Therapeutic efficacy of Neratinib

The safety and efficacy of neratinib were investigated in the ExteNET trial, a multicenter, randomized, double-blind, placebo-controlled study conducted in women with HER2-positive breast cancer who had completed trastuzumab-based adjuvant therapy.

A total of 2,840 patients with early-stage (Stage 1 to 3c) HER2-positive breast cancer were randomized in a 1:1 ratio to receive neratinib (n=1,420) or placebo (n=1,420) within two years after completion of trastuzumab-based adjuvant therapy. Randomization was stratified by the following factors: hormone receptor status, nodal status (0, 1–3, or ≥4 positive lymph nodes), and whether trastuzumab was administered sequentially or concomitantly with chemotherapy. Neratinib 240 mg or placebo was administered orally once daily for one year. The primary efficacy outcome measure was invasive disease-free survival (iDFS), defined as the time from the date of randomization to the first occurrence of invasive recurrence (local/regional, ipsilateral or contralateral breast cancer), distant recurrence, or death from any cause, with a follow-up period of 2 years plus 28 days.

Patient demographics and tumor characteristics were generally balanced across treatment groups. The median age of patients was 52 years (range: 23 to 83 years), with 12% of patients aged 65 years or older. The majority of patients were White (81%), and most patients (99.7%) had an ECOG performance status of 0 or 1. Fifty-seven percent (57%) of patients had hormone receptor-positive disease (defined as ER-positive and/or PR-positive), 24% were node-negative, 47% had 1–3 positive lymph nodes, and 30% had ≥4 positive lymph nodes. Ten percent (10%) of patients had Stage I disease, 41% had Stage II disease, and 31% had Stage III disease. Most patients (81%) were enrolled within one year after completion of trastuzumab therapy. The median time from the last dose of trastuzumab adjuvant therapy to randomization was 4.4 months in the neratinib group and 4.6 months in the placebo group. The median duration of treatment was 11.6 months in the neratinib group and 11.8 months in the placebo group.

Approximately 75% of patients consented to extended follow-up beyond 24 months. Observations with missing data were censored at the date of the last assessment. This exploratory analysis demonstrated that the 5-year iDFS results were consistent with the 2-year iDFS results observed in ExteNET. After a median follow-up of 8 years, there was no statistically significant difference in overall survival (OS) between the neratinib group and the placebo group [HR 0.95 (95% CI: 0.75, 1.21)]. The estimated 5-year OS rate was 94.1% (95% CI: 92.7%, 95.3%) in the neratinib group and 93.3% (95% CI: 91.8%, 94.5%) in the placebo group.

FDA，2021.06