Gefitinib
Gefitinib Prescribing Information
Gefitinib tablets are 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
The efficacy and safety of gefitinib for the first-line treatment of patients with metastatic NSCLC containing EGFR exon 19 deletions or L858R substitution mutations was demonstrated in a multicenter, single-arm, open-label clinical study (Study 1). A total of 106 treatment-naive patients with metastatic EGFR mutation positive NSCLC received gefitinib at a dose of 250 mg once daily until disease progression or intolerable toxicity. The major efficacy outcome measure was objective response rate (ORR) according to RECIST v1.1 as evaluated by both a Blinded Independent Central Review (BICR) and investigators. Duration of response (DOR) was an additional outcome measure. Eligible patients were required to have a deletion in EGFR exon 19 or L858R, L861Q, or G719X substitution mutation and no T790M or S768I mutation or exon 20 insertion in tumor specimens as prospectively determined by a clinical trial assay. Tumor samples from 87 patients were tested retrospectively using the
The study population characteristics were: median age 65 years, age 75 years or older (25%), age less than 65 years (49%), white (100%), female (71%), never smokers (64%), WHO PS 0 (45%), WHO PS 1 (48%), WHO PS 2 (7%), and adenocarcinoma histology (97%). Sixty patients had exon 19 deletions (65%), 29 patients had L858R substitution (31%), while two patients each had tumors harboring L861Q or G719X substitution mutation.
The median duration of treatment was 8.0 months. Efficacy results from Study 1 are summarized below.
| Efficacy Parameter | BICR1Assessment (n=106)2 | Investigator Assessment (n=106) |
| Objective Response Rate3 (95% CI) | 50% (41, 59) | 70% (61, 78) |
| Complete Response Rate | 0.9% | 1.9% |
| Partial Response Rate | 49% | 68% |
| Median Duration of Response (months) (95% CI) | 6 (5.6, 11.1) | 8.3 (7.6, 11.3) |
1BICR, Blinded Independent Central Review
217 patients without target lesion at baseline detected by BICR were deemed non responders
3Determined by RECIST v 1.1
The response rates were similar in patients whose tumors had EGFR exon 19 deletions and exon 21 L858R substitution mutations. Two partial responses were observed in both patients whose tumors had G719X substitution mutation with duration of response of at least 2.8 months and 5.6 months, respectively. One of two patients whose tumors had L861Q substitution mutation also achieved a partial response with duration of response of at least 2.8 months.
The results of Study 1 were supported by an exploratory analysis of a subset of a randomized, multicenter, open-label trial (Study 2) conducted in patients with metastatic adenocarcinoma histology NSCLC receiving first-line treatment. Patients were randomized (1:1) to receive gefitinib 250 mg orally once daily or up to 6 cycles of carboplatin/paclitaxel. The efficacy outcomes included progression-free survival (PFS) and objective response rate (ORR) as assessed by BICR.
The subset population consisted of 186 of 1217 patients (15%) determined to be EGFR positive by the same clinical trial assay as used in Study 1 and had radiographic scans available for a retrospective assessment by BICR. In this subset, there were 88 gefitinib-treated patients and 98 carboplatin/paclitaxel-treated patients.
Demographic and baseline characteristics of this subset were a median age of 59 years, age 75 years or older (7%), age less than 65 (70%), Asian (100%), female (83%), never smokers (96%), adenocarcinoma histology (100%), and PS 0 to 1 (94%).
The median duration of treatment for gefitinib-treated patients was 9.8 months. The hazard ratio for PFS favored the gefitinib-treated patients [HR of 0.54 (95% CI: 0.38, 0.79)] with a median PFS of 10.9 months for the gefitinib-treated patients and 7.4 months for the carboplatin/paclitaxel-treated patients as assessed by BICR. In addition, the objective response rate was 67% (95% CI: 56, 77) for gefitinib-treated patients and 41% (95% CI: 31, 51) for carboplatin/paclitaxel-treated patients based on BICR assessment. The median duration of response was 9.6 months for gefitinib-treated patients and 5.5 months for carboplatin/paclitaxel-treated patients.
Limitation of Use: Safety and efficacy of gefitinib tablets have not been established in patients with metastatic NSCLC whose tumors have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution mutations
The efficacy and safety of gefitinib for the first-line treatment of patients with metastatic NSCLC containing EGFR exon 19 deletions or L858R substitution mutations was demonstrated in a multicenter, single-arm, open-label clinical study (Study 1). A total of 106 treatment-naive patients with metastatic EGFR mutation positive NSCLC received gefitinib at a dose of 250 mg once daily until disease progression or intolerable toxicity. The major efficacy outcome measure was objective response rate (ORR) according to RECIST v1.1 as evaluated by both a Blinded Independent Central Review (BICR) and investigators. Duration of response (DOR) was an additional outcome measure. Eligible patients were required to have a deletion in EGFR exon 19 or L858R, L861Q, or G719X substitution mutation and no T790M or S768I mutation or exon 20 insertion in tumor specimens as prospectively determined by a clinical trial assay. Tumor samples from 87 patients were tested retrospectively using the
The study population characteristics were: median age 65 years, age 75 years or older (25%), age less than 65 years (49%), white (100%), female (71%), never smokers (64%), WHO PS 0 (45%), WHO PS 1 (48%), WHO PS 2 (7%), and adenocarcinoma histology (97%). Sixty patients had exon 19 deletions (65%), 29 patients had L858R substitution (31%), while two patients each had tumors harboring L861Q or G719X substitution mutation.
The median duration of treatment was 8.0 months. Efficacy results from Study 1 are summarized below.
| Efficacy Parameter | BICR1Assessment (n=106)2 | Investigator Assessment (n=106) |
| Objective Response Rate3 (95% CI) | 50% (41, 59) | 70% (61, 78) |
| Complete Response Rate | 0.9% | 1.9% |
| Partial Response Rate | 49% | 68% |
| Median Duration of Response (months) (95% CI) | 6 (5.6, 11.1) | 8.3 (7.6, 11.3) |
1BICR, Blinded Independent Central Review
217 patients without target lesion at baseline detected by BICR were deemed non responders
3Determined by RECIST v 1.1
The response rates were similar in patients whose tumors had EGFR exon 19 deletions and exon 21 L858R substitution mutations. Two partial responses were observed in both patients whose tumors had G719X substitution mutation with duration of response of at least 2.8 months and 5.6 months, respectively. One of two patients whose tumors had L861Q substitution mutation also achieved a partial response with duration of response of at least 2.8 months.
The results of Study 1 were supported by an exploratory analysis of a subset of a randomized, multicenter, open-label trial (Study 2) conducted in patients with metastatic adenocarcinoma histology NSCLC receiving first-line treatment. Patients were randomized (1:1) to receive gefitinib 250 mg orally once daily or up to 6 cycles of carboplatin/paclitaxel. The efficacy outcomes included progression-free survival (PFS) and objective response rate (ORR) as assessed by BICR.
The subset population consisted of 186 of 1217 patients (15%) determined to be EGFR positive by the same clinical trial assay as used in Study 1 and had radiographic scans available for a retrospective assessment by BICR. In this subset, there were 88 gefitinib-treated patients and 98 carboplatin/paclitaxel-treated patients.
Demographic and baseline characteristics of this subset were a median age of 59 years, age 75 years or older (7%), age less than 65 (70%), Asian (100%), female (83%), never smokers (96%), adenocarcinoma histology (100%), and PS 0 to 1 (94%).
The median duration of treatment for gefitinib-treated patients was 9.8 months. The hazard ratio for PFS favored the gefitinib-treated patients [HR of 0.54 (95% CI: 0.38, 0.79)] with a median PFS of 10.9 months for the gefitinib-treated patients and 7.4 months for the carboplatin/paclitaxel-treated patients as assessed by BICR. In addition, the objective response rate was 67% (95% CI: 56, 77) for gefitinib-treated patients and 41% (95% CI: 31, 51) for carboplatin/paclitaxel-treated patients based on BICR assessment. The median duration of response was 9.6 months for gefitinib-treated patients and 5.5 months for carboplatin/paclitaxel-treated patients.
Recommended dose is 250 mg orally, once daily with or without food.
The recommended dose of gefitinib tablets is 250 mg orally once daily with or without food until disease progression or unacceptable toxicity.
Do not take a missed dose within 12 hours of the next dose.
250 mg tablets: Reddish-brown, round, biconvex coated tablet. Engraved "APO" over "250" on one side, plain on the other side.
• Lactation: Discontinue breast-feeding.8.2 LactationRisk SummaryIt is not known whether gefitinib is excreted in human milk. Animal studies indicate the gefitinib and its metabolites are present in rat milk at a concentration higher than those in maternal plasma. Because of the potential for serious adverse reactions in nursing infants from gefitinib, advise women to discontinue breast-feeding during treatment with gefitinib tablets.
DataAnimal DataLevels of gefitinib and its metabolites were 11-to-19-fold higher in milk than in blood, after oral exposure of lactating rats to a dose of 5 mg/kg.
None.
• Interstitial lung disease (ILD): ILD occurred in patients taking gefitinib tablets. Withhold gefitinib tablets for worsening of respiratory symptoms. Discontinue gefitinib tablets if ILD is confirmed. (,2.3 Administration to Patients Who Have Difficulty Swallowing SolidsImmerse gefitinib tablets in 4 to 8 ounces of water by dropping the tablet in water, and stir for approximately 15 minutes. Immediately drink the liquid or administer through a naso-gastric tube. Rinse the container with 4 to 8 ounces of water and immediately drink or administer through the naso-gastric tube.
)5.1 Interstitial Lung Disease (ILD)ILD or ILD-like adverse drug reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or pulmonary fibrosis) occurred in 1.3% of the 2462 patients who received gefitinib across clinical trials; of these, 0.7% were Grade 3 or higher and 3 cases were fatal.
Withhold gefitinib tablets and promptly investigate for ILD in any patient who presents with worsening of respiratory symptoms such as dyspnea, cough and fever. Permanently discontinue gefitinib tablets if ILD is confirmed [
see Dosage and Administration (2.4), Adverse Reactions (6.1)].• Hepatotoxicity: Obtain periodic liver function testing. Withhold gefitinib tablets for Grade 2 or higher for ALT and/or AST elevations. Discontinue for severe hepatic impairment. (,2.3 Administration to Patients Who Have Difficulty Swallowing SolidsImmerse gefitinib tablets in 4 to 8 ounces of water by dropping the tablet in water, and stir for approximately 15 minutes. Immediately drink the liquid or administer through a naso-gastric tube. Rinse the container with 4 to 8 ounces of water and immediately drink or administer through the naso-gastric tube.
)5.2 HepatotoxicityIn patients who received gefitinib across clinical trials, 11.4% of patients had increased alanine aminotransferase (ALT), 7.9% of patients had increased aspartate aminotransferase (AST), and 2.7% of patients had increased bilirubin. Grade 3 or higher liver test abnormalities occurred in 5.1% (ALT), 3.0% (AST), and 0.7% (bilirubin) of patients. The incidence of fatal hepatotoxicity was 0.04%.
Obtain periodic liver function testing. Withhold gefitinib tablets in patients with worsening liver function and discontinue in patients with severe hepatic impairment
[see Dosage and Administration (2.4),Adverse Reactions (6.1), Use in Specific Populations (8.7)].• Gastrointestinal perforation: Discontinue gefitinib tablets for gastrointestinal perforation. (,2.4 Dose ModificationDose Modifications for Adverse Drug ReactionsWithhold gefitinib tablets (for up to 14 days) for any of the following:
• Acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever)[see Warnings and Precautions (5.1)]• NCI CTCAE Grade 2 or higher in ALT and/or AST elevations [see Warnings and Precautions (5.2)]• NCI CTCAE Grade 3 or higher diarrhea[see Warnings and Precautions (5.4)]• Signs and symptoms of severe or worsening ocular disorders including keratitis[see Warnings and Precautions (5.5)]• NCI CTCAE Grade 3 or higher skin reactions[see Warnings and Precautions (5.6)]
Resume treatment with gefitinib tablets when the adverse reaction fully resolves or improves to NCI CTCAE Grade 1.
Permanently discontinue gefitinib tablets for:
• Confirmed interstitial lung disease (ILD)[see Warnings and Precautions (5.1)]• Severe hepatic impairment[see Warnings and Precautions (5.2)]• Gastrointestinal perforation[see Warnings and Precautions (5.3)]• Persistent ulcerative keratitis[see Warnings and Precautions (5.5)]
Dose Modifications for Drug InteractionsStrong CYP3A4 InducersIncrease gefitinib tablets to 500 mg daily in the absence of severe adverse drug reaction, and resume gefitinib tablets at 250 mg seven days after discontinuation of the strong CYP3A4 inducer
[see Drug Interactions (7),Clinical Pharmacology (12.3)].)5.3 Gastrointestinal PerforationGastrointestinal perforation occurred in three (0.1%) of the 2462 gefitinib-treated patients across clinical trials [
see Adverse Reactions (6.1)]. Permanently discontinue gefitinib tablets in patients who develop gastrointestinal perforation [see Dosage and Administration (2.4)].• Diarrhea: Withhold gefitinib tablets for Grade 3 or higher diarrhea. (,2.4 Dose ModificationDose Modifications for Adverse Drug ReactionsWithhold gefitinib tablets (for up to 14 days) for any of the following:
• Acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever)[see Warnings and Precautions (5.1)]• NCI CTCAE Grade 2 or higher in ALT and/or AST elevations [see Warnings and Precautions (5.2)]• NCI CTCAE Grade 3 or higher diarrhea[see Warnings and Precautions (5.4)]• Signs and symptoms of severe or worsening ocular disorders including keratitis[see Warnings and Precautions (5.5)]• NCI CTCAE Grade 3 or higher skin reactions[see Warnings and Precautions (5.6)]
Resume treatment with gefitinib tablets when the adverse reaction fully resolves or improves to NCI CTCAE Grade 1.
Permanently discontinue gefitinib tablets for:
• Confirmed interstitial lung disease (ILD)[see Warnings and Precautions (5.1)]• Severe hepatic impairment[see Warnings and Precautions (5.2)]• Gastrointestinal perforation[see Warnings and Precautions (5.3)]• Persistent ulcerative keratitis[see Warnings and Precautions (5.5)]
Dose Modifications for Drug InteractionsStrong CYP3A4 InducersIncrease gefitinib tablets to 500 mg daily in the absence of severe adverse drug reaction, and resume gefitinib tablets at 250 mg seven days after discontinuation of the strong CYP3A4 inducer
[see Drug Interactions (7),Clinical Pharmacology (12.3)].)5.4 Severe or Persistent DiarrheaGrade 3 or 4 diarrhea occurred in 3% of 2462 gefitinib-treated patients across clinical trials. Withhold gefitinib tablets for severe or persistent (up to 14 days) diarrhea
[see Dosage and Administration (2.4),Adverse Reactions (6.1)].• Ocular Disorders including Keratitis: Withhold gefitinib tablets for signs and symptoms of severe or worsening ocular disorders including keratitis. Discontinue for persistent ulcerative keratitis. (,2.4 Dose ModificationDose Modifications for Adverse Drug ReactionsWithhold gefitinib tablets (for up to 14 days) for any of the following:
• Acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever)[see Warnings and Precautions (5.1)]• NCI CTCAE Grade 2 or higher in ALT and/or AST elevations [see Warnings and Precautions (5.2)]• NCI CTCAE Grade 3 or higher diarrhea[see Warnings and Precautions (5.4)]• Signs and symptoms of severe or worsening ocular disorders including keratitis[see Warnings and Precautions (5.5)]• NCI CTCAE Grade 3 or higher skin reactions[see Warnings and Precautions (5.6)]
Resume treatment with gefitinib tablets when the adverse reaction fully resolves or improves to NCI CTCAE Grade 1.
Permanently discontinue gefitinib tablets for:
• Confirmed interstitial lung disease (ILD)[see Warnings and Precautions (5.1)]• Severe hepatic impairment[see Warnings and Precautions (5.2)]• Gastrointestinal perforation[see Warnings and Precautions (5.3)]• Persistent ulcerative keratitis[see Warnings and Precautions (5.5)]
Dose Modifications for Drug InteractionsStrong CYP3A4 InducersIncrease gefitinib tablets to 500 mg daily in the absence of severe adverse drug reaction, and resume gefitinib tablets at 250 mg seven days after discontinuation of the strong CYP3A4 inducer
[see Drug Interactions (7),Clinical Pharmacology (12.3)].)5.5 Ocular Disorders including KeratitisOcular disorders [keratitis (0.1%), corneal erosion and aberrant eyelash growth (0.2%), conjunctivitis, blephritis and dry eye (6.7%)] occurred in the 2462 gefitinib-treated patients across clinical trials. The incidence of Grade 3 ocular disorders was 0.1% [
see Adverse Reactions (6.1)]. Interrupt or discontinue gefitinib tablets for severe, or worsening ocular disorders [see Dosage and Administration (2.4)].• Bullous and Exfoliative Skin Disorders: Withhold gefitinib tablets for Grade 3 or higher skin reactions or exfoliative conditions. (,2.4 Dose ModificationDose Modifications for Adverse Drug ReactionsWithhold gefitinib tablets (for up to 14 days) for any of the following:
• Acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever)[see Warnings and Precautions (5.1)]• NCI CTCAE Grade 2 or higher in ALT and/or AST elevations [see Warnings and Precautions (5.2)]• NCI CTCAE Grade 3 or higher diarrhea[see Warnings and Precautions (5.4)]• Signs and symptoms of severe or worsening ocular disorders including keratitis[see Warnings and Precautions (5.5)]• NCI CTCAE Grade 3 or higher skin reactions[see Warnings and Precautions (5.6)]
Resume treatment with gefitinib tablets when the adverse reaction fully resolves or improves to NCI CTCAE Grade 1.
Permanently discontinue gefitinib tablets for:
• Confirmed interstitial lung disease (ILD)[see Warnings and Precautions (5.1)]• Severe hepatic impairment[see Warnings and Precautions (5.2)]• Gastrointestinal perforation[see Warnings and Precautions (5.3)]• Persistent ulcerative keratitis[see Warnings and Precautions (5.5)]
Dose Modifications for Drug InteractionsStrong CYP3A4 InducersIncrease gefitinib tablets to 500 mg daily in the absence of severe adverse drug reaction, and resume gefitinib tablets at 250 mg seven days after discontinuation of the strong CYP3A4 inducer
[see Drug Interactions (7),Clinical Pharmacology (12.3)].)5.6 Bullous and Exfoliative Skin DisordersBullous conditions including toxic epidermal necrolysis, Stevens Johnson syndrome and erythema multiforme have been reported from treatment with gefitinib. Erythema multiforme and dermatitis bullous have been reported in two patients (0.08%) across NSCLC trials (Study 2, Study 3 and Study 4). Gefitinib tablets treatment should be interrupted or discontinued if the patient develops severe bullous, blistering or exfoliating conditions.
• Embryo-fetal Toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. (,5.7 Embryo-fetal ToxicityBased on its mechanism of action and data from animal reproduction studies gefitinib tablets can cause fetal harm when administered to a pregnant woman. In animal reproductive studies, oral administration of gefitinib from organogenesis through weaning resulted in fetotoxicity and neonatal death at doses below the recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with gefitinib tablets and for at least two weeks following completion of therapy [
see Use in Specific Populations]., 8.3)8.1 PregnancyRisk SummaryBased on its mechanism of action and animal data, gefitinib tablets can cause fetal harm when administered to a pregnant woman. In animal reproductive studies, oral administration of gefitinib from organogenesis through weaning resulted in fetotoxicity and neonatal death at doses below the recommended human dose (
see Animal Data). Advise pregnant women of the potential hazard to a fetus or potential risk for loss of the pregnancy.The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2 to 4% and miscarriage is 15 to 20% of clinically recognized pregnancies.
DataAnimal DataA single dose study in rats showed that gefitinib crosses the placenta after an oral dose of 5 mg/kg (30 mg/m2, about 0.2 times the recommended human dose on a mg/m2basis). When pregnant rats were treated with 5 mg/kg from the beginning of organogenesis to the end of weaning there was a reduction in the number of offspring born alive. This effect was more severe at 20 mg/kg (approximate the human clinical dose on a mg/m2basis) and was accompanied by high neonatal mortality soon after parturition. In rabbits, a dose of 20 mg/kg/day (240 mg/m2, about twice the recommended dose in humans on a mg/m2basis) caused reduced fetal weight.