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GILOTRIF(阿法替尼 afatinib)tablet

2013-11-29 12:19:49  作者:新特药房  来源:互联网  浏览次数:1296  文字大小:【】【】【
简介: GILOTRIF (afatinib) tablet, film coated[Boehringer Ingelheim Pharmaceuticals, Inc.]批准日期: 2013年7月12日;公司: Boehringer Ingelheim Pharmaceuticals Inc.美国FDA药物评价和研究中心血液 ...

 GILOTRIF (afatinib) tablet, film coated
[Boehringer Ingelheim Pharmaceuticals, Inc.]
批准日期: 2013年7月12日;公司: Boehringer Ingelheim Pharmaceuticals Inc.
美国FDA药物评价和研究中心血液学和肿瘤学室主任Richard Pazdur,M.D.说:“今天的批准进一步示范更多了解所患疾病的分子通路可能导致靶向治疗的发展,”“Gilotrif是今年被批准对有其肿瘤有EGFR外显子19缺失或外显子21 L858R取代突变未治疗的转移NSCLC患者第二个药物。” 美国FDA装置和放射卫生中心在体外诊断和放射卫生室主任Alberto Gutierrez,Ph.D.说:“协同诊断测试和药物的批准在肿瘤学是重要发展,因为它们帮助我们对需要它们患者的安全和有效治疗。”
优先审评


HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use GILOTRIF safely and effectively. See full prescribing information for GILOTRIF.
GILOTRIF™ (afatinib) tablets, for oral use
Initial U.S. Approval: 2013
INDICATIONS AND USAGE
GILOTRIF is a kinase inhibitor indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test (1)
Limitation of Use: Safety and efficacy of GILOTRIF have not been established in patients whose tumors have other EGFR mutations (1)
DOSAGE AND ADMINISTRATION
Recommended dose: 40 mg orally, once daily (2.2)
Instruct patients to take GILOTRIF at least 1 hour before or 2 hours after a meal (2.2)
DOSAGE FORMS AND STRENGTHS
Tablets: 40 mg, 30 mg, and 20 mg (3)
CONTRAINDICATIONS
None (4)
WARNINGS AND PRECAUTIONS
Diarrhea: Diarrhea may result in dehydration and renal failure. Withhold GILOTRIF for severe and prolonged diarrhea not responsive to anti-diarrheal agents. (2.3, 5.1)
Bullous and Exfoliative Skin Disorders: Severe bullous, blistering, and exfoliating lesions occurred in 0.15% of patients. Discontinue for life-threatening cutaneous reactions. Withhold GILOTRIF for severe and prolonged cutaneous reactions. (2.3, 5.2)
Interstitial lung disease (ILD): Occurs in 1.5% of patients. Withhold GILOTRIF for acute onset or worsening of pulmonary symptoms. Discontinue GILOTRIF if ILD is diagnosed. (2.3, 5.3)
Hepatic toxicity: Fatal hepatic impairment occurs in 0.18% of patients. Monitor with periodic liver testing. Withhold or discontinue GILOTRIF for severe or worsening liver tests. (2.3, 5.4)
Keratitis: Occurs in 0.8% of patients. Withhold GILOTRIF for keratitis eva luation. Withhold or discontinue GILOTRIF for confirmed ulcerative keratitis. (2.3, 5.5)
Embryofetal toxicity: Can cause fetal harm. Advise females of the potential hazard to the fetus and to use highly effective contraception. (5.6)
ADVERSE REACTIONS
Most common adverse reactions (≥20%) are diarrhea, rash/dermatitis acneiform, stomatitis, paronychia, dry skin, decreased appetite, pruritus (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906 TTY or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
Co-administration of P-gp inhibitors can increase afatinib exposure. Reduce GILOTRIF by 10 mg per day if not tolerated. Co-administration of chronic P-gp inducers orally can decrease afatinib exposure. Increase GILOTRIF by 10 mg per day as tolerated. (2.3, 7)
USE IN SPECIFIC POPULATIONS
Nursing mothers: Discontinue drug or nursing (8.3)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 07/2013

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

GILOTRIF is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test [see Clinical Studies (14)].

Limitation of Use: Safety and efficacy of GILOTRIF have not been established in patients whose tumors have other EGFR mutations [see Clinical Studies (14)].

2 DOSAGE AND ADMINISTRATION

2.1 Patient Selection

Select patients for the first-line treatment of metastatic NSCLC with GILOTRIF based on the presence of EGFR exon 19 deletions or exon 21 (L858R) substitution mutations in tumor specimens [see Indications and Usage (1) and Clinical Studies (14)]. Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.

2.2 Recommended Dose

The recommended dose of GILOTRIF is 40 mg orally once daily until disease progression or no longer tolerated by the patient. Take GILOTRIF at least 1 hour before or 2 hours after a meal.

Do not take a missed dose within 12 hours of the next dose.

2.3 Dose Modification

Withhold GILOTRIF for any drug-related adverse reactions of:

  • NCI CTCAE* Grade 3 or higher
  • Diarrhea of Grade 2 or higher persisting for 2 or more consecutive days while taking anti-diarrheal medication [see Warnings and Precautions (5.1)]
  • Cutaneous reactions of Grade 2 that are prolonged (lasting more than 7 days) or intolerable [see Warnings and Precautions (5.2)]
  • Renal dysfunction of Grade 2 or higher

*National Cancer Institute Common Terminology Criteria for Adverse Events, v 3.0

Resume treatment when the adverse reaction fully resolves, returns to baseline, or improves to Grade 1. Reinstitute GILOTRIF at a reduced dose, i.e., 10 mg per day less than the dose at which the adverse reaction occurred.

Permanently discontinue GILOTRIF for:

  • Life-threatening bullous, blistering, or exfoliative skin lesions [see Warnings and Precautions (5.2)]
  • Confirmed interstitial lung disease (ILD) [see Warnings and Precautions (5.3)]
  • Severe drug-induced hepatic impairment [see Warnings and Precautions (5.4)]
  • Persistent ulcerative keratitis [see Warnings and Precautions (5.5)]
  • Symptomatic left ventricular dysfunction
  • Severe or intolerable adverse reaction occurring at a dose of 20 mg per day

P-gp Inhibitors
For patients who require therapy with a P-glycoprotein (P-gp) inhibitor, reduce GILOTRIF daily dose by 10 mg if not tolerated. Resume the previous dose after discontinuation of the P-gp inhibitor as tolerated [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

P-gp Inducers
For patients who require chronic therapy with a P-gp inducer, increase GILOTRIF daily dose by 10 mg as tolerated. Resume the previous dose 2 to 3 days after discontinuation of the P-gp inducer [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

GILOTRIF is available as:
40 mg tablets: light blue, film-coated, round, biconvex, bevel-edged tablets debossed with “T40” on one side and the Boehringer Ingelheim company symbol on the other side.

30 mg tablets: dark blue, film-coated, round, biconvex, bevel-edged tablets debossed with “T30” on one side and the Boehringer Ingelheim company symbol on the other side.

20 mg tablets: white to slightly yellowish, film-coated, round, biconvex, bevel-edged tablets debossed with “T20” on one side and the Boehringer Ingelheim company symbol on the other side.

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

5.1 Diarrhea

Diarrhea has resulted in dehydration with or without renal impairment; some of these cases were fatal. In Study 1, diarrhea occurred in 96% of patients treated with GILOTRIF (n=229), of which 15% was Grade 3 in severity and occurred within the first 6 weeks [see Adverse Reactions (6.1)]. Renal impairment as a consequence of diarrhea occurred in 6.1% of patients treated with GILOTRIF, out of which 3 (1.3%) were Grade 3.

For patients who develop prolonged Grade 2 diarrhea lasting more than 48 hours or greater than or equal to Grade 3 diarrhea, withhold GILOTRIF until diarrhea resolves to Grade 1 or less, and resume GILOTRIF with appropriate dose reduction [see Dosage and Administration (2.3)]. Provide patients with an anti-diarrheal agent (e.g., loperamide) for self-administration at the onset of diarrhea and instruct patients to continue anti-diarrheal therapy until loose bowel movements cease for 12 hours.

5.2 Bullous and Exfoliative Skin Disorders

Grade 3 cutaneous reactions characterized by bullous, blistering, and exfoliating lesions occurred in 6 (0.15%) of the 3865 patients who received GILOTRIF across clinical trials [see Adverse Reactions (6.1)]. In Study 1, the overall incidence of cutaneous reactions consisting of rash, erythema, and acneiform rash was 90%, and the incidence of Grade 3 cutaneous reactions was 16%. In addition, the incidence of Grade 1-3 palmar-plantar erythrodysesthesia syndrome was 7%. Discontinue GILOTRIF in patients who develop life-threatening bullous, blistering, or exfoliating lesions [see Dosage and Administration (2.3)]. For patients who develop prolonged Grade 2 cutaneous adverse reactions lasting more than 7 days, intolerable Grade 2, or Grade 3 cutaneous reactions, withhold GILOTRIF until the adverse reaction resolves to Grade 1 or less, and resume GILOTRIF with appropriate dose reduction [see Dosage and Administration (2.3)].

5.3 Interstitial Lung Disease (ILD)

ILD or ILD-like adverse reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or alveolitis allergic) occurred in 1.5% of the 3865 patients who received GILOTRIF across clinical trials; of these, 0.4% were fatal. The incidence of ILD appeared to be higher in patients of Asian ethnicity (2.1%) as compared to non-Asians (1.2%). In Study 1, the incidence of Grade ≥3 ILD was 1.3% and resulted in death in 1% of GILOTRIF-treated patients.

Withhold GILOTRIF during eva luation of patients with suspected ILD, and discontinue GILOTRIF in patients with confirmed ILD [see Dosage and Administration (2.3)].

5.4 Hepatic Toxicity

In 3865 patients who received GILOTRIF across clinical trials, 10.1% had liver test abnormalities, of which 7 (0.18%) were fatal. In Study 1, liver test abnormalities of any grade occurred in 17.5% of the patients treated with GILOTRIF.

Obtain periodic liver testing in patients during treatment with GILOTRIF. Withhold GILOTRIF in patients who develop worsening of liver function [see Dosage and Administration (2.3)]. In patients who develop severe hepatic impairment while taking GILOTRIF, treatment should be discontinued.

5.5 Keratitis

Keratitis, characterized as acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain, and/or red eye occurred in 0.8% of patients treated with GILOTRIF among 3865 patients across clinical trials. Keratitis was reported in 5 (2.2%) patients in Study 1, with Grade 3 in 1 (0.4%). Withhold GILOTRIF during eva luation of patients with suspected keratitis, and if diagnosis of ulcerative keratitis is confirmed, treatment with GILOTRIF should be interrupted or discontinued [see Dosage and Administration (2.3)]. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. GILOTRIF should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye [see Adverse Reactions (6.1)]. Contact lens use is also a risk factor for keratitis and ulceration.

5.6 Embryofetal Toxicity

Based on its mechanism of action, GILOTRIF can cause fetal harm when administered to a pregnant woman. Afatinib was embryotoxic and, in animals with maternal toxicity, led to abortions at late gestational stages in rabbits at doses of 5 mg/kg (approximately 0.2 times the human exposure at the recommended dose of 40 mg daily) or greater. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

Advise females of reproductive potential to use highly effective contraception during treatment, and for at least 2 weeks after the last dose of GILOTRIF. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking GILOTRIF [see Use in Specific Populations (8.1 and 8.6)].

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

  • Diarrhea [see Warnings and Precautions (5.1)]
  • Bullous and Exfoliative Skin Disorders [see Warnings and Precautions (5.2)]
  • Interstitial Lung Disease [see Warnings and Precautions (5.3)]
  • Hepatic Toxicity [see Warnings and Precautions (5.4)]
  • Keratitis [see Warnings and Precautions (5.5)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety eva luation of GILOTRIF is based on the data from more than 3800 patients, including 2135 NSCLC patients receiving GILOTRIF monotherapy at or above the recommended dose.

Controlled Study
The data in Tables 1 and 2 below reflect exposure of 229 EGFR-TKI naïve GILOTRIF-treated patients with EGFR mutation-positive, metastatic, non-squamous, NSCLC enrolled in a randomized, multicenter, open-label trial (Study 1). Patients received GILOTRIF 40 mg daily until documented disease progression or intolerance to the therapy. A total of 111 patients were treated with pemetrexed/cisplatin. Patients were treated with pemetrexed 500 mg/m² followed after 30 minutes by cisplatin 75 mg/m² every three weeks for a maximum of six treatment courses.

The median exposure was 11.0 months for patients treated with GILOTRIF and 3.4 months for patients treated with pemetrexed/cisplatin. The overall trial population had a median age of 61 years; 61% of patients in the GILOTRIF arm and 60% of patients in the pemetrexed/cisplatin arm were younger than 65 years. A total of 64% of patients on GILOTRIF and 67% of pemetrexed/cisplatin patients were female. More than two-thirds of patients were from Asia (GILOTRIF 70%; pemetrexed/cisplatin 72%).

Serious adverse reactions were reported in 29% of patients treated with GILOTRIF. The most frequent serious adverse reactions reported in patients treated with GILOTRIF were diarrhea (6.6%); vomiting (4.8%); and dyspnea, fatigue, and hypokalemia (1.7% each). Fatal adverse reactions in GILOTRIF-treated patients in Study 1 included pulmonary toxicity/ILD-like adverse reactions (1.3%), sepsis (0.43%), and pneumonia (0.43%).

Dose reductions due to adverse reactions were required in 57% of GILOTRIF-treated patients. The most frequent adverse reactions that led to dose reduction in the patients treated with GILOTRIF were diarrhea (20%), rash/acne (19%), paronychia (14%), and stomatitis (10%).

Discontinuation of therapy in GILOTRIF-treated patients for adverse reactions was 14.0%. The most frequent adverse reactions that led to discontinuation in GILOTRIF-treated patients were diarrhea (1.3%), ILD (0.9%), and paronychia (0.9%).

Clinical trials of GILOTRIF excluded patients with an abnormal left ventricular ejection fraction (LVEF), i.e., below the institutional lower limit of normal. In Study 1, all patients were eva luated for LVEF at screening and every 9 weeks thereafter in the GILOTRIF-treated group and as needed in the pemetrexed/cisplatin group. More GILOTRIF-treated patients (2.2%; n=5) experienced ventricular dysfunction (defined as diastolic dysfunction, left ventricular dysfunction, or ventricular dilation; all < Grade 3) compared to chemotherapy-treated patients (0.9%; n=1).

Table 1 Adverse Reactions Reported in ≥10% of GILOTRIF-Treated Patients in Study 1
*None of the adverse reactions in this table were Grade 4 in severity
1Includes stomatitis, aphthous stomatitis, mucosal inflammation, mouth ulceration, oral mucosa erosion, mucosal erosion, mucosal ulceration
2Includes group of rash preferred terms, acne, acne pustular, dermatitis acneiform
3Includes paronychia, nail infection, nail bed infection
  GILOTRIF
n=229
Pemetrexed/Cisplatin
n=111
Adverse Reaction All Grades
(%)
Grade 3*
(%)
All Grades
(%)
Grade 3*
(%)
Gastrointestinal disorders
      Diarrhea 96 15 23 2
      Stomatitis1 71 9 15 1
      Cheilitis 12 0 1 0
Skin and subcutaneous tissue disorders
      Rash/Dermatitis acneiform2 90 16 11 0
      Pruritus 21 0 1 0
      Dry skin 31 0 2 0
Infections and infestations
      Paronychia3 58 11 0 0
      Cystitis 13 1 5 0
Metabolism and nutrition disorders
      Decreased appetite 29 4 55 4
Respiratory, thoracic and mediastinal disorders
      Epistaxis 17 0 2 1
      Rhinorrhea 11 0 6 0
Investigations
      Weight Investigations 17 1 14 1
General disorders and administration site conditions
      Pyrexia 12 0 6 0
Eye disorders
      Conjunctivitis 11 0 3 0
Table 2 Adverse Reactions of Laboratory Abnormalities from the Investigations SOC Reported in ≥5% of GILOTRIF-Treated Patients in Study 1
1Includes hypokalemia, blood potassium decreased
SOC=system organ class
  GILOTRIF
n=229
Pemetrexed/Cisplatin
n=111
Adverse Reaction All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Alanine aminotransferase increased 11 2 4 0
Hypokalemia1 11 4 5 4
Aspartate aminotransferase increased 8 2 2 1

7 DRUG INTERACTIONS

Effect of P-glycoprotein (P-gp) Inhibitors and Inducers
Oral administration of a P-gp inhibitor (ritonavir at 200 mg twice daily) 1 hour before administration of GILOTRIF increased systemic exposure to afatinib by 48%. There was no change in afatinib exposure when ritonavir was administered simultaneously with or 6 hours after GILOTRIF. Concomitant taking of P-gp inhibitors (including but not limited to ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) with GILOTRIF can increase exposure to afatinib [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

Co-administration with oral dose of a P-gp inducer (rifampicin at 600 mg once daily for 7 days) decreased exposure to afatinib by 34%. Concomitant taking of P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John’s Wort) with GILOTRIF can decrease exposure to afatinib [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D

Risk Summary
Based on its mechanism of action, GILOTRIF can cause fetal harm when administered to a pregnant woman. Afatinib was embryotoxic and, in animals with maternal toxicity, led to abortions at late gestational stages in rabbits at doses of 5 mg/kg (approximately 0.2 times the exposure by AUC at the recommended human dose of 40 mg daily) or greater. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.6)].

Animal Data
Administration of afatinib to pregnant rabbits at doses of 5 mg/kg (approximately 0.2 times the exposure by AUC at the recommended human dose of 40 mg daily) or greater during the period of organogenesis caused increased post implantation loss and, in animals showing maternal toxicity, abortion at late gestational stages. In the same study, at the high dose level of 10 mg/kg (approximately 0.7 times the exposure by AUC at the recommended human dose of 40 mg daily) there were reduced fetal weights, and increases in the incidence of runts, as well as visceral and dermal variations. In an embryofetal development study in rats, there were skeletal alterations consisting of incomplete or delayed ossifications and reduced fetal weight at a dose of 16 mg/kg (approximately twice the exposure at the recommended human dose of 40 mg daily).

8.3 Nursing Mothers

It is not known whether afatinib is present in human milk. Afatinib was present in the milk of lactating rats at concentrations 80-150 times higher than those found in plasma from 1 to 6 hours after administration. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from GILOTRIF, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Safety and effectiveness of GILOTRIF in pediatric patients have not been established.

8.5 Geriatric Use

Of the 3865 patients in the clinical studies of GILOTRIF, 32% of patients were 65 years and older, while 7% were 75 years and older. No overall differences in safety were observed between patients 65 years and over and younger patients. In Study 1, 39% of the 345 patients were 65 years of age or older and 4% were 75 years or older. No overall differences in effectiveness were observed between patients 65 years and older and younger patients.

8.6 Females and Males of Reproductive Potential

Contraception
Females
Counsel patients on pregnancy planning and prevention. Advise female patients of reproductive potential to use highly effective contraception during treatment with GILOTRIF, and for at least 2 weeks after the last dose of GILOTRIF. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking GILOTRIF [see Use in Specific Populations (8.1)].

8.7 Renal Impairment

GILOTRIF has not been studied in patients with severely impaired renal function (creatinine clearance [CLcr] <30 mL/min). Adjustments to the starting dose of GILOTRIF are not considered necessary in patients with mild (CLcr 60-89 mL/min) renal impairment. Closely monitor patients with moderate (CLcr 30-59 mL/min) to severe (CLcr <30 mL/min) renal impairment and adjust GILOTRIF dose if not tolerated [see Clinical Pharmacology (12.3)].

8.8 Hepatic Impairment

GILOTRIF has not been studied in patients with severe (Child Pugh C) hepatic impairment. Adjustments to the starting dose of GILOTRIF are not considered necessary in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. Closely monitor patients with severe hepatic impairment and adjust GILOTRIF dose if not tolerated [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

Overdose was reported in 2 healthy adolescents each of whom ingested 360 mg of GILOTRIF (as part of a mixed-drug ingestion) resulting in nausea, vomiting, asthenia, dizziness, headache, abdominal pain, and elevated amylase (<1.5 times upper limit of normal [ULN]). Both subjects recovered.

11 DESCRIPTION

GILOTRIF tablets contain afatinib, a tyrosine kinase inhibitor which is a 4-anilinoquinazoline. Afatinib is presented as the dimaleate salt, with the chemical name 2-butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-,(2E)-, (2Z)-2-butenedioate (1:2). Its structural formula is:

Afatinib dimaleate is a white to brownish yellow powder, water soluble and hygroscopic, with an empirical formula of C32H33ClFN5O11, and a molecular weight of 718.1 g/mol.

GILOTRIF tablets for oral administration are available in 40 mg, 30 mg, or 20 mg of afatinib (equivalent to 59.12 mg, 44.34 mg, or 29.56 mg afatinib dimaleate, respectively). The inactive ingredients of GILOTRIF are the following: Tablet Core: lactose monohydrate, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate. Coating: hypromellose, polyethylene glycol, titanium dioxide, talc, polysorbate 80, FD&C Blue No. 2 (40 mg and 30 mg tablets only).

12 CLINICAL PHARMACOLOGY

12.1 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.

12.2 Pharmacodynamics

Cardiac Electrophysiology
The effect of multiple doses of GILOTRIF (50 mg once daily) on the QTc interval was eva luated 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.

12.3 Pharmacokinetics

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 (2.2)].

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: The median trough afatinib plasma concentrations in patients with mild (CLcr 60-89 mL/min) and moderate (CLcr 30-59 mL/min) renal impairment were 27% and 85% higher than those in patients with normal renal function (CLcr ≥90 mL/min). GILOTRIF has not been studied in patients with severely impaired renal function (CLcr <30 mL/min) [see Use in Specific Populations (8.7)].

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 (8.8)].

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 eva luated 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 (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% (AUC0-∞) and 22% (Cmax) [see Drug Interactions (7)].

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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, 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 the 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.

14  CLINICAL STUDIES

Non-small Cell Lung Cancer (NSCLC)

Study 1
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]) 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 objective 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, the median age was 61 years, the 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 3 and Figure 1. There was no statistically significant difference for overall survival between the treatment arms at the interim analysis conducted at 84% of the planned events for the final analysis.

Table 3: Efficacy Results of Study 1
*Stratified by EGFR mutation status and race.
CR=complete response; PR=partial response
  GILOTRIF
(N=230)
Pemetrexed/Cisplatin
(N=115)
Progression-free Survival
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 (%) 116 (50.4%) 59 (51.2%)
          Median Overall Survival (months) 28.1 28.2
          95% CI (24.6, 33.0) (20.7, 33.2)
          HR (95% CI) 0.91 (0.66, 1.25)
          Stratified Log-Rank Test P-value* 0.55
Objective Response Rate (CR + PR)
          N (%) 116 (50.4%) 22 (19.1%)
Response Duration
Median (months) 12.5 6.7

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.

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 4 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 4 Objective Tumor Responses in GILOTRIF-Treated Patients Based on Investigator Assessment in the “Other” (Uncommon) EGFR Mutation Subgroup
+ Censored observation
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

16 HOW SUPPLIED/STORAGE AND HANDLING

GILOTRIF tablets are available as follows:
40 mg: light blue, film-coated, round, biconvex, bevel-edged tablets debossed with “T40” on one side and the Boehringer Ingelheim company symbol on the other side.
Unit of use bottles of 30                 NDC: 0597-0138-30

30 mg: dark blue, film-coated, round, biconvex, bevel-edged tablets debossed with “T30” on one side and the Boehringer Ingelheim company symbol on the other side.
Unit of use bottles of 30                 NDC: 0597-0137-30

20 mg: white to slightly yellowish, film-coated, round, biconvex, bevel-edged tablets debossed with “T20” on one side and the Boehringer Ingelheim company symbol on the other side.
Unit of use bottles of 30                 NDC: 0597-0141-30

Storage
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Dispense medication in the original container to protect from exposure to high humidity and light.

阿法替尼(GIOTRIF)疗效和安全性再添证据
•新的疗效和安全性分析结果进一步充实了之前已经公布的、日益丰富的关于阿法替尼相较于标准化疗(培美曲塞/顺铂和吉西他滨/顺铂)的临床数据库
•最新数据证实,不可逆性ErbB家族阻滞剂阿法替尼具有可控的安全性,而且适用于EGFR突变阳性的亚洲和非亚洲肺癌患者的长期治疗[1]
•阿法替尼已经在美国、欧盟、墨西哥、智利获准应用于EGFR突变阳性的非小细胞肺癌(NSCLC)患者。在亚洲地区,阿法替尼在台湾获得了上述批准。该药在其他亚洲国家的注册申请正处于审批过程中。
•全球肺癌联盟与勃林格殷格翰公司合作启动“倾听肺癌患者的心声”旨在收集肺癌患者在真实世界中的感受
德国殷格翰2013年11月11日电 /美通社/ -- 来自两项关键性的、大规模、III期、注册临床试验(LUX-Lung 3研究和LUX-Lung 6研究)的数据显示,阿法替尼相较于化疗应用于亚洲和非亚洲患者具有优越的疗效和可控的安全性。[2,3]针对上述试验所开展的最新分析证实,阿法替尼作为一线治疗应用于EGFR突变阳性的非小细胞肺癌(NSCLC)亚洲和非亚洲患者具有一致的安全性。[1]
在NSCLC患者亚群中获得的最新数据也进一步证实了阿法替尼的疗效。基于LUX-Lung研究的其他分析也显示了阿法替尼应用于伴有不常见的EGFR突变类型[1]以及伴有转移性脑病的NSCLC患者的安全性。[5]
在今年的世界肺癌大会(WCLC)上公布的研究结果进一步充实了日益丰富的强大的临床证据库,这些证据支持阿法替尼作为一线治疗药物应用于亚洲和非亚洲患有特定类型的晚期肺癌患者(即表皮生长因子受体(EGFR)突变阳性的NSCLC)。在中国、韩国和泰国开展的全球性临床试验 LUX-Lung 3研究及其并行试验LUX-Lung 6研究是迄今为止在EGFR突变阳性的NSCLC患者中开展过的规模最大的注册临床试验。上述试验早已证实,接受阿法替尼治疗的患者在肿瘤重新开始生长之前的生存(无进展生存,PFS)时间达到将近一年,而接受化疗的患者则略超过半年。具体而言,上述试验显示:[2,3]
•LUX-Lung 3研究:阿法替尼治疗组和培美曲塞/顺铂治疗组的PFS分别为11.1个月和6.9个月
•LUX-Lung 6研究:阿法替尼治疗组和培美曲塞/顺铂治疗组的PFS分别为11.0个月和5.6个月
(这些数据来自基于独立性回顾的主要分析。)
在LUX-Lung 6研究中,接受阿法替尼治疗组有47%患者在治疗1年后仍然存活,而且无疾病进展,化疗组则仅为2%。[3]肿瘤进展的延迟还伴有患者肺癌相关性症状(例如气促、咳嗽和胸痛)的改善以及通过肺癌标准问卷评估的生活质量的改善。[2,3]
在亚洲,肺癌占所有癌症的比例超过了14%,肺癌死亡占所有癌症死亡的比例超过了18%,尽管肺癌发生率在不同地区会有所不同。东亚地区的发病率最高,在中国大陆,每年新诊断的肺癌病例数量超过五十万,在日本和台湾地区则分别超过八万六千例和九千例。[6]由于肺癌的预后较差,从最初开始就选择最佳的治疗方案就变得非常重要。
基于LUX-Lung 3研究和LUX-Lung 6研究最新开展的安全性汇总分析证实了之前已经报告的阿法替尼应用于EGFR突变阳性的亚洲和非亚洲NSCLC患者的不良事件(AE)和耐受性特征。在上述两大患者人群中,最常见的3级副反应的发生率是相似的,包括腹泻、皮疹/痤疮和口腔炎(口腔黏膜的炎症)。[1]此外,阿法替尼的药代动力学暴露结果在上述两大患者人群中也无差异。[1]在此之前,来自LUX-Lung 3研究和LUX-Lung6研究的数据已经证实,阿法替尼的副反应是可预测、可控和可逆的,而且停药率较低。[2,3]
“最新的亚组分析证实,阿法替尼在亚洲患者中和非亚洲患者中的安全性特征是一致的,”来自位于台湾地区台北市的台湾大学医学院肿瘤研究中心主任、LUX-Lung 3研究的主要研究者 James Chih-Hsin Yang教授如此评价道。“这些数据为阿法替尼作为EGFR突变阳性的肺癌患者的有价值的治疗选择提供了进一步的支持,EGFR突变阳性的肺癌在亚洲的发生率是西方国家三倍。”
另一场独立的口头演讲则基于迄今为止规模最大的、针对伴有不常见EGFR突变类型的患者的疗效数据集,这些汇总数据来自3项前瞻性阿法替尼临床试验。这些数据显示,阿法替尼应用于伴有罕见的特定类型EGFR突变的肺癌患者的活性与该药应用于伴有常见类型的EGFR突变(缺失19, L858R)的患者的活性处于同样的范围之内。[4]
一项基于LUX-Lung 3研究的亚组分析显示,阿法替尼可作为伴有常见类型的EGFR突变和转移性脑病的肺癌患者的有效的一线治疗选择。[5]
“阿法替尼所能提供的临床受益已经通过大规模的、设计严谨的LUX-Lung临床试验计划获得了明确的体现,这些结论现在又获得了基于重要的亚组患者人群的、强有力的疗效和安全性数据的进一步支持,”勃林格殷格翰公司全球医学高级副总裁Klaus Dugi如此说道。“这些分析结果非常振奋人心,而且有望使阿法替尼成为伴有EGFR突变的亚洲和非亚洲肺癌患者的有价值的治疗选择的重要补充。”
此外,全球肺癌联盟(GLCC)还在WCLC上宣布了一项由勃林格殷格翰公司(BI)支持的创意活动,此项活动旨在进一步了解并理解肺癌患者及其家庭在现实世界中所面临的挑战。“倾听肺癌患者的心声”项目将收集来自于那些被肺癌疾病所累及的人群的反馈,包括患者及其护理者、家人、朋友、医疗专业人士和同事等。
“倾听肺癌患者的心声”项目采用独特的方法收集患者的反馈,尽可能减少基于书面文本的反馈格式,主要呈现基于视觉的调查材料。通过采用简明浏览格式的新型在线工具,受调研者只需要点击预先定义的图像、标志和基于网络的视觉材料中的元素,就能针对与之相关的议题提供反馈。这些视觉元素代表了肺癌患者及其护理人员以及家人在生活中所面临的挑战以及问题的重要性。受调研者所选取的图像或标志将透露他们最为迫切的问题和顾虑,从而反映肺癌患者随着时间推移在现实世界中的日常事项和经历。
这是有史以来首次采用上述设计方法来“倾听”肺癌患者在现实世界中的感受,并在医疗服务提供方与患者的真实处境之间搭建起沟通桥梁,从而消除间隔。调研结果将会与肺癌社区分享,从中获得的心得也将与为患者提供服务的相关人士进行分享,进而推动旨在更好地满足患者需求的新型项目、服务和宣教材料的开发。
“我们需要理解患者的感受,从而更好地为他们提供帮助,”勃林格殷格翰公司的全球医学高级副总裁Klaus Dugi教授如此说道,“患者始终处于我们在肿瘤领域所作出的承诺的核心位置,通过与GLCC的共同努力,我们就能利用‘倾听肺癌患者的心声’项目为开展全球性活动提供信息,同时有助于更加有效地支持肺癌社区,最终改善患者的生活,而且这一改善作用将不局限于治疗本身。”
“倾听肺癌患者的心声”项目的网站将于11月中旬上线,届时也将与“全球肺癌关注月”的活动相呼应。
供编辑参考信息
关于阿法替尼数据在WCLC上的公布情况
安全性亚组分析[1]
基于LUX-Lung 3研究和LUX-Lung 6研究的最新汇总性亚组分析总共纳入了468名EGFR突变阳性的患者(404名亚洲患者和64名非亚洲患者),上述患者接受阿法替尼40 mg每日一次治疗,直到发生疾病进展或发生不可耐受的不良事件为止。基于预先定义的研究标准,阿法替尼的给药剂量可增至50 mg每日一次、或降至30 mg或20 mg每日一次。所有患者报告了至少1例不良事件,最常见的不良事件包括腹泻、皮疹/痤疮和口腔炎(口腔黏膜的炎症)。导致停药的药物相关性不良事件的发生率在亚洲患者和非亚洲患者中分别为7.2%和4.7%,低于化疗组的28%。
针对不常见的突变类型的亚组分析[4]
此项分析基于被纳入LUX-Lung 2研究(II期临床试验)、LUX-Lung 3研究和LUX-Lung 6研究(两者均为III期临床试验)的EGFR突变阳性的患者。患者所伴有的突变被分为常见(Del 19 或 L858R)和不常见(所有其他单个或多个突变)两大类。通过独立性回顾对客观反应率、疾病控制、反应时间和无进展生存(PFS)进行评估。
针对转移性脑病的亚组分析[5]
在LUX-Lung 3研究中,EGFR突变阳性的患者以2:1的比例随机接受阿法替尼40 mg 每日一次治疗或最多达6个疗程的培美曲塞/顺铂标准剂量方案。伴有稳定性脑转移的患者被允许纳入。由研究者在筛选期记录脑转移。每6周进行一次肿瘤评估,直到48周为止,在此之后每12周进行一次肿瘤评估,直到出现疾病进展为止。
关于LUX-Lung 3试验[2]
LUX-Lung 3试验是规模最大的、随机、开放标记、III期注册临床试验,此项试验针对阿法替尼与由两种化疗药物培美曲塞和顺铂组成的化疗方案作为一线治疗选择应用于伴有EGFR突变的IIIb期或IV期NSCLC患者的效果进行了比较。此项试验在全球范围内纳入了345名EGFR突变阳性的NSCLC患者。LUX-Lung 3试验也是第一项在EGFR突变阳性的NSCLC患者中开展的、将培美曲塞/顺铂作为对照药物的临床试验。
在LUX-Lung 3试验中,与阿法替尼有关的最常见的3级不良事件是腹泻(14%)、皮疹(16%)和甲沟炎(11%)。与化疗(培美曲塞/顺铂)相关的最常见的3级不良事件是中性粒细胞减少症(15%)、虚弱(13%)和白细胞减少(8%)。在此项试验中,与治疗有关的不良事件有关的停药率较低(阿法替尼治疗组织和化疗组的停药率分别为8%和12%)。在阿法替尼治疗组中,有1%患者由于腹泻而停药。
关于 LUX-Lung 6试验[3]
LUX-Lung 6试验是迄今为止在伴有EGFR突变阳性的亚洲晚期肺癌患者中开展的规模最大 (n = 364)、前瞻性、注册临床试验。LUX-Lung 6试验是一项多中心、随机、开放标记的III期临床试验,对于阿法替尼相较化疗(顺铂/吉西他滨)作为一线治疗方案应用于伴有EGFR突变的晚期和转移性NSCLC的效果进行了考察。
此项试验共纳入了364名来自中国、韩国和泰国的患者(IIIB/IV期,功能状态评分 0–1,之前未接受过化疗),这些患者以2:1的比例随机接受每日口服阿法替尼* 40 mg (n=242) 或静脉接受顺铂/吉西他滨(第1天75 mg/m2/第1天和第8天1000 mg/m2,每21天一个疗程,共6个疗程,n=122)。主要终点是由中心独立审核而确定的无进展生存期。[1]
顺铂/吉西他滨是目前在中国、韩国和泰国被经常使用的NSCLC一线治疗选择。
关于阿法替尼
在欧盟、台湾地区、智利和墨西哥,阿法替尼以GIOTRIF®为商品名获准应用于肿瘤细胞具有表皮生长因子受体(EGFR)突变的转移性NSCLC的治疗。
阿法替尼在美国以GILOTRIFTM为商品名获得批准作为一线治疗药物应用于通过经FDA批准的检测方法检出存在表皮生长因子受体(EGFR)外显子19缺失或外显子21(L858R)替代突变的转移性非小细胞肺癌(NSCLC)患者。
阿法替尼是一种不可逆性ErbB家族抑制剂,该药能够不可逆性地阻断EGFR (ErbB1)以及ErbB家族的其他相关成员,上述受体在某些最为常见的肿瘤和某些死亡率较高的肿瘤的生长和播散过程中发挥了关键性的作用。阿法替尼与受体的共价、不可逆性结合与其他化合物与受体的可逆性结合的不同之处在于能够提供持久的、选择性的、完全性的ErbB家族的阻断,从而可能带来独特的治疗受益。
阿法替尼目前正处于针对NSCLC和头颈癌的III期临床试验过程中。
关于肺癌
肺癌是在全球范围内最为常见的一种癌症,每年的新发病例数达到一百六十万,其中超过半数(54%)发生在亚洲。总体而言,肺癌死亡人数占到所有亚洲癌症死亡人数18.5%。肺癌约占所有新发癌症的13%,吸烟是肺癌的主要病因。
有10%至15%的白种人NSCLC患者和 40%的亚洲NSCLC患者的肿瘤存在EGFR突变,其中约有90%的病例伴有两种EGFR突变中的一种(Del19或 L858R)。

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