Regulatory Decision Summary for Nerlynx

This New Drug Submission - New Active Substance (NDS-NAS) was submitted to obtain market authorization for Nerlynx for the extended adjuvant treatment of adult patients with early-stage HER2-overexpressed/amplified breast cancer following trastuzumab-based adjuvant therapy. The large, randomized, double blind, pivotal study (ExteNET, study 3004) was conducted in women with HER2-positive, early-stage breast cancer who have previously been treated with standard trastuzumab adjuvant therapy. The extended adjuvant therapy with Nerlynx for one year resulted in a statistically significant and clinically meaningful 34% reduction in the risk of disease recurrence or death (invasive disease-free survival, iDFS) compared to placebo in the intent-to-treat (ITT) population at 24 months. A modest improvement of 2.3% for the estimated 2-year event-free rate was also identfied. The primary endpoint, iDFS, was supported by sensitivity analyses including high-risk patients for disease recurrence and in patients with centrally confirmed HER2-positive tumours.

Based on the pre-specified subgroup analyses, the risk of disease recurrence or death was reduced by 51% in Nerlynx-treated HRc-positive women relative to placebo. The treatment effect of Nerlynx on iDFS was also evident in patients who completed adjuvant trastuzumab treatment within 1 year from randomization. On the other hand, Nerlynx did not show any benefit in HRc-negative patients or in patients who completed trastuzumab adjuvant therapy >1 year prior to randomization. Given the modest benefit observed in the ITT population, the HRc-positive subgroup appeared to drive the overall positive outcome, albeit comprising only 57% of the ITT population. An exploratory analysis showed a similar magnitude of benefit in patients who were HRc-positive and completed prior trastuzumab within one year, which is the patient population at a higher risk of disease recurrence. The event-free rate at 24 months was 95.3% for the Nerlynx arm and 90.8% for the placebo arm, resulting in a 4.5% difference in the event-free rate. The very different outcomes among those subgroups were confirmed by positive interactions between neratinib treatment and HRc status, and between Nerlynx and time to prior trastuzumab therapy. The secondary efficacy endpoints supported the primary endpoint in the ITT population and the subgroups. For instance, only disease free-survival-ductal carcinoma in situ (DFS-DCIS) was statistically significant for the ITT population. When the analysis was limited to the HRc-positive patient population, a statistically significant benefit was noted in DFS-DCIS, distant disease-free survival (DDFS) and time-to-distant recurrence (TTDR). The incidences of cumulative incidence of CNS recurrence were too low for a meaningful analysis. None of the secondary endpoints were statistically significant for patients who had HRc-negative tumours or randomized >1 year after completion of trastuzumab treatment.

Additionally, the 5-year updated efficacy data from the pivotal study provided further evidence to support the primary efficacy analysis of Nerlynx in the extended adjuvant setting as potentially the first therapeutic intervention to improve iDFS in patients with HRc-positive and HER2-positive early breast cancer previously treated with trastuzumab.

To this end, the patient population with HRc-positive and HER2-positive tumours comprises approximately 10% of all primary breast cancers. Nerlynx in combination with endocrine therapy was administered for patients who were HRc-positive and HER2-positive in the pivotal study. Moreover, only women were enrolled in the pivotal study, thus there is uncertainty in extrapolating the female patient data to male patients at the extended adjuvant setting. Therefore, based on the latter and the subgroups that drove the results, the proposed indication was restricted to "the extended adjuvant therapy of women with early-stage hormone receptor positive, HER2-overexpressed/amplified breast cancer within one year after completion of trastuzumab-based adjuvant therapy."

The safety profile was established based upon the pivotal study. Patients treated with Nerlynx experienced higher incidences of treatment-emergent adverse events, severe adverse events, and treatment-related adverse events than those treated with placebo. Adverse events leading to treatment discontinuation, dose reduction, or dose interruption were also higher in the Nerlynx arm. The most common adverse events (AEs) associated with Nerlynx consisted primarily of diarrhea and other gastrointestinal disorders, fatigue, rash and hepatic transaminase elevations. Moreover, older patients may also experience higher toxicity and/or lower tolerance when compared to younger patients. Overall, these AEs are considered to be manageable by dose modification, discontinuation and/or standard medical practice. These mitigation strategies are captured in the Product Monograph (PM).

In summary, the multicenter, randomized, placebo-controlled, double-blind Phase 3 Study in women with early-stage HER2-positive breast cancer provided strong evidence for a clinically meaningful benefit of Nerlynx as extended adjuvant treatment within one year after trastuzumab-based adjuvant therapy. As there is no treatment option for the extended adjuvant treatment of early HRc-positive and HER2-positive early breast cancer, Nerlynx is the first therapeutic intervention to show significant improvement of iDFS in this patient population. Moreover, Nerlynx is considered to have a manageable and tolerable safety profile. As such, Nerlynx demonstrates a favourable benefit-risk profile under the proposed conditions of use.