Case Study Shows Early Efficacy for Neratinib in HER2-Mutated Metastatic Breast Cancer

Treatment with the second-generation HER2/EGFR-targeted TKI neratinib resulted in a partial response and dramatic improvement in functional status for a patient with HER2-mutated breast cancer.

Ron Bose, MD, PhD

Treatment with the second-generation HER2/EGFR-targeted TKI neratinib resulted in a partial response and dramatic improvement in functional status for a patient with HER2-mutated breast cancer, according to a single-patient case study published in the Journal of the National Comprehensive Cancer Network.

"The treatment of this patient is an excellent example of collaboration between basic research, clinical application and biotechnology companies for the benefit of patients," co-author of the publication Noa Efrat Ben-Baruch, MD, head of the Department of Oncology, Kaplan Medical Center, Rehovot, Israel, said in a statement. "With the advent of molecular profiling of patients with metastatic disease, such collaborations are of utmost importance for the development of new drug candidates outside of formal clinical trials.”

According to the authors of the study, these findings represent the first successful single-agent treatment for patients with breast cancer harboring an activating mutation in the HER2 tyrosine kinase. In most situations, HER2 tyrosine kinase mutations occur independently from HER2 gene amplifications, making these patients ineligible or unlikely to respond to traditional HER2-targeted therapies.

In the single-patient case study, a female patient with advanced stage IV invasive ductal carcinoma of the breast was treated with neratinib following chemotherapy and hormonal therapy. By next-generation sequencing conducted by Foundation Medicine, the tumor was found to harbor an activating mutation in the TKI binding site of the HER2 kinase domain (HER2 L755S). This specific alteration is known to cause resistance to the HER2 TKI lapatinib.

Following treatment, the patient experienced a partial response that lasted 11 months. At the time of progression, capecitabine was added to neratinib, resulting in a second response, the magnitude of which rivaled responses seen with trastuzumab in HER2-amplified tumors.

“Prior to treatment, the patient’s ECOG performance status deteriorated and she was essentially homebound with massive ascites and profound weakness,” Ben-Baruch said. “The patient began treatment with neratinib, and within two months her performance status improved. She was able to resume normal daily activities, and a CT scan performed showed a partial response that persisted for 11 months. Capecitabine was then added to neratinib and the patient’s tumor again responded. This clinical response markedly improved the patient’s performance status and quality of life."

These findings build on evidence presented at the 2012 San Antonio Breast Cancer Symposium (SABCS), which demonstrated promising activity for neratinib across HER2-mutated cell lines. In this study, various HER2-targeted therapies were tested across HER2-mutated cell lines, with neratinib demonstrating the highest level of activity.

In the SABCS analysis, which was subsequently published in the journal Cancer Discovery, HER2 mutations were present in 1.5% to 2% of patients with breast cancer. Given the number of patients with newly diagnosed breast cancer each year, these findings could translates to approximately 4000 patients annually with HER2-mutated breast cancer in the United States, explained lead investigator Ron Bose, MD, PhD, who was also a co-author on the single-patient case study.

“This case is the first published report of a patient with HER2-mutated breast cancer responding to treatment with a single-agent, HER2-targeted drug,” Bose, from the Siteman Cancer Center and Washington University School of Medicine, said in a statement. "This also validates our previously published preclinical data with neratinib that showed potent antitumor activity in HER2 mutations. Additional study of neratinib in patients with HER2 mutations is clearly warranted.”

Based on the preclinical results, a phase II trial was launched to assess the efficacy of neratinib once daily in patients with HER2 non-amplified, HER2-mutant stage IV breast cancer. In the study, patients are being randomized to receive neratinib alone or with fulvestrant, with the option of administering trastuzumab across arms. The primary outcome measures for the study focus on overall clinical activity (NCT01670877).

Additionally, an open-label phase II study is assessing neratinib in patients with solid tumors and somatic mutations in EGFR, HER2, and HER3 or with EGFR gene amplification (NCT01953926). This study is founded on findings from The Cancer Genome Atlas, which identified HER2 mutations across a wide variety of solid tumors. In fact, the primary basis for the exploration of neratinib in the preclinical breast cancer study was based on its activity in non—small cell lung cancer.

“Neratinib has been shown to be effective in a number of cases where we’re seeing drug resistance to gefitinib in lung cancer, and that was one of the reasons we were interested in it,” said Bose, when the findings were presented. "We don't have to go out and spend 5 years developing new drugs for this mutation. There are drugs right now that could potentially benefit these women. Four thousand patients per year is a population that is similar in size to chronic myelogenous leukemia—it is also similar in size to ALK altered lung cancer."


  1. Ben-Baruch NE, Bose R, Kavuri SM, et al. HER2-Mutated Breast Cancer Responds to Treatment With Single-Agent Neratinib, a Second-Generation HER2/EGFR Tyrosine Kinase Inhibitor. J Natl Compr Canc Netw. 2015;13::1061-1064.
  2. Bose R, Kavuri SM, Searleman AC, et al. Activating HER2 mutations in HER2 gene amplification negative breast cancers. Cancer Res. 2012;72(24)(suppl 3): Abstract S5-6.