NEW YORK (Reuters Health) - Twelve months of neratinib after chemotherapy and trastuzumab-based adjuvant therapy may significantly improve two-year invasive-disease-free survival in women with HER2-positive breast cancer, a new study reports.
"The administration of the tyrosine-kinase inhibitor neratinib for 12 months is the first treatment intervention to show a statistical reduction in the rates of recurrent invasive disease in HER2-positive early breast cancer patients who have already received trastuzumab and chemotherapy in the adjuvant setting," lead author Dr. Arlene Chan, professor and medical oncologist in the School of Medicine of Curtin University in Perth, Western Australia, told Reuters Health by email.
"Patients who have already completed or are near completing their adjuvant trastuzumab-based treatment and are considered to have a high risk of recurrence can potentially benefit from the results of our study," she said.
Dr. Chan and colleagues conducted the double-blind, phase 3 multinational ExteNET trial at 495 medical centers and reported their results online February 10 in the Lancet Oncology.
Women with stage 1 to 3 HER2-positive breast cancer who had completed neoadjuvant and adjuvant trastuzumab therapy up to two years before randomization were eligible. Roughly seven months into the study, the researchers amended the inclusion criteria to include patients with stage 2 to 3 HER2-positive breast cancer who had completed trastuzumab therapy up to one year previously.
Over about two years, the authors randomly assigned 1,420 women to receive oral neratinib 240 mg/d and 1,420 to receive matching placebo. The median follow-up time was 24 months in each group. At the two-year follow-up, 70 invasive-disease-free survival events had occurred in patients in the neratinib group compared with 109 events in patients in the placebo group (stratified hazard ratio 0.67, p=0.0091).
The two-year invasive-disease-free survival rate was 93.9% in the neratinib group and 91.6% in the placebo group. The most common grade 3 to 4 adverse events in patients taking neratinib were diarrhea, vomiting, and nausea.
QT was prolonged in 49 (3%) patients taking neratinib and in 93 (7%) patients taking placebo; left ventricular ejection fraction (grade 2 or higher) decreased in 19 (1%) on neratinib and in 15 (1%) on placebo.
Serious adverse events occurred in 103 (7%) patients in the neratinib group and in 85 (6%) in the placebo group.
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Dr. Hope S. Rugo, professor of medicine at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, who coauthored a related editorial, told Reuters Health by phone, "HER2-positive disease is particularly intriguing because we've improved outcomes tremendously, but some patients still relapse and die of this disease."
"The mechanism of action of these agents is clearly important," she said. "One reason postulated for the efficacy results, specifically seen in the patients with hormone-receptor-positive disease, is that by using a drug with an alternative mechanism of action, we may be able to overcome resistance developing within residual cancer cells."
Dr. Rugo cautioned, "Neratinib has toxicity not found with intravenous administration of antibodies: neratinib causes significant diarrhea. There is a suggestion that antidiarrheal prophylaxis will reduce this diarrhea, but it will not eliminate it. It is critical that toxicity be carefully reviewed and taken into consideration and appropriate preventive measures applied."
The authors say longer follow-up is needed to explore whether the improvement in breast cancer outcome is maintained. "The results of ongoing trials of other anti-HER2 agents and a greater understanding of patient selection of those who will benefit most with neratinib are important aspects that remain to be shown," Dr. Chan told Reuters Health.
Wyeth, Pfizer, and Puma Biotechnology funded the study. Ten coauthors and the editorialists reported financial relationships with pharmaceutical companies, and four coauthors were employed by Puma Biotechnology.
SOURCE: http://bit.ly/20QmZdp and http://bit.ly/1O8mlAM
Lancet Oncol 2016.
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