Neratinib in Patients with Advanced HER2-Positive Breast Cancer

By Jason Broderick
Published: Monday, May 17, 2010
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In a new report, published in the March issue of the Journal of Clinical Oncology, investigators led by Harold J. Burstein, MD, PhD, associate professor of medicine, Harvard Medical School, Cambridge, Massachusetts, say monotherapy with neratinib, an investigational tyrosine kinase inhibitor, demonstrated substantial clinical activity in patients with HER2-positive breast cancer with manageable toxicity (Table). Burstein said the researchers studied neratinib in two groups of women with advanced HER2 positive breast cancer. “The first group [consisted of] women who had not previously received trastuzumab; neratinib made the cancer shrink in over half of these patients. In a group of women who previously had had trastuzumab, over one-quarter responded to neratinib,” said Burstein.

The open-label, multicenter, phase II trial administered 240 mg of neratinib once daily to 136 patients with advanced HER2-positive breast cancer. Patients were divided into two cohorts; 66 had prior treatment with trastuzumab (Herceptin) and 70 were trastuzumab-naive. The trial’s primary endpoint was 16-week progression-free survival, and at the end of this period, 63 patients in the prior-trastuzumab arm and 64 patients in the trastuzumab- naive arm were evaluable.

Based on an independent radiologic assessment, investigators reported a much higher rate and duration of PFS for patients that had not received trastuzumab previously and a higher objective response rate (ORR). In the trastuzumab-treated group, 59% of patients experienced 16-week PFS and PFS persisted a median of 22.3 weeks. Patients not treated previously with trastuzumab had a 16-week PFS rate of 78% and a median PFS of 39.6 weeks. ORR for prior trastuzumab patients was 24% (95% confidence interval [CI], 14%-36%) compared with 56% (95% CI, 43%-69%) for trastuzumab-naive patients.

Median onset of first complete response or partial response was 7.1 weeks in both groups, with 39 patients treated previously with trastuzumab experiencing tumor shrinkage compared with 52 that did not get trastuzumab therapy. Median duration of objective tumor response for the trastuzumab-treated cohort was 39.3 weeks (95% CI, 32.3 weeks-93.7 weeks) versus 52.4 weeks (95% CI, 33.1 weeks to not estimable) for the trastuzumabnaive cohort. In total, 14 patients (6 in the prior-trastuzumab arm and 8 in the trastuzumab-naive arm) achieved stable disease lasting ≥24 weeks. The clinical benefit rate was 33% for patients treated with trastuzumab and 69% for patients that were not.

The most common grade 3-4 adverse event was diarrhea, experienced by 30% of patients in the prior-trastuzumab cohort and 13% in the trastuzumab- naive cohort. Diarrhea occurred almost immediately, with a median time to onset of 2 to 3 days. Each episode lasted a median of 5 to 7 days. The diarrhea resulted in dose reductions for 29% of patients with prior trastuzumab treatment and 4% of patients with no prior trastuzumab treatment. Management with dose adjustment and antidiarrheal agents allowed 99% of patients to continue on neratinib, with 22 receiving neratinib for >1 year. Only 1 patient discontinued prior to 16 weeks. Additional adverse events included nausea, vomiting, and fatigue; and approximately 25% of patients developed mild skin rash. No incidents of grade 3-4 neratinib-related cardiotoxicity were reported. Burstein said, “Neratinib is quite well tolerated,” adding that “many patients develop mild diarrhea that is controlled with over-the-counter medications.”

Burstein noted that the distinct subset of HER2- positive tumors “have a more aggressive natural history than other kinds of breast cancers.” He described trastuzumab as an antibody against HER2 that is effective for HER2-positive cancers and explained that neratinib “is a different kind of anti-HER2 therapy” known as a dual-kinase inhibitor. “It is an oral medication that targets both the HER2 protein and a related protein, EGFR,” Burstein said.

“These results suggest that neratinib may be a potent drug for women with HER2-positive breast cancer,” said Burstein. He said the study’s findings “set the stage for ongoing trials that will compare neratinib against other dual-kinase inhibitors, or separately, study whether adding neratinib to trastuzumab is clinically valuable.”




Burstein HJ, Sun Y, Dirix LY, et al. Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J Clin Oncol. 2010;28(8)1301-1307.


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