Neratinib, an irreversible erbB receptor tyrosine kinase inhibitor, in patients with advanced erbB2-positive breast cancer.
Since the introduction of trastuzumab , there has been considerable interest in treating metastatic human epidermal growth factor 2-positive (HER2-positive) overexpressing breast cancer. Lapatinib  and trastuzumab are the routinely used therapeutic agents in these individuals with advanced disease. Although significant improvements in overall survival have been made, toxicity and drug resistance remain two important factors in treatment.
This study is an open-label, Phase II trial conducted at 28 centres throughout the world to assess the efficacy and safety of neratinib (an oral, irreversible pan-ErbB receptor tyrosine- kinase inhibitor) in advanced HER2-positive breast cancer. Neratinib (HKI-272) is a potent, low-molecular-weight, orally administered, irreversible, pan-ErbB (i.e., Erb 1,2, and 4) receptor tyrosine-kinase inhibitor which has been successfully evaluated in Phase I studies involving HER2-positive metastatic breast cancer patients previously treated with trastuzumab, anthracyclines and taxanes.
Women with stage IIIB, IIIC, or stage IV breast cancer, who were previously treated with taxanes, anthracyclines or trastuzumab, were included in this study. HER2 amplification needed to be confirmed by the fluorescent in situ hybridisation technique (FISH). Exclusion criteria were active CNS disease, uncontrolled cardiac disease or baseline left ventricular ejection fraction (LVEF) below 50%.
A total of 136 patients with advanced HER2-positive breast cancer were enrolled on this study and they were distributed into two cohorts: 66 had prior trastuzumab treatment and 70 had no prior trastuzumab treatment. All patients received 240 mg of neratinib once daily and the treatment continued until it was well tolerated or there were signs of disease progression. The 16-week progression-free survival (PFS) rate for patients with prior trastuzumab treatment was 59%, while the rate was 78% for those with no prior trastuzumab treatment. The objective response rates were 24% and 56% for patients with and without prior trastuzumab treatment, respectively. Neratinib was shown to have improved the median PFS in the trastuzumab-naive patients by 39.6 weeks as compared to 22.3 weeks in the trastuzumab-pretreated cohort. Diarrhoea was the most common toxicity seen, followed by nausea, vomiting and fatigue. Grade 3 or 4 diarrhoea was seen in 10% of the patients and was associated with dose reduction in 29% of patients in the trastuzumab pretreated group and 4% of patients in the other group. No significant cardiac deterioration was seen in any of these patient groups.
This study demonstrates the efficacy of neratinib in HER2-positive advanced breast cancer patients. However, the results were significantly better in the trastuzumab-naive group. Larger Phase III trials are required to compare it with other agents and various chemotherapeutic regimens. This drug offers further clinical benefit to this particular subgroup of individuals (with HER2-positive disease) who have aggressive disease with a particular propensity for brain metastases. Optimising efficacy and minimising toxicity are the two important factors which require assessment in a larger cohort of patients in order for this drug to be used on a routine basis.
[1.] Salmon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl 1 Med, 2001, 344, 783-792.
[2.] Geyer CE, Forster J, Lindquist D et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl 1 Med, 2006, 355, 2733-2743.
Correspondence to: Anand Sharma
Department of Medical Oncology
Imperial College Healthcare NHS Trust
1st Floor, E Wing
Charing Cross Hospital
Fulham Palace Road, London W6 8RF, UK
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|Author:||Sharma, Anand; Jayanth, Akali|
|Publication:||Advances in Breast Cancer|
|Date:||Apr 1, 2010|
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