Date: 2016-07-21
Type of information: Results
phase: 3
Announcement: results
Company: Puma Biotechnology (USA - CA)
Product: neratinib - PB272
Action
mechanism: kinase inhibitor/tyrosine kinase inhibitor. PB272 (neratinib) is a potent irreversible tyrosine kinase inhibitor that blocks signal transduction through the epidermal growth factor receptors, or EGFRs, HER1, HER2 and HER4.
Disease: extended adjuvant treatment of HER2-positive early stage breast cancer
Therapeutic area: Cancer - Oncology
Country: Australia, Bahamas, Belgium, Brazil, Bulgaria, Canada, China, Colombia, Croatia, Czech Republic, Denmark, France, Germany, Greece, Hong Kong, Hungary, Israel, Italy, Japan, Republic of Korea, Lithuania, Macedonia, The Former Yugoslav Republic of, Malaysia, Malta, Mexico, Netherlands, New Zealand, Peru, Poland, Romania, Serbia, Singapore, Slovakia, Spain, Sweden, Switzerland, Taiwan, Turkey, UK, USA, Argentina, Chile, Jordan, Lebanon, Saudi Arabia
Trial
details: The ExteNET trial is a double-blind, placebo-controlled, Phase III trial of neratinib versus placebo after adjuvant treatment with trastuzumab (Herceptin) in women with early stage HER2-positive breast cancer. The trial randomized 2,840 patients in 41 countries with early-stage HER2-positive breast cancer who had undergone surgery and adjuvant treatment with trastuzumab. After completion of adjuvant treatment with trastuzumab, patients were randomized to receive extended adjuvant treatment with either neratinib or placebo for a period of one year. Patients were then followed for recurrent disease, ductal carcinoma in situ (DCIS), or death for a period of two years after randomization in the trial. The primary endpoint of the trial was invasive disease free survival (DFS). (NCT00878709 )
Latest
news: * On July 21, 2016, Puma Biotechnology announced updated results from the Phase III clinical trial of Puma's investigational drug PB272 (neratinib) for the extended adjuvant treatment of HER2-positive early stage breast cancer (ExteNET trial). The ExteNET trial is a double-blind, placebo-controlled, Phase III trial of neratinib versus placebo after adjuvant treatment with trastuzumab (Herceptin) in women with early stage HER2-positive breast cancer. The ExteNET trial randomized 2,840 patients in 41 countries with early-stage HER2-positive breast cancer who had undergone surgery and adjuvant treatment with trastuzumab. After completion of adjuvant treatment with trastuzumab, patients were randomized to receive extended adjuvant treatment with either neratinib or placebo for a period of one year. Patients were then followed for recurrent disease, ductal carcinoma in situ, or death for a period of two years after randomization in the trial. The primary endpoint of the trial was invasive disease free survival (DFS). The results of the trial demonstrated that treatment with neratinib resulted in a 33% reduction of risk of invasive disease recurrence or death versus placebo (hazard ratio = 0.67, p = 0.009). The 2-year invasive DFS rate for the neratinib arm was 93.9% and the 2-year invasive DFS rate for the placebo arm was 91.6%. These results were previously reported at the 2015 American Society of Clinical Oncology meeting and updated results, including interim 3-year invasive DFS data, were presented at the 2015 CTRC-AACR San Antonio Breast Cancer Symposium (SABCS). As part of the data analysis for the New Drug Application (NDA) filing in the United States and the Marketing Authorisation Application (MAA) submission in Europe, an updated analysis that included an interim 5-year invasive DFS analysis was performed. This data analysis was performed in order to examine the durability of treatment effect beyond the 2-year data included in the primary analysis. This interim analysis was not a pre-planned analysis in the statistical analysis plan for the trial. For the primary endpoint of the trial, invasive DFS, the 5-year interim results of the trial demonstrated that treatment with neratinib resulted in a 26% reduction of risk of invasive disease recurrence or death versus placebo (hazard ratio = 0.74, p = 0.017). The 5-year interim invasive DFS rate for the neratinib arm was 90.4% and the 5-year interim invasive DFS rate for the placebo arm was 87.9%. Additional updated results for the 3-year invasive DFS rate and 4-year invasive DFS rate are shown in the table below: DFS for Intent to Treat (ITT) Population As an inclusion criteria for the ExteNET trial, patients needed to have tumors that were HER2 positive using local assessment. In addition, as a pre-defined subgroup in the trial, patients had centralized HER2 testing performed on their tumor as well. To date, centralized HER2 testing has been performed on 2,140 (75%) of the patients in the ExteNET trial, and further central testing on available samples is currently ongoing. For the 1,777 patients whose tumors were HER2 positive by central confirmation, the interim results of the trial demonstrated that treatment with neratinib resulted in a 30% reduction of risk of invasive disease recurrence or death versus placebo (hazard ratio = 0.70, p = 0.026). The 5-year interim invasive DFS rate for the centrally confirmed patients in the neratinib arm was 90.8% and the 5-year interim invasive DFS rate for the centrally confirmed patients in the placebo arm was 88.1%. For the pre-defined subgroup of 1,631 patients with hormone receptor positive disease, the interim results of the trial demonstrated that treatment with neratinib resulted in a 41% reduction of risk of invasive disease recurrence or death versus placebo (hazard ratio = 0.59, p = 0.002). The 5-year interim invasive DFS rate for the neratinib arm was 91.7% and the 5-year interim invasive DFS rate for the placebo arm was 86.9%. Additional updated results for the 3-year invasive DFS rate and 4-year invasive DFS rate are shown in the table below: DFS for Hormone Receptor Positive (HR-positive) Population Full 5-year DFS data are expected in 2017. * On February 11, 2016, Puma Biotechnology announced that results from the ExteNET Phase III clinical trial of neratinib in patients with early stage HER2 positive breast cancer were published in the journal The Lancet Oncology . The article entitled “Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET); a multicentre, randomized, double-blind, placebo-controlled, phase 3 trial” appears in the February 10, 2016 online issue and will be published in a future print issue of the journal. The study demonstrated that the trial hit its primary endpoint and that treatment with neratinib resulted in a 33% reduction of risk of invasive disease recurrence or death versus placebo (hazard ratio = 0.67, p = 0.009). The 2-year DFS rate for the neratinib arm was 93.9% and the 2-year DFS rate for the placebo arm was 91.6%. For the pre-defined subgroup of patients with hormone receptor positive disease, the results of the trial demonstrated that treatment with neratinib resulted in a 49% reduction of risk of invasive disease recurrence or death versus placebo (hazard ratio = 0.51, p = 0.001). For the patients with hormone receptor positive disease, the 2-year DFS rate for the neratinib arm was 95.4% and the 2-year DFS rate for the placebo arm was 91.2%. The safety results of the ExteNET study showed that the most frequently observed adverse event for the neratinib-treated patients was diarrhea, with approximately 39.9% of the neratinib-treated patients experiencing grade 3 or higher diarrhea (1 (0.1%) patient had grade 4 diarrhea). Patients who received neratinib in the ExteNET trial did not receive any prophylaxis with antidiarrheal agents to prevent the neratinib-related diarrhea. Recently announced interim results of a Phase II study of neratinib monotherapy in patients with HER2 positive early stage breast cancer who have previously been treated with adjuvant trastuzumab where patients received anti-diarrheal prophylaxis with loperamide demonstrated that treatment with prophylactic loperamide reduced the rate of grade 3 or higher diarrhea to between 13.0-18.5%. In addition, the grade 3 diarrhea that was seen in the interim analysis of this Phase II trial was limited to the first 3 weeks of the 12 month treatment period. 3-Year DFS 4-Year DFS 5-Year Interim DFS Neratinib 92.5% 91.4% 90.4% Placebo 90.3% 89.2% 87.9% Absolute invasive DFS Difference 2.2% 2.2% 2.5% 3-Year DFS 4-Year DFS 5-Year Interim DFS Neratinib 93.8% 92.9% 91.7% Placebo 89.9% 88.6% 86.9% Absolute invasive DFS Difference 3.9% 4.3% 4.8%
