The U.S. Food and Drug Administration approved Nerlynx (neratinib) for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy.
About Nerlynx™ (neratinib)
Nerlynx is a novel tyrosine kinase inhibitor that is targeted against several biochemical pathways implicated in the growth and spread of cancer. Specifically, Nerlynx is targeted against the HER1, HER2, and HER4 pathways and was approved by the U.S. Food and Drug Administration (FDA) in July 2017 for the extended adjuvant treatment of adult patients with early stage HER2-positive breast cancer following adjuvant trastuzumab-based therapy.
Neratinib Improves Cancer-Free Survival in Early Breast Cancer.
The targeted agent neratinib (PB272), which is still in clinical trials, demonstrated an improvement in cancer-free survival when used after Herceptin® (trastuzumab) in early-stage, HER2-positive breast cancer.
Approximately 20-30% of breast cancer is referred to as human epidermal growth factor receptor-2 (HER2)-positive. This means that the breast cancer cells have too many HER2 proteins on their surface, which stimulates the cancer cells to grow and spread.
Agents targeting the HER2 proteins and HER2 pathway have been approved for the treatment of HER2-positive breast cancers. These agents reduce the excessive biochemical signaling that stimulates cancer growth and spread in HER2-positive cancers.
Trastuzumab is a commonly used agent in breast cancer that is targeted against HER2 proteins. It has demonstrated improvements in outcomes among patients with HER2-positive breast cancers, including early-stage breast cancers.
Neratinib is a novel agent referred to as a tyrosine kinase inhibitor that is targeted against several biochemical pathways implicated in the growth and spread of cancer. Specifically, neratinib is targeted against the HER1, HER2, and HER4 pathways, and is currently in phase III clinical trials.
Researchers recently conducted a clinical trial to further evaluate neratinib in early breast cancer. This trial, referred to as the exteNET trial, included 2,840 patients from 41 countries with HE2-positive early breast cancer who had received treatment with surgery, followed by treatment including trastuzumab.
Following the completion of therapy with trastuzumab, one group of patients in the trial received further treatment with neratinib, while the other group of patients received placebo (inactive substitute) for one year.
- Among patients treated with neratinib, survival rates without an invasive recurrence of cancer were as follows: approximately 94% at 2 years; 92.5% at 3 years; 91.4% at 4 years; and 90.4% at 5 years.
- Among patients who received placebo, the survival rates without an invasive recurrence of cancer were as follows: 91.6% at 2 years; 90.3% at 3 years; 89.2% at 4 years; 87.9% at 5 years.
Among the group of patients with hormone-receptor positive (HR-positive) breast cancer (meaning the patient’s breast cancer is stimulated to grow from exposure to the female hormones estrogen and/or progesterone), the survival rates without an invasive recurrence of cancer were as follows:
- 8% at 3 years; 92.9% at 4 years; and 91.7% at 5 years among those who were treated with neratinib
- 9% at 3 years; 88.6% at 4 years; and 86.9% at 5 years among those who received placebo.
These results indicate that neratinib improves survival without a recurrence of invasive cancer among patients with early-stage, HER2-positive breast cancer who have completed treatment with surgery and Herceptin.
Although neratinib is not yet approved by the FDA, it represents a potential for additional treatment options among women with breast cancer.
Reference: Puma Biotech Inc. News Release. Puma Biotechnology Announces Interim 5-Year Disease Free Survival Data from Phase III Trial of PB272 (Neratinib) in Extended Adjuvant HER2-Positive Early Stage Breast Cancer (ExteNET Trial). Available at: <a href="http://www.pumabiotechnology.com/pr20160721\_2.html.">http://www.pumabiotechnology.com/pr20160721_2.html.</a> Accessed July 25, 2016.
The ExteNET clinical trial directly evaluated Nerlynx versus placebo after surgery and adjuvant treatment with Herceptin in patients with early stage HER2-positive breast cancer. Overall 2,840 patients in 41 countries with early stage HER2-positive breast cancer who had undergone surgery and adjuvant treatment with Herceptin were treated additionally with either Nerlynx or placebo for a period of one year.
The trial demonstrated that after a median follow up of 5.2 years, treatment with Nerlynx resulted in a 27% reduction in the risk of invasive disease recurrence or death.
Approval was based on the ExteNET trial (NCT00878709), a multicenter, randomized, double-blind, placebo-controlled trial of Nerlynx following adjuvant trastuzumab treatment. Women (n=2,840) with early-stage HER2-positive breast cancer and within two years of completing adjuvant trastuzumab were randomized to receive either Nerlynx (n=1420) or placebo (n=1420) for one year.
The major efficacy outcome measure was invasive disease-free survival (iDFS) defined as the time between the randomization date to the first occurrence of invasive recurrence (local/regional, ipsilateral or contralateral breast cancer), distant recurrence, or death from any cause, within two years and 28 days of follow-up. After two years, iDFS was 94.2% in patients treated with Nerlynx compared with 91.9% in those receiving placebo (HR 0.66; 95% CI: 0.49, 0.90, p=0.008).
The most common adverse reactions were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, nail disorder, dry skin, abdominal distention, weight loss, and urinary tract infection. The most common adverse reaction leading to discontinuation was diarrhea, observed in 16.8% of treated patients.
The recommended dose is 240 mg (6 tablets) given orally once daily with food, continuously for one year. Antidiarrheal prophylaxis should be initiated with the first Nerlynx dose and continued during the first 2 cycles (56 days) of treatment and as needed thereafter.
Burstein HJ, Sun Y, Dirix LY et al. Neratinib, an irreversible ErbB Receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. Journal of Clinical Oncology. 2010; 28: 1301-1307.