NERLYNX Film-coated tablet Ref.[10146] Active ingredients: Neratinib

Cardiac Electrophysiology

The effect of NERLYNX on the QTc interval was evaluated in a randomized, placebo, and positive-controlled, double-blind, single-dose, crossover study in 60 healthy subjects. At 140% the therapeutic exposures of NERLYNX, there was no clinically relevant effect on the QTc interval.

Neratinib exhibits a non-linear PK profile with less than dose proportional increase of AUC with the increasing daily dose over the range of 40 to 400 mg.

Absorption

The neratinib and major active metabolites M3, M6 and M7 peak concentrations are reached in the range of 2 to 8 hours after oral administration.

Effect of Food

The food-effect assessment was conducted in healthy volunteers who received NERLYNX 240 mg under fasting conditions and with high-fat food (approximately 55% fat, 31% carbohydrate, and 14% protein) or standard breakfast (approximately 50% carbohydrate, 35% fat, and 15% protein). A high-fat meal increased neratinib C_max and AUC_inf by 70% (90% CI: 1.1–2.7) and 120% (90% CI: 1.4–3.5), respectively. A standard breakfast increased the C_max and AUC_inf by 20% (90% CI: 0.97–1.42) and 10% (90% CI: 1.02–1.24), respectively [see Dosage and Administration (2.2)].

Distribution

In patients, following multiple doses of NERLYNX, the mean (CV) apparent volume of distribution at steady-state (V_ss/F) was 6433 (19) L. In vitro protein binding of neratinib in human plasma was greater than 99% and independent of concentration. Neratinib bound predominantly to human serum albumin and human alpha-1 acid glycoprotein.

Elimination

Following 7 days of daily 240 mg oral doses of NERLYNX in healthy subjects, the mean (CV) plasma half-life of neratinib, M3, M6, and M7 was 14.6 (38), 21.6 (77%), 13.8 (50%) and 10.4 (33%) hours, respectively. The mean elimination half-life of neratinib ranged from 7 to 17 hours following a single oral dose in patients. Following multiple doses of NERLYNX at once-daily 240 mg in cancer patients, the mean (CV) CL/F after first dose and at steady state (day 21) were 216 (34) and 281 (40%) L/hour, respectively.

Metabolism

Neratinib is metabolized primarily in the liver by CYP3A4 and to a lesser extent by flavin-containing monooxygenase (FMO).

After oral administration of NERLYNX, neratinib represents the most prominent component in plasma. At steady state after 240 mg daily oral doses of NERLYNX in a healthy subject study (n=25), the systemic exposures (AUC) of the active metabolites M3, M6, M7 and M11were 15%, 33%, 22% and 4% of the systemic neratinib exposure (AUC) respectively.

Excretion

After oral administration of 200 mg (0.83 times of approved recommended dosage) radiolabeled neratinib oral formulation, fecal excretion accounted for approximately 97% and urinary excretion accounted for 1.1% of the total dose. Sixty-one percent of the excreted radioactivity was recovered within 96 hours and 98% was recovered after 10 days.

Specific Populations

Age, gender, race, and renal function do not have a clinically significant effect on neratinib pharmacokinetics.

Patients With Hepatic Impairment

Neratinib is mainly metabolized in the liver. Single doses of 120 mg NERLYNX were evaluated in non-cancer patients with chronic hepatic impairment (n=6 each in Child Pugh Class A, B, and C) and in healthy subjects (n=9) with normal hepatic function. Neratinib exposures in the patients with Child Pugh Class A (mild impairment) and Child Pugh Class B (moderate impairment) were similar to that in normal healthy volunteers. Patients with severe hepatic impairment (Child Pugh Class C) had neratinib C_max and AUC increased by 173% and 181%, respectively, as compared to the normal hepatic function controls [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)].

Drug Interaction Studies

Gastric Acid Reducing Agents

NERLYNX solubility decreases with increasing GI tract pH values. Drugs that alter the pH values of the GI tract may alter the solubility of neratinib and hence its absorption and systemic exposure. When multiple doses of lansoprazole (30 mg daily), a proton pump inhibitor, were co-administered with a single 240 mg oral dose of NERLYNX, the neratinib C_max and AUC decreased by 71% and 65%, respectively. When a single oral dose of 240 mg NERLYNX was administered 2 hours following a daily dose of 300 mg ranitidine, an H₂ receptor antagonist, the neratinib C_max and AUC were reduced by 57% and 48%, respectively. When a single oral dose of 240 mg NERLYNX was administered 2 hours prior to 150 mg ranitidine twice daily (administered in the morning and evening, approximately 12 hours apart), the neratinib C_max and AUC were reduced by 44% and 32%, respectively [see Dosage and Administration (2.3) and Drug Interactions (7.1)].

Strong CYP3A4 inhibitors

Concomitant use of ketoconazole (400 mg once-daily for 5 days), a strong inhibitor of CYP3A4 and an inhibitor of P-gp, with a single oral 240 mg NERLYNX dose in healthy subjects (n=24) increased neratinib C_max by 221% and AUC by 381% [see Drug Interactions (7.1)].

Moderate CYP3A4 and P-gp dual Inhibitors

Simulations using physiologically based pharmacokinetic (PBPK) models suggested that a moderate CYP3A4 and P-gp dual inhibitor (verapamil) may increase the C_max and AUC of neratinib by 203% and 299%, respectively [see Drug Interactions (7.1)].

Moderate CYP3A4 inhibitors

Simulations using PBPK models suggested that a moderate CYP3A4 inhibitor (fluconazole) may increase the C_max and AUC of neratinib by 30% and 68%, respectively.

Strong and Moderate CYP3A4 Inducers

Concomitant use of rifampin, a strong inducer of CYP3A4, with a single oral 240 mg NERLYNX dose in healthy subjects (n=24) reduced neratinib C_max by 76% and AUC by 87%. The AUC of active metabolites M6 and M7 were also reduced by 37–49% when compared to NERLYNX administered alone. Simulations using PBPK models suggested that a moderate CYP3A4 inducer (efavirenz) may decrease the C_max and AUC of neratinib by 36% and 52%, respectively [see Drug Interactions (7.1)].

Effect of NERLYNX on P-gp Transporters

Concomitant use of digoxin (a single 0.5 mg oral dose), a P-gp substrate, with multiple oral doses of NERLYNX 240 mg in healthy subjects (n=18) increased the mean digoxin C_max by 54% and AUC by 32% [see Drug Interactions (7.2)].

A two-year carcinogenicity study was conducted in rats at oral neratinib doses of 1, 3, and 10 mg/kg/day. Neratinib was not carcinogenic in male and female rats at exposure levels >25 times the AUC in patients receiving the maximum recommended dose of 240 mg/day. Neratinib was not carcinogenic in a 26-week study in Tg.rasH2 transgenic mice when administered daily by oral gavage at doses up to 50 mg/kg/day in males and 125 mg/kg/day in females.

Neratinib was not mutagenic in an in vitro bacterial reverse mutation (AMES) assay or clastogenic in an in vitro human lymphocyte chromosomal aberration assay or an in vivo rat bone marrow micronucleus assay.

In a fertility study in rats, neratinib administration up to 12 mg/kg/day (approximately 0.5 times the maximum recommended dose of 240 mg/day in patients on a mg/m² basis) caused no effects on mating or the ability of animals to become pregnant. In repeat-dose toxicity studies in dogs with oral administration of neratinib daily for up to 39 weeks, tubular hypoplasia of the testes was observed at ≥0.5 mg/kg/day. This finding was observed at AUCs that were approximately 0.4 times the AUC in patients at the maximum recommended dose of 240 mg.

14.1 Extended Adjuvant Treatment of Early Stage Breast Cancer

The safety and efficacy of NERLYNX were investigated in the ExteNET trial (NCT00878709), a multicenter, randomized, double-blind, placebo-controlled study of NERLYNX after adjuvant treatment with a trastuzumab based therapy in women with HER2-positive breast cancer.

A total of 2840 patients with early-stage (Stage 1 to 3c) HER2-positive breast cancer within two years of completing treatment with adjuvant trastuzumab was randomized to receive either NERLYNX (n=1420) or placebo (n=1420). Randomization was stratified by the following factors: hormone receptor status, nodal status (0, 1–3 vs 4 or more positive nodes) and whether trastuzumab was given sequentially versus concurrently with chemotherapy. NERLYNX 240 mg or placebo was given orally once daily for one year. The major efficacy outcome measure was invasive disease-free survival (iDFS) defined as the time between 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 2 years and 28 days of follow-up.

Patient demographics and tumor characteristics were generally balanced between treatment arms. Patients had a median age of 52 years (range 23 to 83) and 12% of patients were 65 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 one to three positive nodes and 30% had four or more positive nodes. Ten percent (10%) of patients had Stage I disease, 41% had Stage II disease and 31% had Stage III disease. The majority of patients (81%) were enrolled within one year of completion of trastuzumab 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. Median duration of treatment was 11.6 months in the NERLYNX arm vs 11.8 months in the placebo arm.

The efficacy results from the ExteNET trial are summarized in Table 11 and Figure 1.

Table 11. Efficacy iDFS Results for the ITT Population:

CI= Confidence Interval; HR=Hazard Ratio; iDFS=Invasive Disease Free-Survival; ITT=Intent to Treat
* Kaplan-Meier estimate
^† Stratified by prior trastuzumab (concurrent vs sequential), nodal status (0–3 positive nodes vs ≥4 positive nodes), and ER/PR status (positive vs negative)
^‡ Stratified log-rank test

Figure 1. iDFS in the ExteNET Trial – ITT Population:

CI=Confidence Interval; HR=Hazard Ratio; iDFS=Invasive Disease Free-Survival; ITT=Intent to Treat

Table 12. Subgroup Analyses*:

CI= Confidence Interval; HR=Hazard Ratio; iDFS=Invasive Disease Free-Survival; ITT=Intent to Treat
CI=Confidence Interval; HR=Hazard Ratio
* Exploratory analyses without adjusting multiple comparisons
^† Kaplan-Meier estimate

Approximately 75% of patients were re-consented for extended follow-up beyond 24 months. Observations with missing data were censored at the last date of assessment. This exploratory analysis suggests that the iDFS results at 5 years are 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 OS between the NERLYNX and the placebo arm [HR 0.95 (95% CI: 0.75, 1.21)]. The 5-year estimate of OS was 94.1% (95% CI, 92.7%, 95.3%) in the NERLYNX arm and 93.3% (95% CI, 91.8%, 94.5%) in the placebo arm.

14.2 Advanced or Metastatic Breast Cancer

The safety and efficacy of NERLYNX in combination with capecitabine was studied in NALA (NCT01808573), a randomized, multicenter, open-label clinical trial in patients (n=621) with metastatic HER2 positive breast cancer who had received 2 or more prior anti-HER2 based regimens in the metastatic setting. HER2 expression was based on archival tissue tested at a central laboratory prior to enrollment. HER2 positivity was defined as a HER2 immunohistochemistry (IHC) score of 3+ or IHC 2+ with confirmatory in situ hybridization (ISH) positive. Fifty-nine percent of these patients were hormone receptor positive (HR+) and 41% were hormone receptor negative (HR-); 69% had received two prior anti-HER2 based regimens, 31% had received three or more prior anti-HER2 based regimens, 81% had visceral disease, and 19% had non-visceral-only disease. Patients with asymptomatic or stable brain metastases were included in NALA trial (16%).

Patients were randomized (1:1) to receive NERLYNX 240 mg orally once daily on Days 1–21 in combination with capecitabine 750 mg/m² given orally twice daily on Days 1–14 for each 21–day cycle (n=307) or lapatinib 1250 mg orally once daily Days 1–21 in combination with capecitabine 1000 mg/m² given orally twice daily on Days 1-14 for each 21-day cycle (n=314). Patients were treated until disease progression or unacceptable toxicity.

The efficacy results from the NALA trial are summarized in Table 13, Figure 2, and Figure 3.

Table 13. Efficacy Results – NALA Trial (Central Assessment):

HR=Hazard Ratio
* Hazard ratio is presented as NERLYNX plus Capecitabine (N+C) vs Lapatinib plus Capecitabine (L+C).
^† Stratified log-rank test
^‡ The total number of patients remaining on study at 24 months is 11; with 9 patients on N+C and 2 patients on L+C.
^α Exploratory analysis
^§ Confirmed ORR

Figure 2. Progression Free Survival (Central Assessment – ITT Population):

Figure 3. Overall Survival (ITT Population):

Table 14. Progression-Free Survival Rates – Subgroup Analyses^α:

^α Exploratory Analysis