Neratinib Shows Numerical OS Improvement in Early Stage HER2+ Breast Cancer

In In The News by Barbara Jacoby

By: Kristi Rosa


Neratinib was shown to have a numerical overall survival benefit in addition to improvements in invasive disease-free survival and central nervous system recurrence in patients with HER2-positive, hormone receptor–positive, early stage breast cancer.

Neratinib (Nerlynx) was shown to have a numerical overall survival (OS) benefit in addition to improvements in invasive disease-free survival (iDFS) and central nervous system (CNS) recurrence in patients with HER2-positive, hormone receptor (HR)–positive, early stage breast cancer, according to final efficacy data from the phase 3 ExteNET trial (NCT00878709).1

Updated results showed that the absolute 5-year iDFS benefit achieved with neratinib versus placebo was 5.1% (HR, 0.58; 95% CI, 0.41-0.82) in patients with HR-positive disease who initiated treatment within 1 year of completing an adjuvant trastuzumab (Herceptin)-containing therapy. The absolute 8-year OS benefit achieved with neratinib was 2.1% (HR, 0.79; 95% CI, 0.55-1.13). Moreover, the 5-year cumulative incidence of CNS metastases was 0.7% with neratinib versus 2.1% with placebo.

In patients with HR-positive disease who began treatment within 1 year of completing an adjuvant trastuzumab-containing therapy who did not achieve a pathologic complete response (pCR) and were at high risk of disease recurrence experienced an absolute 5-year iDFS benefit of 7.4% with neratinib versus placebo (HR, 0.60; 95% CI, 0.33-1.07); in this patient subgroup, the 8-year OS benefit was 9.1% (HR, 0.47; 95% CI, 0.23-0.92).

With regard to safety, the most frequently reported grade 3 toxicities included diarrhea (39% with neratinib versus 1% with placebo), vomiting (4% vs less than 1%, respectively), and fatigue (2% vs less than 1%).

“Deciding on which patients benefit most from a given therapy is an important goal for clinicians,” Arlene Chan, MBBS, FRACP, vice chair of the Breast Cancer Research Centre Western Australia, stated in a press release.2 “This newly published study provides consistent and durable benefits of neratinib in a subset of [patients with] HER2-positive early stage breast cancer who are considered to be at greater risk of relapse: namely patients with HR-positive tumors who did not achieve a pCR after neoadjuvant treatment. The benefits demonstrated are meaningful in all end points evaluated, including iDFS, OS, and CNS recurrence, and thus should help guide future clinical decisions.”

Previously, neratinib was found to reduce the risk of invasive disease recurrence or death by 27% versus placebo when used as extended adjuvant treatment for patients with HER2-positive early stage breast cancer after 12 months of trastuzumab.3 The 5-year iDFS rate was 90.2% (95% CI, 88.3-91.8) with neratinib versus 87.7% (95% CI, 85.7-89.4) with placebo.

In the phase 3 ExteNET trial, a total of 2840 patients who remained free of disease after 1 year of adjuvant trastuzumab treatment and chemotherapy were randomized to receive neratinib (n = 1420) or placebo (n = 1420). The interval between receiving trastuzumab and entering the trial was about 4.5 months. Participants were given either a daily dose of neratinib at 240 mg or placebo for the duration of 12 months.

The median age of participants was 52 years and about 23.8% had node-negative disease. Additionally, just under half, or 46.6%, had 1 to 3 positive nodes; 29.6% had 4 or more positive nodes. Seventy-seven percent of patients had anthracyclines administered as adjuvant chemotherapy. Ninety-four patients with HR-positive disease had appropriate endocrine therapy.

Although neratinib was linked with an improvement in DFS, this was not true in terms of distant DFS and time to distant recurrence. Sixteen patients in the neratinib arm and 23 patients in the control arm experienced CNS events as the first distant recurrence. The 5-year cumulative incidence of CNS events was 1.3% (95% CI, 0.8-2.1) and 1.8% (95% CI, 1.2-2.7) in the neratinib and placebo arms, respectively (P =.333).

The primary safety analysis was reported at 2 years of follow-up; no evidence of long-term toxicities was observed with the 5-year follow-up. Across the full study population, 95.4% of patients who received neratinib had all-grade diarrhea; 40% of these patients had effects that were grade 3 or 4 in severity. Additional gastrointestinal-associated toxicities included nausea (43%), fatigue (27%), vomiting (26%), and abdominal pain (24%). In the placebo arm, 36% of patients experienced diarrhea; 2.0% of these patients were grade 3 or 4 in severity.

“HER2-positive HR+ patients who do not achieve a pCR are at increased risk of recurrence, even after receiving current standard of care treatment. In a descriptive subset analysis, extended adjuvant therapy with neratinib demonstrated a positive benefit in these patients not only in iDFS, but also in OS,” Hope S. Rugo, MD, professor of medicine at the University of California San Francisco Comprehensive Cancer Center, added in the release. “In addition, the trend toward lower CNS involvement is a very important consideration, given the profound impact of CNS metastasis on future prognosis. These data coupled with the recently published data from the CONTROL study, which shows improved tolerability with dose escalation, should allow more patients to benefit from this important therapy.”

In July 2017, the FDA approved neratinib for use as extended adjuvant treatment in patients with early stage, HER2-positive breast cancer after postoperative trastuzumab. The decision was based on data from ExteNET and the phase 2 CONTROL trial.


  1. Chan A, Moy B, Mansi J, et al. Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer from the phase III ExteNET trial. Clin Breast Cancer. Published online October 5, 2020. doi:10.1016/j.clbc.2020.09.014
  2. Puma Biotechnology announces publication of overall survival results from phase III ExteNET trial evaluating neratinib in HER2-positive, hormone receptor-positive, early stage breast cancer. News release. Puma Biotechnology, Inc. October 5, 2020. Accessed October 6, 2020.
  3. Martin M, Holmes FA, Ejlertsen B, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(12):1688-1700. doi:10.1016/S1470-2045(17)30717-9