February 26, 2017
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Mechanism 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.

Afatinib demonstrated inhibition of autophosphorylation and in vitro proliferation of cell lines expressing wild-type EGFR or those expressing selected EGFR exon 19 deletion mutations or exon 21 L858R mutations, including some with a secondary T790M mutation, at afatinib concentrations achieved, at least transiently, 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.


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.


Absorption And Distribution

Following oral administration of GILOTRIF tablets, time to peak afatinib plasma concentrations (Tmax) is 2 to 5 hours. Maximum concentration (Cmax) and area under the concentration-time curve from time zero to infinity (AUC0-∞) 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. In vitro binding of afatinib to human plasma proteins is approximately 95%.

A high-fat meal decreased Cmax by 50% and AUC0-∞ by 39% relative to the fasted condition [see DOSAGE AND ADMINISTRATION].

Metabolism And Elimination

Covalent adducts to proteins are the major circulating metabolites of afatinib and enzymatic metabolism of afatinib is minimal.

In humans, excretion of afatinib is primarily via the feces (85%) with 4% recovered in the urine following a single oral dose of [14C]-labeled afatinib solution. The parent compound accounted for 88% of the recovered dose.

The elimination half-life of afatinib is 37 hours after repeat dosing in cancer patients. 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 Cmax.

Specific Populations

Renal Impairment

A pharmacokinetic study was conducted in 14 subjects with normal (eGFR ≥90 mL/min/1.73 m2) renal function, 8 subjects with moderate (eGFR=30 to 59 mL/min/1.73 m2) and 8 subjects with severe (eGFR=15 to 29 mL/min /1.73 m2) renal impairment. All subjects received a single 40 mg oral dose of GILOTRIF. The geometric mean AUCinf 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 Cmax was 22% higher in subjects with severe renal impairment and was comparable in subjects with moderate renal impairment as compared to subjects with normal renal function [see DOSAGE AND ADMINISTRATION and Use In Specific Populations]. GILOTRIF has not been studied in patients with eGFR <15 mL/min/1.73 m2 or on dialysis.

Hepatic Impairment

Afatinib is eliminated mainly by biliary/fecal excretion. 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 dysfunction have not been studied [see Use In Specific Populations].

Body Weight, Gender, Age, And Race

Based on the population pharmacokinetic analysis, weight, gender, age, and race do not have a clinically important effect on exposure of afatinib.

Drug Interactions

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 AUC0-∞ and Cmax 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 AUC0-∞ and 39% for Cmax [see DRUG INTERACTIONS].

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% (AUC0-∞) and 22% (Cmax) [see DRUG INTERACTIONS].

P-Glycoprotein (P-Gp)

Based on in vitro data, afatinib is a substrate and an inhibitor of P-gp.

Breast Cancer Resistance Protein (BCRP)

Based on in vitro data, afatinib is a substrate and an inhibitor of the transporter BCRP.

Effect Of CYP450 Enzyme Inducers And Inhibitors On Afatinib

In vitro data indicated that drug-drug interactions with GILOTRIF due to inhibition or induction of CYP450 enzymes by concomitant medications are unlikely. The metabolites formed by CYP450-dependent reactions were approximately 9% of the total metabolic turnover in sandwich-cultured human hepatocytes. In humans, enzyme-catalyzed metabolic reactions play a negligible role for the metabolism of afatinib. Approximately 2% of the afatinib dose was metabolized by FMO3; the CYP3A4-dependent N-demethylation was not detected.

Effect Of Afatinib On CYP450 Enzymes

Afatinib is not an inhibitor or an inducer of CYP450 enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, and 3A4) in cultured primary human hepatocytes. Therefore, afatinib is unlikely to affect the metabolism of other drugs that are substrates of CYP450 enzymes.

Clinical Studies

EGFR Mutation-Positive Non-Small Cell Lung Cancer

The efficacy and safety of GILOTRIF in the first-line treatment of 345 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)] non-small cell lung cancer (NSCLC) were established in a randomized, multicenter, open-label trial (Study 1). Patients were randomized (2:1) to receive GILOTRIF 40 mg orally once daily (n=230) or up to 6 cycles of pemetrexed/cisplatin (n=115). Randomization was stratified according to EGFR mutation status (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 overall survival (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 was 0 (39%) or 1 (61%), 26% were Caucasian 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 overall survival between the treatment arms at the final pre-planned analysis.

Table 5 Efficacy Results

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* 0.39
Overall Response Rate (CR + PR) by IRC
N (%) 116 (50.4%) 22 (19.1%)
Response Duration
Median (months) 12.5 6.7
*Stratified by EGFR mutation status and race.
HR=hazard ratio; CR=complete response; PR=partial response

Figure 1 Kaplan-Meier Curve for PFS by Independent Review by Treatment Group

Kaplan-Meier Curve for PFS by Independent Review by Treatment Group - Illustration

Subgroup analyses were conducted based on the stratification factor of EGFR mutation status (Del19, L858R, other) and mutation category (common [Del19, L858R] vs uncommon [other]). See Figure 2.

Figure 2 Forest Plot of PFS and OS for Common (Del19, L858R) and Uncommon (other) EGFR Mutation Categories

Forest Plot of PFS and OS for Common (Del19, L858R) and Uncommon (other) EGFR Mutation Categories - Figure 1 - Illustration

Forest Plot of PFS and OS for Common (Del19, L858R) and Uncommon (other) EGFR Mutation Categories - Figure 1 - Illustration

There were 26 GILOTRIF-treated patients in the “other” (uncommon) EGFR mutations subgroup with nine unique mutation patterns. None of these 26 patients achieved a complete response, while four achieved a partial response (see Table 6 below). No responses were seen in GILOTRIF-treated patients with the following mutations: T790M alone (n=2), deletion 19 and T790M (n=3), G719X and T790M (n=1), exon 20 insertion (n=6), and L861Q alone (n=3). There were 11 chemotherapy-treated patients in the “other” uncommon EGFR mutation subgroup; of these, four (36%) achieved a partial response.

Table 6 Objective Tumor Responses in GILOTRIF-Treated Patients Based on Investigator Assessment in the “Other” (Uncommon) EGFR Mutation Subgroup

EGFR Mutations Number of GILOTRIF-Treated Patients Number of Patients with Partial Responses Duration of Response
L858R and T790M 5 1 6.9 months
L858R and S768I 2 1 12.4+ months
S768I 1 1 16.5+ months
G719X 3 1 9.6 months
+ Censored observation

Previously Treated, Metastatic Squamous NSCLC

The efficacy and safety of GILOTRIF were demonstrated in a randomized, multicenter, open-label, active-controlled study (Study 2). Patients were required to have histologically documented, metastatic squamous NSCLC and have experienced disease progression following an adequate course (≥ 4 cycles) of a platinum-based doublet chemotherapy regimen. Patients were randomized (1:1) to receive GILOTRIF 40 mg or erlotinib 150 mg orally once daily until progression. Randomization was stratified by region (Eastern Asia vs other). The major efficacy outcome measure was PFS as assessed by an independent review committee (IRC) using RECIST v 1.1. Additonal efficacy outcome measures were OS and ORR as assessed by IRC.

Baseline patient demographics of the 795 patients were: median age 64 years (range: 35 to 88); 73% White; 24% Asian; 84% male; 33% ECOG performance status (PS) 0 and 67% ECOG PS 1; and 95% current or former smokers. With regard to tumor characteristics, 96% had squamous cell histology and 3.5% had mixed cell histology. All patients received platinum-based doublet therapy.

The study demonstrated a statistically significant improvement in PFS and OS for patients randomized to GILOTRIF as compared with erlotinib (see Table 7 and Figure 3).

Table 7 Efficacy Results

  GILOTRIF Erlotinib
Overall Survival
  N=398 N=398
Number of Deaths, N (%) 307 (77%) 325 (82%)
  Median overall survival (months) 7.9 6.8
  95% CI (7.2, 8.7) (5.9, 7.8)
  HR (95% CI) 0.81 (0.69, 0.95)
  p-value* 0.008
Progression-Free Survival (PFS) by IRC
  N=335 N=334
Number of Events, N (%) 202 (60%) 212 (64%)
  Median PFS (months) 2.4 1.9
  95% CI (1.9, 2.9) (1.9, 2.2)
  HR (95% CI) 0.82 (0.68, 0.998)
  p-value* 0.0427
Overall Response Rate (ORR) by IRC
  N=335 N=334
  ORR 3% 2%
  (95% CI) (1.7, 5.8) (1.7, 5.8)
*Log-rank test stratified by region.
HR=hazard ratio

Figure 3 Kaplan-Meier Curves of Overall Survival

Kaplan-Meier Curves of Overall Survival - Illustration

Last reviewed on RxList: 10/24/2016
This monograph has been modified to include the generic and brand name in many instances.

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