Summary Basis of Decision for Nerlynx

 

Clinical Pharmacology

Neratinib, the medicinal ingredient in Nerlynx, is a protein kinase inhibitor. It binds irreversibly to human epidermal growth factor receptor 2 (HER2), HER4, and epidermal growth factor receptor (EGFR or HER1). Neratinib reduces EGFR and HER2 autophosphorylation, which in turn reduces downstream signalling through the mitogen activated protein kinase (MAPK) and AKT signaling pathways, resulting in antitumour activity in EGFR and/or HER2 expressing carcinoma cell lines.

The single- and multiple-dose pharmacokinetics of neratinib have been evaluated in patients and in healthy volunteers. Following single doses of neratinib, the mean apparent plasma half-life of neratinib was 17 hours in patients. Neratinib exhibits a non-linear PK profile with less than dose proportional increase of exposure with increasing daily dose over the range of 40 to 400 mg.

Neratinib is metabolized primarily in the liver by cytochrome P450 (CYP) 3A4 and to a lesser extent by flavin-containing monooxygenase (FMO). A pharmacokinetic study demonstrated that mild to moderate hepatic impairment did not have a significant effect on neratinib exposure. However, in patients with severe hepatic impairment, the maximum plasma concentration (C_max) and total exposure (as measured by the area under the concentration-time curve [AUC]) of neratinib increased by 273% and 281%, respectively, relative to healthy volunteers. Based on these results, a reduced starting dose of 80 mg is recommended in patients with severe hepatic impairment.

A population pharmacokinetic analysis indicated that mild to moderate renal impairment had no impact on the exposure of neratinib. Nerlynx has not been studied in patients with severe renal impairment (defined as <30 mL/min/1.73 m₂).

Neratinib is a substrate of CYP3A4 and P-glycoprotein (P-gp). Drug interactions were observed when Nerlynx was coadministered with a combined strong CYP3A4 and P-gp inhibitor and a combined strong CYP3A4 and P-gp inducer. The relative contributions of CYP3A4 and P-gp to the pharmacokinetics of neratinib are unknown.

The solubility of neratinib maleate increases dramatically as neratinib becomes protonated at acidic pH. Concomitant use of agents that reduce gastric acid, such as proton pump inhibitors, H2-receptor antagonists and antacids, can reduce the solubility of neratinib and hence its bioavailability.

Nerlynx is recommended to be taken with food. A high-fat meal may lead to higher exposures of neratinib than a standard breakfast.

The effect of Nerlynx on electrocardiogram (ECG) interval parameters was evaluated in healthy volunteers. Cardiac parameters (including the QTc interval, QRS duration, PR interval, and ventricular heart rate) were not affected to a clinically relevant extent following a single dose of 240 mg neratinib, both in the presence and absence of a CYP3A inhibitor (400 mg ketoconazole). The mean C_max of single dose neratinib 240 mg was 68.0 ng/mL when administered alone and 162.6 ng/mL when administered with ketoconazole 400 mg/day.

Overall, the clinical pharmacology data support the use of Nerlynx for the recommended indication. The key findings from these data and the related risks are identified in the Product Monograph.

For further details, please refer to the Nerlynx Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Nerlynx was demonstrated primarily in the pivotal study ExteNET (Study 3004), an international, randomized, double blind, Phase III trial in women with early-stage HER2-positive breast cancer following standard adjuvant treatment with trastuzumab (completed up to two years prior to randomization).

Patients were randomized to receive either 240 mg neratinib (number of patients [n] = 1,420) or a placebo (n = 1,420) daily for one year. Randomization was stratified based on hormone receptor (HRc) status, nodal disease, and prior trastuzumab-chemotherapy regimen (sequential versus concurrent). The study was amended to include only patients who had a high risk of disease recurrence (amended intention-to-treat [aITT] population: node positive, tumour sizes classified as T2 [>20 mm to ≤50 mm in diameter] to T3 [>50 mm in diameter], and within one year after completion of trastuzumab-based adjuvant therapy). Concurrent endocrine therapy was recommended for 57% of patients who had HRc-positive disease, defined as estrogen receptor (ER)-positive and/or progesterone receptor (PgR)-positive.

At baseline, patient demographics and disease characteristics were balanced between the two treatment arms. Overall, patients had a median age of 52 years (range: 23 to 83 years). The majority of patients were Caucasian (81%), with Eastern Cooperative Oncology Group (ECOG) performance status of "0" (92%). The majority of patients (81%) were enrolled within one year of completion of trastuzumab-based adjuvant treatment. Median time from the last adjuvant trastuzumab treatment to randomization was 4.4 months in the Nerlynx arm, versus 4.6 months in the placebo arm.

The primary efficacy endpoint was invasive disease-free survival (iDFS) in the ITT population at 24 months, which was defined as the time from randomization to the first occurrence of invasive tumour recurrence, distant recurrence, or death from any cause. A significant reduction of 34% in the risk of disease recurrence or death was observed among patients treated with Nerlynx, relative to the placebo. A modest improvement of 2.3% in event-free rate at 24 months was also concluded (94.2% in the Nerlynx arm versus 91.9% in the placebo arm). The benefit of treatment with Nerlynx over placebo was also observed in the aITT population (i.e., higher-risk patients) and in those with centrally confirmed HER2-positive disease, through predefined sensitivity analyses. Based on an exploratory analysis conducted in 75% of the ITT population at five years post-randomization, similar iDFS benefit was observed.

The secondary efficacy endpoints were disease-free survival including ductal carcinoma in situ (DFS-DCIS), distant disease-free survival (DDFS), time to distant recurrence (TTDR), and cumulative incidence of central nervous system (CNS) recurrences. In the ITT population, a statistically significant 39% improvement in DFS-DCIS was observed in patients treated with Nerlynx relative to patients treated with the placebo. Although favourable trends were observed for DDFS and TTDR in patients treated with Nerlynx relative to patients who received the placebo, the results were statistically insignificant. The rate of cumulative CNS recurrences was too low for a meaningful analysis.

The subgroup analyses showed that the treatment effect on iDFS was in favor of Nerlynx in most pre-defined subgroups. Hormone receptor (HRc)-positive patients treated with Nerlynx plus endocrine therapy had a 51% reduction in the risk of disease recurrence or death, relative to patients who received the placebo plus endocrine therapy. The benefit of Nerlynx was also observed in patients who completed trastuzumab adjuvant therapy within one year prior to randomization in the ExteNET study. However, Nerlynx treatment did not show a clear benefit over placebo in HRc negative patients, or in patients who completed trastuzumab adjuvant therapy more than one year prior to randomization, although with limited number of patients.

The different outcomes of the subgroups were confirmed by positive interactions between Nerlynx treatment and HRc status, and between Nerlynx treatment and time to prior trastuzumab therapy in the centrally confirmed HER2-positive population. Given the modest benefit in the ITT population, the efficacy of the HRc-positive subgroup appeared to drive the overall positive outcome, albeit composing only 57% of the ITT population. The primary endpoint appeared to be supported by the analyses of the secondary endpoints in those subgroups. A subgroup analysis of the HRc-positive patient population showed statistically significant benefits with respect to DFS DCIS, DDFS, and TTDR in patients treated with Nerlynx plus endocrine therapy. No secondary endpoints were statistically significant with respect to Nerlynx treatment versus placebo in HRc negative patients, or in patients who were randomized over one year after completing trastuzumab adjuvant therapy.

The five-year updated efficacy data of the pivotal study provided further evidence to support the efficacy results of Nerlynx plus endocrine therapy in the extended adjuvant setting as potentially the first therapeutic intervention to improve iDFS in patients with HRc-positive and HER2-postivie early breast cancer previously treated with trastuzumab-based adjuvant therapy.

Overall, the pivotal study provides strong evidence that the benefit of treatment with Nerlynx in combination with endocrine therapy is clinically meaningful when used as an extended adjuvant treatment within one year after trastuzumab-based adjuvant therapy in patients with HRc-positive and HER2-positive, early disease. At the time of authorization, there were no other treatment options for the extended adjuvant treatment after trastuzumab-based adjuvant therapy.

Indication

Sponsor's proposed indication	Health Canada-approved indication
Nerlynx (neratinib) is a protein kinase inhibitor indicated as monotherapy for the extended adjuvant treatment of adult patients with early-stage HER2-overexpressed/ amplified breast cancer, to follow adjuvant trastuzumab based therapy.	Nerlynx (neratinib) is indicated for the extended adjuvant treatment of women with early-stage hormone receptor positive, HER2-overexpressed/amplified breast cancer within one year after completion of trastuzumab-based adjuvant therapy.

The proposed indication was for adult patients. However, there were concerns due to a lack of information regarding extrapolation of the data collected from female patients to male patients in the extended adjuvant setting for breast cancer. The indication was therefore limited to women.

Based on Health Canada's review, the indication was also restricted to the two subgroups that were shown to benefit from treatment with Nerlynx: patients with hormone receptor positive, HER2-overexpressed/amplified breast cancer, and within one year after completion of trastuzumab-based adjuvant therapy. As all patients with HRc-positive disease were treated with endocrine therapy in addition to Nerlynx in the pivotal study, the wording 'monotherapy' in the sponsor's proposed indication was removed.

For more information, refer to the Nerlynx Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The data reviewed to evaluate the clinical safety of Nerlynx were derived mainly from patients with early-stage breast cancer enrolled in the pivotal study, ExteNET (n = 1,408). This study is described in detail in the Clinical Efficacy section. The median duration of treatment was similar between patients who received Nerlynx and patients who received the placebo (11.6 and 11.8 months, respectively), which is similar to the recommended treatment duration of one year for Nerlynx.

In ExteNET study, higher incidences of treatment-emergent adverse events, Grade 3 or 4 adverse events, and treatment-related adverse events were reported in patients treated with Nerlynx relative to patients who received the placebo. Additionally, treatment discontinuation, dose reduction or dose hold due to adverse events were also more frequently reported in patients treated with Nerlynx.

The most common adverse events in patients treated with Nerlynx (reported in ≥10% of patients) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, and dyspepsia. The most common serious adverse events (SAE), each reported in less than 2% of patients, were diarrhea, vomiting, dehydration, cellulitis, renal failure, erysipelas, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), nausea, fatigue, and abdominal pain. There were no adverse events with a fatal outcome reported during treatment.

Diarrhea was the most frequently reported severe adverse event, and the most common adverse event leading to treatment discontinuation. Severe diarrhea was reported in 40% of patients treated with Nerlynx, and was accompanied by dehydration, hypotension, and renal failure in some cases. The onset of diarrhea generally occurred during the first week of treatment with Nerlynx, and incidence declined and stabilized thereafter. The available data from an ongoing clinical study (PUMA-NER 6201) have shown that the prophylactic administration of loperamide effectively mitigated the frequency and severity of diarrhea. Instructions for the prophylactic management of diarrhea are included in the Nerlynx Product Monograph.

Nerlynx has been associated with hepatotoxicity, characterized by increased liver enzymes following the treatment. The median time to onset for any hepatotoxicity was 31 days. Based on these observations, liver function tests are recommended prior to and during treatment with Nerlynx. Nerlynx doses should be modified in patients with treatment-emergent hepatotoxicity and treatment should be permanently discontinued in patients with Grade 4 increased liver transaminases, Grade 4 bilirubin, or when Hy's Law criteria were met.

Cardiac monitoring, including assessment of left ventricular ejection fraction (LVEF), is recommended in patients with known cardiac risk factors. In ExteNET study, slightly higher incidence of Grade 3 ejection fraction decreased or congestive cardiac failure (0.4% vs. 0.1%) and higher incidence of patients discontinued treatment due to decreased ejection fraction or left ventricular dysfunction (1.1% vs. 0.4%) in patients treated with Nerlynx versus placebo were reported. Patients with LVEF either below the institutional lower limit of normal or below 50%, symptomatic congestive heart failure of New York Heart Association (NYHA) class 2 or higher, a QT interval (using Fridericia's correction formula; QTcF) >450 ms, ventricular arrhythmia requiring medical therapy, or with a history of myocardial infarction within the last 12 months were excluded from the pivotal study.

Geriatric patients (≥65 years of age) had a higher frequency of treatment discontinuations due to adverse reactions or serious adverse reactions relative to younger patients (45% versus 25%). The most frequently reported serious adverse events in the geriatric patient population were diarrhea, vomiting, renal failure, and dehydration. Diarrhea was also the adverse reaction, which most commonly led to treatment discontinuation.

Overall, the safety profile of Nerlynx is considered acceptable for its intended use. Appropriate warnings and precautions are in place in the approved Nerlynx Product Monograph to address the identified safety concerns.

For more information, refer to the Nerlynx Product Monograph, approved by Health Canada and available through the Drug Product Database.