AT ESMO 2017

MADRID (FRONTLINE MEDICAL NEWS) Five years on, extended adjuvant therapy with neratinib (Nerlynx) continues to show a significant clinical benefit in women with HER2-positive breast cancer who received postoperative trastuzumab (Herceptin) and chemotherapy, long-term follow-up results from the ExteNET trialshow.

In a planned intention-to-treat analysis at 5 years of follow-up, extended adjuvant therapy with the tyrosine kinase inhibitor neratinib was associated with a small but significant improvement in invasive disease-free survival (iDFS), compared with placebo, with most of the benefit occurring in women with hormone receptor–positive disease, reported Miguel Martin, MD, of the Gregorio Marañón Health Research Institute in Madrid.

“The 5-year analysis of the ExteNET trial confirms the early results of sustained benefit with extended adjuvant neratinib after chemotherapy and trastuzumab,” he said at the European Society for Medical Oncology Congress.

Data from an earlier analysis of the trial supported the Food and Drug Administration’s decision to approve neratinib in the extended adjuvant setting in July 2017.

In the ExteNET trial , 2,840 women with early HER2-positive breast cancer who had undergone surgery and adjuvant treatment with trastuzumab and chemotherapy were stratified by nodal and hormone receptor status and by concurrent vs. sequential chemotherapy and trastuzumab, and were then randomly assigned to receive oral neratinib 240 mg/day for 1 year, or placebo. Analyses of iDFS were planned for 2 and 5 years, and an overall survival analysis was planned after 248 patient deaths had occurred. Overall survival data have not matured as yet, Dr. Martin noted.

Results of an unspecified 3-year analysis of the trial, presented at the San Antonio Breast Cancer Symposium in 2015, showed a continued benefit for the addition of neratinib, a finding that has now been extended out to 5 years.

At ESMO 2017, Dr. Martin presented data on all efficacy endpoints except overall survival in the intention-to-treat population.

By the cutoff date in March 2017, 2,117 of the original 2,840 patients (76%) gave consent for collection of additional data, including 1,028 who had been assigned to neratinib, and 1,089 assigned to placebo.

The 5-year iDFS rate was 90.2% for patients assigned to neratinib, compared with 87.7% for those assigned to placebo, an absolute difference of 2.5%. This translated into a hazard ratio favoring neratinib of 0.73 (P = .008). Neratinib was also significantly better than placebo for DFS in patients with ductal carcinoma in situ (89.7% vs. 86.8, HR, 0.71, P = .004).

However, there were no significant differences at 5 years between trial arms in either distant DFS, time to distant recurrence, or central nervous system recurrences. Dr. Martin noted that the although there were fewer CNS recurrences with neratinib (1.30% vs. 1.82%), the total number of cases was too small to detect a possible difference.

In a subgroup analysis, neratinib trended toward better performance in all categories, but was significantly better than placebo only among patients from Asia, Eastern Europe, and South America, and among patients with four or more positive lymph nodes. ­

An analysis of iDFS by hormone receptor status showed that for HR-positive patients, the 5-year iDFS rate was 91.2% with neratinib vs. 86.8% with placebo, translating into a hazard ratio of 0.60, P = .002). In contrast, iDFS rates were nearly identical among HR-negative patients, at 88.9% vs. 88.8%, respectively.

Following treatment discontinuation, there was no evidence of increased symptomatic cardiotoxicity or second primary malignancies vs. placebo, and no late-term consequences of neratinib-associated diarrhea, Dr. Martin said.

A separate poster on health-related quality of life, also presented at ESMO 2017, showed that patients assigned to neratinib had a drop in quality-of-life measures during the first month of treatment, possibly because of diarrhea, but then had a steady improvement toward baseline. There is an ongoing study to evaluate whether loperamide-based regimens can reduce or prevent neratinib-associated diarrhea, the investigators noted.

“In ExteNET, we’ve seen continued demonstration of clinically significant benefit, particularly in higher-risk, hormone receptor–positive disease, despite many limitations, with change in sponsor and initial plan for only 2 years of follow-up,” said Hope S. Rugo, MD, from the University of California, San Francisco, the invited discussant.

“Survival data is pending, and we’re looking forward to seeing that in 2019, but the reduction in distant events, although small, is still encouraging,” she said.

The trial is sponsored by Puma Biotechnology. Dr. Martin disclosed honoraria from Roche/Genentech, Novartis, Amgen, AstraZeneca, Pfizer, PharmaMar, and Lilly, and research grants from Roche and Novartis. Dr Rugo disclosed travel support from PUMA and Mylan, research support from Genentech/Roche, and honoraria from Biotheranostics. She also serves on the Oncology Practice Advisory Board.