Health Canada Approves Extended Adjuvant Neratinib for Early-Stage HR+ Breast Cancer

Neratinib has received approval from Health Canada for the treatment of patients with early-stage, hormone receptor&ndash;positive, HER2-overexpressed/amplified breast cancer in the extended adjuvant setting. The agent should be given to patients 1 year after completing trastuzumab-based adjuvant therapy.<br /> &nbsp;

Jonathan Ross Goodman

Neratinib (Nerlynx) has received approval from Health Canada for the treatment of patients with early-stage, hormone receptor (HR)—positive, HER2-overexpressed/amplified breast cancer in the extended adjuvant setting.1The agent should be given to patients 1 year after completing trastuzumab (Herceptin)-based adjuvant therapy.

Findings from the phase III ExteNET trial supported the approval, showing a 2-year invasive disease-free survival (iDFS) rate of 95.3% in those who received neratinib compared with 90.8% in the placebo arm for this patient population (HR, 0.49; 95% CI, 0.30-0.78;P= .002). Knight Therapeutics, Inc., which is a licensing partner with neratinib’s manufacturer Puma Biotechnology, announced the approval in a press release.

“Health Canada approval marks the first time Canadian women are being presented with an opportunity for extended-adjuvant therapy that will reduce the risk of disease recurrence in patients who would otherwise have had a relapse,” Jonathan Ross Goodman, chief executive officer of Knight, stated in the press release.

In the multicenter, randomized, double-blind, placebo-controlled ExteNET trial, investigators evaluated neratinib following adjuvant trastuzumab treatment in 2840 patients with early-stage HER2-positive breast cancer were randomized to receive either neratinib (n = 1420) or placebo (n = 1420) for 1 year.

The median age was 52 years and approximately 23.8% of patients had node-negative disease; 46.6% of patients had 1 to 3 positive nodes and 29.6% had ≥4 positive nodes. Anthracyclines were administered as adjuvant chemotherapy in 77% of patients, and appropriate endocrine therapy was administered to 94% of patients.

Results at 2 years of follow-up showed that treatment with neratinib led to a 51% reduction in the risk invasive disease recurrence or death at 2 years compared with placebo. Updated findings showed that at a median follow-up of 5.2 years, the iDFS rate with neratinib was 90.2% (95% CI, 88.3-91.8) compared with 87.7% (95% CI, 85.7-89.4) with placebo, leading to a 27% reduction in the risk of invasive disease recurrence or death (HR, 0.73; 95% CI, 0.57-0.92;P= .0083).2

Moreover, the longer-term data showed that the restricted mean iDFS was 56.5 months (95% CI, 55.9-57.2) with neratinib (mean loss of 3.5 months from a total of 60 months) versus 55.2 months (95% CI, 54.4-55.9) with placebo (mean loss of 4.8 months from a total of 60 months). The between group difference was 1.3 months (95% CI, 0.3-2.3;P= .0085).

Moreover, 16 patients (1%) in the neratinib arm and 23 (2%) in the placebo group had central nervous system (CNS) events as the first distant recurrence. The 5-&shy;year cumulative incidence of CNS events was 1.3% (95% CI, 0.8-2.1) with neratinib and 1.8% (95% CI, 1.2-2.7) in the placebo arm (P= .333). Overall survival data are not yet mature.

The safety population included 2816 patients who received ≥1 dose of study treatment, which comprised 1408 patients in each group. The primary safety analysis was reported at the 2-&shy;year follow&shy;-up, but investigators saw no evidence of long-&shy;term toxicity in the 5-year data.

In the 2-year readout, the most common adverse events (AEs; >5%) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, alanine aminotransferase and aspartate aminotransferase increase, nail disorder, dry skin, abdominal distention, weight loss, and urinary tract infection. The most common adverse AEs leading to treatment discontinuation was diarrhea (16.8%) in the neratinib arm. Hepatotoxicity led to drug discontinuation in 1.7% of neratinib-treated patients.

“Reducing the risk of disease recurrence remains a need for patients, despite advances in the treatment of early stage HER2-positive breast cancer,” Alan H. Auerbach, CEO and president of Puma Biotechnology, stated in the press release. “We are pleased that our partner, Knight Therapeutics, will be bringing Nerlynx to patients throughout Canada. Health Canada represents the second international approval of Nerlynx this year and we are committed to supporting our partners to expand Nerlynx commercial accessibility to patients around the world.”

The FDA approved neratinib for the extended adjuvant treatment of patients with early-stage, HER2-positive breast cancer following postoperative trastuzumab in July 2017.


  1. Puma Biotechnology&rsquo;s Licensing Partner Knight Therapeutics Receives Regulatory Approval from Health Canada to Commercialize NERLYNX (neratinib) for Extended Adjuvant Treatment of Hormone Receptor Positive, HER2-Positive Early Stage Breast Cancer. Puma Biotechnology. Published July 16, 2019. Accessed July 16, 2019.
  2. 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):1688-16700. doi: 10.1016/S1470-2045(17)30717-9.