Gilotrif afatinib 40 mg Tablet, Film Coated, 30-count — NDC 0597-0138-30 (Billing 00597-0138-30)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Afatinib covalently binds to the kinase domains of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4) and irreversibly inhibits tyrosine kinase autophosphorylation, resulting in downregulation of ErbB signaling. Certain mutations in EGFR, including non-resistant mutations in its kinase domain, can result in increased autophosphorylation of the receptor, leading to receptor activation, sometimes in the absence of ligand binding, and can support cell proliferation in NSCLC. Non-resistant mutations are defined as those occurring in exons constituting the kinase domain of EGFR that lead to increased receptor activation and where efficacy is predicted by 1) clinically meaningful tumor shrinkage with the recommended dose of afatinib and/or 2) inhibition of cellular proliferation or EGFR tyrosine kinase phosphorylation at concentrations of afatinib sustainable at the recommended dosage according to validated methods.

The most commonly found of these mutations are exon 21 L858R substitutions and exon 19 deletions. Afatinib demonstrated inhibition of autophosphorylation and/or in vitro proliferation of cell lines expressing wild-type EGFR and in those expressing selected EGFR exon 19 deletion mutations, exon 21 L858R mutations, or other less common non-resistant mutations, at afatinib concentrations achieved in patients. In addition, afatinib inhibited in vitro proliferation of cell lines overexpressing HER2.

Treatment with afatinib resulted in inhibition of tumor growth in nude mice implanted with tumors either overexpressing wild type EGFR or HER2 or in an EGFR L858R/T790M double mutant model.

12.2Pharmacodynamics Cardiac Electrophysiology The effect of multiple doses of GILOTRIF (50 mg once daily) on the QTc interval was evaluated in an open-label, single-arm study in patients with relapsed or refractory solid tumors. No large changes in the mean QTc interval (i.e., >20 ms) were detected in the study.

12.3Pharmacokinetics Absorption Following oral administration of GILOTRIF tablets, time to peak afatinib plasma concentrations (T max ) is 2 to 5 hours. Maximum concentration (C max ) and area under the concentration-time curve from time zero to infinity (AUC 0-INF ) values increased slightly more than dose proportional in the range of 20 to 50 mg. The geometric mean relative bioavailability of 20 mg GILOTRIF tablets was 92% as compared to an oral solution.

Steady-state plasma concentrations are achieved within 8 days of repeat dosing of GILOTRIF resulting in an accumulation of 2.8-fold for AUC and 2.1-fold for C max . Effect of Food A high-fat meal decreased C max by 50% and AUC 0-INF by 39% relative to the fasted condition [see Dosage and Administration (2.2) ] . Distribution In vitro binding of afatinib to human plasma proteins is approximately 95%.

Elimination The elimination half-life of afatinib is 37 hours after repeat dosing in cancer patients. Metabolism Covalent adducts to proteins are the major circulating metabolites of afatinib and enzymatic metabolism of afatinib is minimal. The metabolites formed by CYP450-dependent reactions were approximately 9% of the total metabolic turnover in sandwich-cultured human hepatocytes.

Approximately 2% of the afatinib dose was metabolized by FMO3; the CYP3A4-dependent N-demethylation was not detected. Excretion In humans, excretion of afatinib is primarily via the feces (85%) with 4% recovered in the urine following a single oral dose of [ 14 C]-labeled afatinib solution. The parent compound accounted for 88% of the recovered dose.

Specific Populations Based on the population pharmacokinetic analysis, weight, gender, age, and race do not have a clinically important effect on exposure of afatinib. Patients with Renal Impairment A pharmacokinetic study was conducted in 14 subjects with normal (eGFR ≥90 mL/min/1.73 m 2 ) renal function, 8 subjects with moderate (eGFR 30 to 59 mL/min/1.73 m 2 ) and 8 subjects with severe (eGFR 15 to 29 mL/min/1.73… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Afatinib covalently binds to the kinase domains of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4) and irreversibly inhibits tyrosine kinase autophosphorylation, resulting in downregulation of ErbB signaling. Certain mutations in EGFR, including non-resistant mutations in its kinase domain, can result in increased autophosphorylation of the receptor, leading to receptor activation, sometimes in the absence of ligand binding, and can support cell proliferation in NSCLC. Non-resistant mutations are defined as those occurring in exons constituting the kinase domain of EGFR that lead to increased receptor activation and where efficacy is predicted by 1) clinically meaningful tumor shrinkage with the recommended dose of afatinib and/or 2) inhibition of cellular proliferation or EGFR tyrosine kinase phosphorylation at concentrations of afatinib sustainable at the recommended dosage according to validated methods.

The most commonly found of these mutations are exon 21 L858R substitutions and exon 19 deletions. Afatinib demonstrated inhibition of autophosphorylation and/or in vitro proliferation of cell lines expressing wild-type EGFR and in those expressing selected EGFR exon 19 deletion mutations, exon 21 L858R mutations, or other less common non-resistant mutations, at afatinib concentrations achieved in patients. In addition, afatinib inhibited in vitro proliferation of cell lines overexpressing HER2.

Treatment with afatinib resulted in inhibition of tumor growth in nude mice implanted with tumors either overexpressing wild type EGFR or HER2 or in an EGFR L858R/T790M double mutant model.

12.3Pharmacokinetics Absorption Following oral administration of GILOTRIF tablets, time to peak afatinib plasma concentrations (T max ) is 2 to 5 hours. Maximum concentration (C max ) and area under the concentration-time curve from time zero to infinity (AUC 0-INF ) values increased slightly more than dose proportional in the range of 20 to 50 mg. The geometric mean relative bioavailability of 20 mg GILOTRIF tablets was 92% as compared to an oral solution.

Steady-state plasma concentrations are achieved within 8 days of repeat dosing of GILOTRIF resulting in an accumulation of 2.8-fold for AUC and 2.1-fold for C max . Effect of Food A high-fat meal decreased C max by 50% and AUC 0-INF by 39% relative to the fasted condition [see Dosage and Administration (2.2) ] . Distribution In vitro binding of afatinib to human plasma proteins is approximately 95%.

Elimination The elimination half-life of afatinib is 37 hours after repeat dosing in cancer patients. Metabolism Covalent adducts to proteins are the major circulating metabolites of afatinib and enzymatic metabolism of afatinib is minimal. The metabolites formed by CYP450-dependent reactions were approximately 9% of the total metabolic turnover in sandwich-cultured human hepatocytes.

Approximately 2% of the afatinib dose was metabolized by FMO3; the CYP3A4-dependent N-demethylation was not detected. Excretion In humans, excretion of afatinib is primarily via the feces (85%) with 4% recovered in the urine following a single oral dose of [ 14 C]-labeled afatinib solution. The parent compound accounted for 88% of the recovered dose.

Specific Populations Based on the population pharmacokinetic analysis, weight, gender, age, and race do not have a clinically important effect on exposure of afatinib. Patients with Renal Impairment A pharmacokinetic study was conducted in 14 subjects with normal (eGFR ≥90 mL/min/1.73 m 2 ) renal function, 8 subjects with moderate (eGFR 30 to 59 mL/min/1.73 m 2 ) and 8 subjects with severe (eGFR 15 to 29 mL/min/1.73 m 2 ) renal impairment. All subjects received a single 40 mg oral dose of GILOTRIF.

The geometric mean AUC INF for afatinib was 50% higher in subjects with severe renal impairment and was 22% higher in subjects with moderate renal impairment as compared to subjects with normal renal function. Geometric mean C max was 22% higher in subjects with severe renal impairment and was comparable in subjects with moderate renal impairment to subjects with normal renal function [see Dosage and Administration (2.4) , Use in Specific Populations (8.6) ] . GILOTRIF has not been studied in patients with eGFR <15 mL/min/1.73 m 2 or on dialysis.

Patients with Hepatic Impairment Mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment had no influence on the afatinib exposure following a single dose of GILOTRIF. Subjects with severe (Child Pugh C) hepatic impairment have not been studied [see Use in Specific Populations (8.7) ] . Drug Interactions Studies Clincial Studies Effect of P-gp Inhibitors and Inducers on Afatinib: The effect of ritonavir dosing time relative to a single oral dose of GILOTRIF was evaluated in healthy subjects taking 40 mg of GILOTRIF alone as compared to those after ritonavir (200 mg twice daily for 3 days) co-administration at 6 hours after GILOTRIF administration.

The relative bioavailability for AUC 0-INF and C max of afatinib was 119% and 104% when co-administered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after taking GILOTRIF. In another study, when ritonavir (200 mg twice daily for 3 days) was administered 1 hour before a 20 mg single dose of GILOTRIF, exposure to afatinib increased by 48% for AUC 0-INF and 39% for C max [see Drug Interactions (7) ]. Pre-treatment with a potent inducer of P-gp, rifampicin (600 mg once daily for 7 days) decreased the plasma exposure to afatinib by 34% (AUC 0-INF ) and 22% (C max ) [see Drug Interactions (7) ] .

In Vitro Studies Effect of Afatinib on P-gp… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Cardiac Electrophysiology The effect of multiple doses of GILOTRIF (50 mg once daily) on the QTc interval was evaluated in an open-label, single-arm study in patients with relapsed or refractory solid tumors. No large changes in the mean QTc interval (i.e., >20 ms) were detected in the study.

14 CLINICAL STUDIES

14.1EGFR Mutation-Positive, Metastatic NSCLC The efficacy of GILOTRIF for the first-line treatment of patients with EGFR mutation-positive, metastatic [Stage IV and Stage IIIb with pleural and/or pericardial effusion as classified by the American Joint Commission on Cancer (AJCC, 6th edition)] NSCLC was established in a randomized, multicenter, open-label trial (LUX-Lung 3 [NCT00949650]). Patients were randomized (2:1) to receive GILOTRIF 40 mg orally once daily (n=230) or intravenous pemetrexed (500 mg/m 2 ) plus cisplatin (75 mg/m 2 ) once every 21 days for up to 6 cycles (n=115).

Randomization was stratified according to EGFR mutation category (exon 19 deletion vs exon 21 L858R vs other) and race (Asian vs non-Asian). The major efficacy outcome was progression-free survival (PFS) as assessed by an independent review committee (IRC). Other efficacy outcomes included overall response rate (ORR) and OS.

EGFR mutation status was prospectively determined for screening and enrollment of patients by a clinical trial assay (CTA). Tumor samples from 264 patients (178 randomized to GILOTRIF and 86 patients randomized to chemotherapy) were tested retrospectively by the companion diagnostic therascreen ® EGFR RGQ PCR Kit, which is FDA-approved for selection of patients for GILOTRIF treatment. Among the patients randomized, 65% were female, median age was 61 years, baseline ECOG performance status (PS) was 0 (39%) or 1 (61%), 26% were White and 72% were Asian.

The majority of the patients had a tumor sample with an EGFR mutation categorized by the CTA as either exon 19 deletion (49%) or exon 21 L858R substitution (40%), while the remaining 11% had other mutations. A statistically significant improvement in PFS as determined by the IRC was demonstrated for patients randomized to GILOTRIF compared with those randomized to chemotherapy. See Table 5 and Figure 1 .

There was no statistically significant difference for OS between the treatment arms at the final pre-planned analysis. Table 5 Efficacy Results in LUX-Lung 3 GILOTRIF (N=230) Pemetrexed/Cisplatin (N=115) *Stratified by EGFR mutation status and race. HR=hazard ratio; CR=complete response; PR=partial response Progression-Free Survival by IRC Number of Deaths or Progressions, N (%) 152 (66.1%) 69 (60.0%) Median Progression-Free Survival (months) 11.1 6.9 95% CI (9.6, 13.6) (5.4, 8.2) HR (95% CI) 0.58 (0.43, 0.78) Stratified Log-Rank Test p-value* <0.001 Overall Survival Number of Deaths, N (%) 140 (60.9%) 73 (63.5%) Median Overall Survival (months) 28.2 28.2 95% CI (24.6, 33.6) (20.7, 33.2) HR (95% CI) 0.88 (0.66, 1.17) Stratified Log-Rank Test p-value*

0.39Overall Response Rate (CR + PR) by IRC N (%) 116 (50.4%) 22 (19.1%) Response Duration Median (months) 12.5

6.7Figure 1 Kaplan-Meier Curve for PFS by Independent Review by Treatment Group in LUX-Lung 3 Pre-specified exploratory subgroup analyses were conducted according to the stratification factor of EGFR mutation category. See Figure 2 and text below Figure 2. Figure 2 Forest Plots of PFS and OS by EGFR Mutation Subgroups in LUX-Lung 3 Overall Response Rate in Other EGFR Mutations The efficacy of GILOTRIF in patients with NSCLC harboring non-resistant EGFR mutations (S768I, L861Q, and G719X) other than exon 19 deletions or exon 21 L858R substitutions was evaluated in a pooled analysis of such patients enrolled in one of three clinical trials (LUX-Lung 2 [NCT00525148], LUX-Lung 3 [NCT00949650], and LUX-Lung 6 [NCT01121393]).

LUX-Lung 2 was a single arm, multicenter study of afatinib 40 or 50 mg orally once daily until disease progression or intolerable side effects. EGFR status was determined by bi-directional Sanger sequencing of tumor tissue. LUX-Lung 3 was a randomized, multicenter study comparing treatment with afatinib 40 mg orally once daily to intravenous cisplatin 75 mg/m 2 plus pemetrexed 500 mg/m 2 every 21 days for up to 6 cycles.

EGFR status was determined by the therascreen ® EGFR RGQ PCR Kit. L… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with afatinib. A marginal response to afatinib was observed in a single tester strain of a bacterial (Ames) mutagenicity assay. No mutagenic or genotoxic potential was identified in an in vitro chromosomal aberration test at non-cytotoxic concentrations as well as in the in vivo bone marrow micronucleus assay, the in vivo Comet assay, and an in vivo 4-week oral mutation study in the Muta ™ Mouse.

In a dedicated fertility study, male and female rats received afatinib daily by oral administration at doses of 4, 6, or 8 mg/kg. In males at doses of 6 mg/kg (approximately equal to the exposure by AUC in patients at the recommended human dose of 40 mg daily) or greater, there was an increase in the incidence of low or no sperm count, though overall fertility was not affected; decreases in sperm count were supported by findings of increased apoptosis in the testes and atrophy in the seminal vesicles and the prostate in general toxicology studies.

In females at the high dose of 8 mg/kg (approximately 0.63 times the exposure by AUC in patients at the recommended human dose of 40 mg daily), there was a mild decrease in the number of corpora lutea along with a mild increase in post-implantation loss due to early resorptions. In a 4-week general toxicology study, female rats had decreases in ovarian weights at all dose levels; organ weight had not fully recovered by the end of a 2-week recovery period.