stage HER2-positive breast cancer, MBC, and HER2-mutant tumors, neratinib is anticipated to become the new standard of care across multiple breast cancer treatment settings.

Barrios C, et al. ONS Abstract IS-2.

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