Afatinib dimaleate, a second-generation inhibitor of receptor tyrosine kinases, is an antineoplastic agent.1, 7, 8
First-line Therapy for Metastatic Non-small Cell Lung Cancer
Afatinib is used for the first-line treatment of metastatic non-small cell lung cancer (NSCLC) in patients whose tumors harbor nonresistant epidermal growth factor receptor (EGFR) mutations (e.g., exon 19 deletions [del19], exon 21 substitution [L858R]) mutations as detected by an FDA-approved diagnostic test.1, 2, 3, 5, 16, 28 Nonresistant EGFR mutations are those where efficacy of afatinib may be predicted by a clinically meaningful reduction in tumor size at the recommended dosage of the drug and/or inhibition of cellular proliferation or EGFR tyrosine kinase phosphorylation is expected at the recommended dosage.1
EGFR-activating mutations are present in approximately 15-22% of NSCLC cases in North America and Europe and are present in up to 30-50% of cases in patients of East Asian descent.25, 26 The majority of EGFR mutations are exon 19 deletions and an L858R substitution in exon 21, which together account for about 90% of EGFR mutations in patients with NSCLC;27 less frequently occurring EGFR mutations are a heterogeneous group of molecular alterations within exons 18-21 (i.e., uncommon EGFR mutations), which exhibit variable responses to EGFR tyrosine kinase inhibitor therapy.28
The current indication for afatinib in the first-line treatment of metastatic NSCLC is based principally on the results of a randomized, multinational, open-label phase 3 study (LUX-Lung 3) in adults with previously untreated EGFR mutation-positive locally advanced or metastatic (stage IIIB with pleural and/or pericardial effusion or stage IV) NSCLC.1, 2 In this study, 345 patients were randomized (stratified by type of EGFR mutation and race) in a 2:1 ratio to receive either afatinib (40 mg orally once daily) alone or cisplatin (75 mg/m2 by IV infusion) in combination with pemetrexed (500 mg/m2 by IV infusion) once every 3 weeks (for a maximum of 6 cycles) until disease progression.1, 2 The primary measure of efficacy was progression-free survival as assessed by an independent review committee (IRC); secondary end points included objective response rate (complete plus partial responses) and overall survival.1, 2 The median age of patients was 61 years.1, 2 The majority (72%) of patients were of East Asian ancestry.1, 2 Patients enrolled in the study were required to have evidence of an EGFR mutation as determined by a standardized polymerase chain reaction (PCR) assay;2 the majority of patients had exon 19 deletions (49%) or exon 21 (L858R) substitution mutations (40%), while the remaining (11%) had other mutations.1, 2
At a median follow-up of 16.4 months, patients receiving afatinib had a longer median IRC-assessed progression-free survival compared with patients receiving combined therapy with cisplatin and pemetrexed (11.1 versus 6.9 months).1, 2 Effects of afatinib on investigator-assessed progression-free survival and IRC-assessed progression-free survival were comparable.2 Patients receiving afatinib also had a higher objective response rate (50.4 versus 19.1%) and a longer median duration of response (12.5 versus 6.7 months) compared with those receiving combined therapy with cisplatin and pemetrexed.1 A planned subgroup analysis indicated that the magnitude of progression-free survival benefit from afatinib was greater in patients with common EGFR mutations (del19 and L858R) compared with those in the general study population; among patients with common EGFR mutations, the median IRC-assessed progression-free survival reportedly was 13.6 months in those receiving afatinib and 6.9 months in those receiving combined therapy with cisplatin and pemetrexed.2 No significant difference in overall survival was observed between patients receiving afatinib and those receiving combined therapy with cisplatin and pemetrexed at the time of final analysis.1 Another planned subgroup analysis indicated that the magnitude of progression-free survival and overall survival benefit in Japanese patients with common EGFR mutations was greater in those receiving afatinib compared with those receiving combined therapy with cisplatin and pemetrexed; however, no significant difference in overall survival was observed between treatment groups in Japanese patients with L858R mutations.18 In a pooled analysis of 3 clinical studies involving 32 patients with uncommon EGFR mutations (i.e., S768I; S768I and G719X; S768I and L858R; G719X; G719X and L861Q; L861Q; L861Q and del19 mutations) receiving afatinib (40 or 50 mg orally once daily), responses were observed in 66% of patients.1, 28 At the time of analysis, 52% of responders maintained a response for 12 months or longer and 33% had ongoing responses.1 In the LUX-Lung 3 study, approximately 10% of patients were long-term responders who received afatinib therapy for at least 3 years; baseline characteristics of these patients were similar to the overall study population except a higher proportion of long-term responders were female or had NSCLC harboring an EGFR del19 mutation.31 The median duration of treatment in long-term responders was 50 months, and median progression-free survival was 49.5 months.31
In a randomized, open-label phase 3 study (LUX-Lung 6) evaluating afatinib or combined therapy with gemcitabine and cisplatin in 364 patients with previously untreated EGFR mutation-positive locally advanced or metastatic (stage IIIB with pleural effusion or stage IV) NSCLC in East Asia (i.e., China, Thailand, South Korea), patients receiving afatinib had longer IRC-assessed progression-free survival (11 versus 5.6 months), higher objective response rates (66.9 versus 23%) and disease control rates (92.6 versus 76.2%), and a longer median duration of response (9.7 versus 4.3 months) compared with those receiving combined therapy with gemcitabine and cisplatin.5 In a planned subgroup analysis of 86 patients 65 years of age or older, the median progression-free survival was substantially longer in patients receiving afatinib compared with combined therapy with gemcitabine and cisplatin (13.7 versus 4.1 months; HR of 0.16; 95% CI of 0.07-0.39); however, no substantial difference in overall survival was observed between patients receiving afatinib and those receiving combined gemcitabine and cisplatin.30 In the LUX-Lung 6 study, approximately 10% of patients were long-term responders who received afatinib therapy for at least 3 years; baseline characteristics of these patients were similar to the overall study population except a higher proportion of long-term responders were female or had NSCLC harboring an EGFR del19 mutation.31 The median duration of treatment was 56 months, and median progression-free survival was 55.5 months.31
In a planned subgroup analysis of 134 patients 65 years of age or older, median PFS was prolonged in patients receiving afatinib compared with those receiving combined therapy with cisplatin and pemetrexed (11.3 versus 8.2 months; hazard ratio [HR] of 0.64; 95% confidence interval [CI] of 0.39-1.03).30 Although a trend toward overall survival was observed in older adults in the LUX-Lung 6 study and in those with tumors harboring common EGFR mutations in the LUX-Lung 3 study, overall survival was substantially prolonged in older afatinib-treated adults with NSCLC harboring an EGFR del19 mutation compared with those who received combined therapy with cisplatin and pemetrexed (41.5 versus 14.3 months; HR of 0.39; 95% CI of 0.19-0.80).30
The safety and efficacy of afatinib compared with gefitinib was evaluated in a multinational, randomized, open-label, phase 2b trial (LUX-Lung 7) in 319 patients with previously untreated EGFR mutation-positive stage IIIB (ineligible for curative surgery or local radiotherapy) or recurrent or metastatic stage IV NSCLC.32 Median progression-free survival (11 versus 10.9 months) and time to treatment failure (13.7 versus 11.5 months) were prolonged in patients receiving afatinib compared with those receiving gefitinib.32 At a median duration of follow-up of 42.6 months, median overall survival was not significantly different between patients receiving afatinib and those receiving gefitinib (27.9 versus 24.5 months).33 In the LUX-Lung 7 study, approximately 12% of patients were long-term responders who received afatinib for at least 3 years.31 The median duration of treatment was 42 months, and median progression-free survival was 42.2 months.31
A prospective, observational, phase II study evaluated a lower initial dosage of afatinib (30 mg daily) in 40 treatment-naive patients 70 years of age or older with EGFR mutation-positive stage IIIB or IV NSCLC.34 In this study, 19 patients required a dosage reduction to 20 mg daily.34 After a median follow-up duration of 17.6 months, the objective overall response was 72.5% and progression-free survival was 12.9 months.34 Median overall survival had not been reached at the time of analysis.34
In a pooled analysis of 3 clinical studies involving 32 patients with nonresistant EGFR mutations (i.e., S768I; S768I and G719X; S768I and L858R; G719X; G719X and L861Q; L861Q; L861Q and del19 mutations) receiving afatinib (40 or 50 mg orally once daily), responses were confirmed in 66% of patients.1, 28 At the time of analysis, responses were ongoing in 33% of these patients, and 52% of responders had a durable response of at least 12 months.1 Safety and efficacy of afatinib have not been established in patients whose tumors harbor resistant EGFR mutations.1
Previously Treated Metastatic Non-small Cell Lung Cancer
Afatinib is used for the treatment of metastatic squamous NSCLC that has progressed following therapy with platinum-based chemotherapy.1, 22
The current indication for afatinib in the treatment of previously treated metastatic squamous NSCLC is based principally on the results of a randomized, multicenter, open-label, active-controlled study (LUX-Lung 8) in 795 adults with stage IIIb or IV squamous NSCLC whose disease progressed following a platinum-based doublet chemotherapy regimen for at least 4 cycles.1, 22 Patients were randomized (stratified by geographic region) in a 1:1 ratio to receive afatinib (40 mg orally once daily) or erlotinib (150 mg orally once daily).1, 22 Treatment was continued until disease progression, unacceptable toxicity, or study withdrawal occurred.1, 22 The primary efficacy end point of the study was progression-free survival as assessed by an independent review committee according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1); secondary end points included objective response rate and overall survival.1, 22 The median age of patients was 64 years; the majority of patients were male (84%), 73% were Caucasian, 24% were of Asian ancestry, 95% were current or former smokers, 96% had squamous cell histology, and 3.5% had mixed cell histology.1 All patients enrolled in the study had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.1
At a median follow-up of 6.7 months, patients receiving afatinib had a longer median progression-free survival compared with patients receiving erlotinib (2.4 versus 1.9 months).1, 22 At a median follow-up of 18.4 months, median overall survival also was prolonged in patients receiving afatinib compared with those receiving erlotinib (7.9 versus 6.8 months).1, 22 The objective response rate was 3 or 2% in afatinib-treated or erlotinib-treated patients, respectively.1 Results of subgroup analyses (based on age, gender, ethnicity, response to first-line chemotherapy, interval between first- and second-line therapies, histology, smoking status, ECOG performance status, use of maintenance therapy) suggested that the effect of afatinib on progression-free survival and overall survival was consistent across all subgroups.22 Improved global health status and quality of life scores have been observed in a larger proportion of patients receiving afatinib compared with those receiving erlotinib (36 versus 28%).38 Afatinib substantially delayed the time to deterioration of dyspnea compared with erlotinib.38 No differences were observed between the treatment groups in time to deterioration of cough or pain.38
First-line Therapy for Metastatic Non-small Cell Lung Cancer
The American Society of Clinical Oncology (ASCO) and Ontario Health (OH; formerly known as Cancer Care Ontario) 2021 joint guideline specifically addresses treatment of stage IV NSCLC harboring driver alterations such as EGFR mutations.35 For patients with previously untreated stage IV NSCLC harboring sensitizing EGFR mutations (L858R/exon 19 deletion) and a performance status of 0 to 2, ASCO/OH states that afatinib monotherapy or the combination of erlotinib with a VEGF inhibitor (e.g., bevacizumab, ramucirumab) may be used when first-line treatment with osimertinib, dacomitinib, or gefitinib in combination with carboplatin and pemetrexed are not treatment options.35 Although progression-free survival benefit has been demonstrated with afatinib monotherapy or combination erlotinib therapy, overall survival benefit has not been demonstrated compared with first-generation EGFR tyrosine kinase inhibitors alone.35 For patients with previously untreated stage IV NSCLC harboring sensitizing EGFR mutations (L858R/exon 19 deletion) and a performance status of 3, monotherapy with an EGFR tyrosine kinase inhibitor may be offered based on access and toxicity.35 For patients with an activating EGFR mutation other than exon 20 insertion mutations, T790M, L858R, or exon 19 deletion (e.g., G719X, L861Q, and S768I), and a performance status of 0 to 2, who have not received systemic therapy, ASCO/OH states that clinicians may offer afatinib monotherapy, osimertinib, or standard treatment based on the ASCO/OH nondriver mutation guideline.35
A 2021 Cochrane review on first-line treatment options for patients with EGFR mutation-positive NSCLC concluded that erlotinib, gefitinib, afatinib, and icotinib (not commercially available in the US market) demonstrate increased tumor response, prolonged progression-free survival, less toxicity, and greater quality of life compared to cytotoxic chemotherapy.36 The analysis also states that single agent tyrosine kinase inhibitor therapy remains the standard of care and the benefit of combining a tyrosine kinase inhibitor with chemotherapy remains uncertain.36 Cytotoxic chemotherapy is less effective for the treatment of NSCLC harboring EGFR mutations compared with erlotinib, gefitinib, afatinib or icotinib, and is associated with greater toxicity.36
Previously Treated Metastatic Squamous Non-small Cell Lung Cancer
The ASCO guideline on systemic therapy for patients with stage IV NSCLC states that a recommendation for or against use of afatinib in patients with squamous cell carcinoma who are not eligible for further therapy cannot be made due to the minor survival gain compared with erlotinib and the potential benefit of therapy with immune checkpoint inhibitors.39
Afatinib also has been used for the treatment of malignant brain and central nervous system tumors† and pancreatic cancer†.4
Administer orally once daily.1 Administer on an empty stomach, at least 1 hour before or 2 hours after a meal.1
If a dose of afatinib is missed, the prescribed dose should be taken as soon as possible unless the next dose is within 12 hours; an additional dose should not be administered to replace the missed dose.1
Store at 25ºC (excursions permitted between 15-30ºC).1 Store in original container and protect from excessive humidity and light.1
Dosage of afatinib dimaleate is expressed in terms of afatinib.1
For the first-line treatment of metastatic NSCLC in patients whose tumors harbor nonresistant EGFR mutations (e.g., exon 19 deletions or exon 21 substitution [L858R] mutations), the recommended dosage of afatinib in adults is 40 mg once daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1 In the LUX-Lung 3 study, afatinib therapy was continued for a median of 11 months.1, 2 Approximately one-half (53.3%) of patients required dosage reductions within the initial 6 months of therapy; however, median progression-free survival was similar among patients who received a dosage reduction and those who received the recommended dosage.23
For the treatment of metastatic squamous NSCLC that has progressed following therapy with platinum-based chemotherapy, the recommended dosage of afatinib in adults is 40 mg once daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1 In the LUX-Lung 8 study, afatinib therapy was continued for a median of 2.1 months.1
If adverse effects occur during afatinib therapy, temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of the drug may be necessary.1
Permanently discontinue afatinib in patients who develop life-threatening bullous, blistering, or exfoliative skin lesions; interstitial lung disease; severe drug-induced hepatic impairment; GI perforation; persistent ulcerative keratitis; or symptomatic left ventricular dysfunction.1 The drug also should be permanently discontinued in patients who experience severe or intolerable adverse reactions to an afatinib dosage of 20 mg daily.1
If grade 3 or 4 toxicity occurs, interrupt afatinib therapy.1 When the toxicity resolves completely or improves to grade 1, resume afatinib at a reduced dosage (i.e., 10 mg less than the daily dosage used prior to the event).1
If grade 2 diarrhea persists for 2 or more consecutive days despite anti-diarrheal therapy or grade 3 or greater diarrhea occurs, interrupt afatinib therapy.1 When diarrhea improves to grade 1 or less, resume afatinib at a reduced dosage (i.e., 10 mg less than the daily dosage used prior to the event).1
If intolerable or prolonged (lasting more than 7 days) grade 2 cutaneous reactions or grade 3 cutaneous reactions occur, interrupt afatinib therapy.1 When the cutaneous reaction improves to grade 1 or less, resume afatinib at a reduced dosage (i.e., 10 mg less than the daily dosage used prior to the event).1
If life-threatening bullous, blistering, or exfoliating lesions occur, permanently discontinue afatinib.1
Concomitant Use with Drugs Affecting the P-glycoprotein Transport System
If afatinib is used concomitantly with an inhibitor of P-glycoprotein (P-gp), reduce daily dosage of afatinib by 10 mg daily if not tolerated.1 If concomitant use of the P-gp inhibitor is discontinued, the afatinib dosage should be returned to the dosage used prior to initiation of the P-gp inhibitor as tolerated.1
If afatinib is used concomitantly with an inducer of P-gp, increase daily dosage of afatinib by 10 mg daily as tolerated.1 If concomitant use of the P-gp inducer is discontinued, return the afatinib dosage (2-3 days following discontinuance of the P-gp inducer) to the dosage used prior to initiation of the P-gp inducer.1
No initial dosage adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1 Closely monitor patients with severe hepatic impairment (Child-Pugh class C), and adjust dosage of afatinib if not tolerated.1 Afatinib has not been studied in patients with severe hepatic impairment.1
For patients with severe renal impairment (estimated glomerular filtration rate [eGFR] 15-29 mL/minute per 1.73 m2), the manufacturer recommends a reduced afatinib dosage of 30 mg once daily.1 Dosage adjustment is not necessary in patients with mild or moderate renal impairment (eGFR 30-89 mL/minute per 1.73 m2).1 Afatinib has not been studied in patients with eGFR less than 15 mL/minute per 1.73 m2 or in those receiving dialysis.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
The manufacturer states there are no known contraindications to the use of afatinib.1
Diarrhea, resulting in dehydration with or without renal impairment, has been reported in patients receiving afatinib; some of these cases were fatal.1 In clinical studies, grade 3 or 4 diarrhea was reported in 16% of patients receiving afatinib.1 In the LUX-Lung 3 study in patients with previously untreated metastatic non-small cell lung cancer (NSCLC), diarrhea was reported in 96% of patients receiving afatinib and was grade 3 in 15% of patients;1, 2 diarrhea occurred within the first 6 weeks of therapy.1 In the LUX-Lung 8 study in patients with previously treated metastatic squamous NSCLC, diarrhea was reported in 75% of patients receiving afatinib and was grade 3 or 4 in 10 or 0.8%, respectively, of patients.1 In the LUX-Lung 3 and LUX-Lung 8 studies, renal impairment secondary to diarrhea was reported in 6 and 7% of patients receiving afatinib, respectively, and was grade 3 in 1.3 and 2%, respectively, of patients.1
Although the mechanism for development of diarrhea has not been fully determined, an increased incidence and greater severity of diarrhea have been observed with second-generation pan-human epidermal growth factor receptor (pan-HER) inhibitors (e.g., afatinib, dacomitinib) compared with single-target tyrosine kinase inhibitors selective for epidermal growth factor receptor (EGFR) (e.g., erlotinib, gefitinib); therefore, it has been suggested that other members of the HER tyrosine kinase family may have an essential role in the development of diarrhea.29
If persistent or severe diarrhea occurs, temporary interruption of therapy followed by dosage reduction may be required.1 Antidiarrheal therapy (e.g., loperamide) should be provided for subsequent home use by the patient as needed.1 Patients should be advised to take an antidiarrheal agent at the onset of diarrhea and to continue antidiarrheal therapy until loose bowel movements have ceased for 12 hours.1
Cutaneous reactions have been reported frequently in patients receiving afatinib.1 Grade 3 cutaneous reactions (characterized by bullous, blistering, and exfoliating lesions) occurred in 0.2% of 4257 patients receiving afatinib across clinical trials.1 In the LUX-Lung 3 study in patients with previously untreated metastatic NSCLC, cutaneous reactions (i.e., rash, erythema, acneiform rash) were reported in 90% of patients receiving afatinib, and grade 3 cutaneous reactions were reported in 16% of patients.1 In the LUX-Lung 8 study in patients with previously treated metastatic squamous NSCLC, cutaneous reactions were reported in 70% of patients receiving afatinib, and grade 3 cutaneous reactions were reported in 7% of patients.1 In the LUX-Lung 3 and LUX-Lung 8 studies, grade 1-3 palmar-plantar erythrodysesthesia (hand-foot syndrome) was reported in 7 and 1.5%, respectively, of patients receiving afatinib.1
Management of afatinib-associated rash may include use of topical or systemic corticosteroids, anti-infectives, or antihistamines.17 If persistent or severe cutaneous reactions occur, temporary interruption of therapy followed by dosage reduction may be required.1 Afatinib should be permanently discontinued in patients who develop life-threatening bullous, blistering, or exfoliating lesions.1
Toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported during postmarketing experience in patients receiving afatinib.1 Toxic epidermal necrolysis and Stevens-Johnson syndrome bullous cutaneous reactions have occurred from a distinct and separate mechanism of toxicity than bullous lesions secondary to inhibition of EGFR.1 If toxic epidermal necrolysis or Stevens-Johnson syndrome is suspected, afatinib should be discontinued.1
Interstitial lung disease or interstitial lung disease-like events (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome [ARDS], allergic alveolitis) occurred in 1.6% of 4257 patients receiving afatinib across clinical trials; fatal interstitial lung disease occurred in 0.4% of patients receiving the drug.1, 17 In the LUX-Lung 3 study in patients with previously untreated metastatic NSCLC, grade 3 or greater interstitial lung disease was reported in 1.3% of patients receiving afatinib and was fatal in 1% of patients.1, 2 In the LUX-Lung 8 study in patients with previously treated metastatic squamous NSCLC, grade 3 or greater interstitial lung disease was reported in 0.9% of patients receiving afatinib and was fatal in 0.8% of patients.1 The incidence of interstitial lung disease appears to be higher in Asian patients (2.3%) compared with Caucasian patients (1%).1
If interstitial lung disease is suspected, afatinib therapy should be interrupted.1 If a diagnosis of interstitial lung disease is confirmed, afatinib should be permanently discontinued.1
Abnormal liver function tests were reported in 9.7% of 4257 patients receiving afatinib across clinical trials; fatal hepatic toxicity occurred in 0.2% of patients receiving the drug.1, 17 In the LUX-Lung 3 study in patients with previously untreated metastatic NSCLC, liver function test abnormalities of any grade were reported in 17.5% of patients receiving afatinib, and were grade 3 or 4 in 3.5% of patients.1 In the LUX-Lung 8 study in patients with previously treated metastatic squamous NSCLC, liver function test abnormalities of any grade were reported in 6% of patients receiving afatinib, and were grade 3 or 4 in 0.2% of patients.1
Liver function tests should be performed periodically during afatinib therapy.1 Afatinib therapy should be temporarily interrupted in patients who develop worsening of liver function.1 Afatinib should be permanently discontinued in patients who develop severe hepatic impairment.1
GI perforation were reported in 0.2% of 3213 patients receiving afatinib across clinical trials.1 Factors that may increase the risk of GI perforation include increased age, history of GI ulceration, underlying diverticular disease or bowel metastases, or concomitant use of corticosteroids, nonsteroidal anti-inflammatory agents (NSAIAs) or anti-angiogenic agents.1
Keratitis (characterized as acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain, and/or red eye) occurred in 0.7% of 4257 patients receiving afatinib across clinical trials; grade 3 keratitis occurred in 0.05% of patients receiving the drug.1 In the LUX-Lung 3 study in patients with previously untreated metastatic NSCLC, keratitis was reported in 2.2% of patients receiving afatinib; grade 3 keratitis was reported in 0.4% of patients.1 In the LUX-Lung 8 study in patients with previously treated metastatic squamous NSCLC, keratitis was reported in 0.3% of patients receiving afatinib; grade 3 or greater keratitis was reported in none of the patients.1
If keratitis is suspected, afatinib therapy should be interrupted; if a diagnosis of keratitis is confirmed, the potential benefit of the drug to the patient must be carefully weighed against the risks of continued therapy.1 Afatinib therapy should be temporarily interrupted or discontinued in patients with confirmed ulcerative keratitis; therapy should be permanently discontinued in patients with persistent ulcerative keratitis.1
Afatinib should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye.1 Contact lens use is a risk factor for development of keratitis and ulceration.1
Fetal/Neonatal Morbidity and Mortality
Afatinib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1 Embryofetal toxicity (e.g., decreased fetal weight, abortion) and teratogenicity (e.g., skeletal alterations) have been demonstrated in animals.1 Females of reproductive potential should use effective contraception while receiving afatinib and for at least 2 weeks after the drug is discontinued.1 Patients should be apprised of the potential fetal hazard if afatinib is used during pregnancy.1
Left ventricular dysfunction has been reported in patients receiving afatinib.1 In the principal efficacy study in patients with previously untreated NSCLC, left ventricular dysfunction was reported in 2.2% of patients receiving afatinib compared with 0.9% of patients receiving combined therapy with cisplatin and pemetrexed.1, 17 Afatinib therapy should be permanently discontinued if symptomatic left ventricular dysfunction occurs.1
Afatinib does not appear to have substantial effects on the corrected QT (QTc) interval.1 In an open-label, single-arm study evaluating potential effects of afatinib on the QTc interval, substantial (i.e., by more 20 msec) increases in the mean QTc interval were not observed in patients with relapsed or refractory solid tumors who received multiple doses of the drug (50 mg once daily).1
Results of animal studies suggest that afatinib may impair female and male fertility; it is not known whether these effects are reversible.1
In female rats, administration of afatinib at exposure levels approximately 0.63 times the human exposure at the recommended dosage resulted in decreased corpora lutea and increased postimplantation loss.1 In a general toxicology study, the effects of afatinib on reduced ovarian weights were not reversible at 2 weeks.1
In male rats, administration of afatinib at exposure levels approximately equal to the human exposure at the recommended dosage resulted in reduced or absent sperm count; however overall fertility was not affected.1 In a general toxicology study, increased apoptosis in the testes and atrophy in seminal vesicles were observed.1
Afatinib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1
Afatinib is distributed into milk in rats; it is not known whether the drug is distributed into milk in humans or if the drug has any effect on milk production or the nursing infant.1 Because of the potential for serious adverse reactions to afatinib in nursing infants, women should be advised to discontinue nursing while receiving the drug and for 2 weeks after the drug is discontinued.1
Safety and efficacy of afatinib have not been established in pediatric patients.1
The LUX-Lung 3 study evaluating afatinib in patients with previously untreated metastatic NSCLC did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults.1 In subgroup analyses of 3 clinical studies, including LUX-Lung 3, evaluating afatinib as first-line therapy in patients with EGFR mutation-positive NSCLC, efficacy of afatinib in patients 65 years of age and older was consistent with that observed in the overall study population.19
In the LUX-Lung 8 study evaluating afatinib in patients with previously treated metastatic squamous NSCLC, 53% of patients were 65 years of age or older and 11% were 75 years of age or older.1 In an exploratory subgroup analysis, afatinib reduced the risk of death by 5% in patients 65 years of age and older and 32% in those younger than 65 years of age.1 No overall differences in safety were observed between geriatric patients and younger adults.1
Following administration of a single dose of afatinib, systemic exposure to the drug was not affected by mild or moderate hepatic impairment (Child-Pugh class A or B).1 Afatinib has not been studied in patients with severe hepatic impairment (Child-Pugh class C); therefore, such patients should be monitored closely.1
Following administration of a single 40-mg dose of afatinib, peak plasma concentrations and systemic exposure of afatinib in individuals with severe renal impairment (estimated glomerular filtration rate [eGFR] 15-29 mL/minute per 1.73 m2) were increased by 22 and 50%, respectively, compared with individuals with normal renal function; however, peak plasma concentrations of afatinib in individuals with moderate renal impairment (eGFR 30-59 mL/minute per 1.73 m2) were similar to those in individuals with normal renal function but systemic exposure was increased by 22%.1 Dosage adjustment is required in patients with severe renal impairment.1 Afatinib has not been studied in patients with eGFR less than 15 mL/minute per 1.73 m2 or in those receiving dialysis.1
The most common adverse reactions (≥20%) in patients receiving afatinib include diarrhea, rash/acneiform dermatitis, stomatitis, paronychia, dry skin, decreased appetite, nausea, vomiting, and pruritus.1
In vitro studies in human hepatocytes indicate that afatinib does not inhibit or induce cytochrome P-450 (CYP) isoenzyme 1A2, 2B6, 2C8, 2C9, 2C19, or 3A4.1 CYP-mediated mechanisms play a minor role in the drug's overall metabolism.1, 9
In vitro data indicate that afatinib is a substrate and inhibitor of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).1
Drugs Affecting Hepatic Microsomal Enzymes
Clinically important pharmacokinetic interactions with CYP inhibitors and inducers are unlikely.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Clinically important pharmacokinetic interactions with drugs metabolized by CYP isoenzymes are unlikely.1
Drugs Affecting the P-glycoprotein Transport System
Concomitant use of afatinib with inhibitors of P-gp may result in increased systemic exposure to afatinib.1 When the P-gp inhibitor ritonavir (200 mg twice daily for 3 days) was administered 1 hour prior to afatinib (single 20-mg dose) in healthy individuals, area under the plasma concentration-time curve (AUC) and peak plasma concentrations of afatinib were increased by 48 and 39%, respectively.1, 6 However, AUC of afatinib was not substantially affected when ritonavir (200 mg twice daily for 3 days) was administered concomitantly with or 6 hours following administration of afatinib (single 40-mg dose) in healthy individuals.1, 6 If afatinib is used concomitantly with a P-gp inhibitor (e.g., amiodarone, cyclosporine, erythromycin, itraconazole, ketoconazole, nelfinavir, quinidine, ritonavir, saquinavir, tacrolimus, verapamil), dosage of afatinib should be reduced by 10 mg daily if not tolerated.1 If concomitant use of the P-gp inhibitor is discontinued, the afatinib dosage should be returned to the dosage used prior to initiation of the P-gp inhibitor as tolerated.1
Concomitant use of afatinib with inducers of P-gp may result in decreased systemic exposure to afatinib.1 When the potent P-gp inducer rifampin (600 mg once daily for 7 days) was administered concomitantly with afatinib, AUC and peak plasma concentrations of afatinib were decreased by 34 and 22%, respectively.1, 6 If afatinib is used concomitantly with a P-gp inducer (e.g., carbamazepine, phenobarbital, phenytoin, rifampin, St. John's wort [ Hypericum perforatum ]), dosage of afatinib should be increased by 10 mg daily as tolerated.1 If concomitant use of the P-gp inducer is discontinued, the afatinib dosage should be returned (2-3 days following discontinuance of the P-gp inducer) to the dosage used prior to initiation of the P-gp inducer.1
Concomitant use of afatinib with antiangiogenic agents may increase the risk of GI perforation.1
In patients receiving a cisplatin-containing regimen concomitantly with afatinib, the pharmacokinetics of cisplatin were not substantially altered when cisplatin (50-100 mg/m2 as a 1-hour IV infusion) was given 3 or 5 days prior to administration of afatinib (20-50 mg orally once daily).15
In patients receiving a paclitaxel-containing regimen concomitantly with afatinib, the pharmacokinetics of paclitaxel were not substantially altered when paclitaxel (175 mg/m2 as a 3-hour IV infusion) was given 3 days prior to administration of afatinib (20-50 mg orally once daily).15
In patients receiving a fluorouracil-containing regimen concomitantly with afatinib, the pharmacokinetics of fluorouracil were not substantially altered when afatinib (20-40 mg orally once daily) was given 1 day after completion of fluorouracil IV infusion (750 or 1000 mg/m2 infused over 96 hours).15
Concomitant use of afatinib with corticosteroids may increase the risk of GI perforation.1
Nonsteroidal Anti-Inflammatory Agents
Concomitant use of afatinib with nonsteroidal anti-inflammatory agents (NSAIAs) may increase the risk of GI perforation.1
Afatinib dimaleate, a second-generation inhibitor of receptor tyrosine kinases, is an antineoplastic agent.1, 7, 8 The drug covalently binds to the kinase domains of epidermal growth factor receptor (EGFR/human epidermal growth factor receptor type 1 [HER1]/ErbB1), HER2/ErbB2, and HER4/ErbB4, and irreversibly inhibits tyrosine kinase phosphorylation, resulting in downregulation of ErbB signaling.1, 7, 8, 9, 11 Some EGFR-activating mutations, including nonresistant mutations, increase autophosphorylation and activation, sometimes independent of ligand binding, of the tyrosine kinase receptor resulting in increased cell proliferation in non-small cell lung cancer (NSCLC) cells harboring these mutations.1 Nonresistant EGFR mutations are defined as kinase domain mutations in EGFR that lead to activation of tyrosine kinase activity and where efficacy of afatinib is predicted by a clinically meaningful reduction in tumor size at the recommended dosage of the drug and/or inhibition of cellular proliferation or EGFR tyrosine kinase phosphorylation is expected at afatinib concentrations sustainable at the recommended dosage.1
Although first-generation (reversible) EGFR tyrosine kinase inhibitors (e.g., erlotinib, gefitinib) have demonstrated improved outcomes in patients with NSCLC harboring EGFR mutations (e.g., EGFR exon 19 deletion [del19], exon 21 substitution [L858R]), secondary resistance to these agents eventually develops following 9-13 months of treatment.9, 10 Clinical resistance to first-generation EGFR tyrosine kinase inhibitors has been attributed to several mechanisms, but development of the secondary T790M mutation in exon 20 appears to be the most common, occurring in 50-60% of patients who develop this resistance;7, 8, 9, 10, 11 this mutation results in production of a bulky methionine side chain in the receptor kinase domain of EGFR that is thought to sterically hinder the binding of first-generation EGFR tyrosine kinase inhibitors to EGFR.8, 9, 17 It has been suggested that second-generation EGFR tyrosine kinase inhibitors (e.g., afatinib, dacomitinib) may theoretically delay or prevent the emergence of secondary resistance through their irreversible inhibition of EGFR, more complete blockade of the EGFR signaling pathway (i.e., inhibition of EGFR as well as HER2/ErbB2 and HER4/ErbB4), and inhibitory effects against tumors harboring the T790M mutation.7, 8, 9, 17, 20, 21, 24 Afatinib has been shown to inhibit phosphorylation and in vitro proliferation of cell lines expressing wild-type EGFR and cell lines expressing del19 or L858R mutations, including other less common EGFR-activating (nonresistant) mutations.1 The drug also has been shown to inhibit in vitro proliferation of cell lines that overexpress HER2.1 Treatment with afatinib has resulted in inhibition of tumor growth in mice implanted with tumors overexpressing wild-type EGFR, HER2/ErbB2, or the EGFR L858R/T790M mutation.1 In vitro, afatinib appears to be approximately 100 times more potent than gefitinib against EGFR L858R/T790M EGFR mutations and as potent as lapatinib against HER2.9, 11
Following oral administration, peak plasma concentrations of afatinib are achieved within 2-5 hours.1, 7 The area under the plasma concentration-time curve (AUC) and peak plasma concentration of afatinib increase in a slightly more than dose-proportional manner over a dosage range of 20-50 mg.1 The geometric mean bioavailability of 20 mg afatinib tablets is 92% compared to an oral solution.1 Steady-state concentrations are achieved within 8 days of repeated afatinib dosing.1 Administration of afatinib with a high-fat meal decreased the peak plasma concentration and AUC of afatinib by 50 and 39%, respectively, compared with administration in the fasted state.1 Cytochrome P-450 (CYP)-mediated mechanisms play a minor role in the drug's overall metabolism;1, 9 however, in vitro data indicate that afatinib is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).1 In vitro, afatinib is approximately 95% bound to plasma proteins.1 Biliary and fecal excretion are the principal routes of elimination of the drug.1 Following oral administration of a single radiolabeled dose of afatinib as an oral solution (not commercially available in the US), 85% of the dose was recovered in feces and 4% was recovered in urine, mostly (88%) as unchanged drug.1 Following repeated administration of afatinib in cancer patients, the elimination half-life of afatinib was 37 hours.1, 7, 9
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Afatinib is available only be obtained through specialty distributors.41 Consult the manufacturer's website for specific availability information.41
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 20 mg (of afatinib) | ||
30 mg (of afatinib) | Gilotrif® | Boehringer Ingelheim | ||
40 mg (of afatinib) | Gilotrif® | Boehringer Ingelheim |
1. Boehringer Ingelheim Pharmaceuticals, Inc. Gilotrif® (afatinib) tablets prescribing information. Ridgefield, CT; 2019 Oct. [Web]
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3. Yang JC, Hirsh V, Schuler M et al. Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J Clin Oncol . 2013; 31:3342-50. [PubMed 23816967]
4. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2014 Feb 25. [Web]
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7. Murakami H, Tamura T, Takahashi T et al. Phase I study of continuous afatinib (BIBW 2992) in patients with advanced non-small cell lung cancer after prior chemotherapy/erlotinib/gefitinib (LUX-Lung 4). Cancer Chemother Pharmacol . 2012; 69:891-9. [PubMed 22071596]
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23. Yang JC, Sequist LV, Zhou C et al. Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation-positive lung adenocarcinoma: post hoc analyses of the randomized LUX-Lung 3 and 6 trials. Ann Oncol . 2016; 27:2103-2110. [PubMed 27601237]
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26. Takahashi T, Boku N, Murakami H et al. Phase I and pharmacokinetic study of dacomitinib (PF-00299804), an oral irreversible, small molecule inhibitor of human epidermal growth factor receptor-1, -2, and -4 tyrosine kinases, in Japanese patients with advanced solid tumors. Invest New Drugs . 2012; 30:2352-63. [PubMed 22249430]
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28. Yang JC, Sequist LV, Geater SL et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol . 2015; 16:830-8. [PubMed 26051236]
29. Van Sebille YZ, Gibson RJ, Wardill HR et al. Gastrointestinal toxicities of first and second-generation small molecule human epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer. Curr Opin Support Palliat Care . 2016; 10:152-6. [PubMed 27035390]
30. Wu YL, Sequist LV, Tan EH et al. Afatinib as First-line Treatment of Older Patients With EGFR Mutation-Positive Non-Small-Cell Lung Cancer: Subgroup Analyses of the LUX-Lung 3, LUX-Lung 6, and LUX-Lung 7 Trials. Clin Lung Cancer . 2018; 19:e465-e479. [PubMed 29653820]
31. Schuler M, Paz-Ares L, Sequist LV et al. First-line afatinib for advanced EGFRm+ NSCLC: Analysis of long-term responders in the LUX-Lung 3, 6, and 7 trials. Lung Cancer . 2019; 133:10-19. [PubMed 31200814]
32. Park K, Tan EH, O'Byrne K et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol . 2016; 17:577-89. [PubMed 27083334]
33. Paz-Ares L, Tan EH, O'Byrne K et al. Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial. Ann Oncol . 2017; 28:270-277. [PubMedCentral][PubMed 28426106]
34. Imai H, Kaira K, Suzuki K et al. A phase II study of afatinib treatment for elderly patients with previously untreated advanced non-small-cell lung cancer harboring EGFR mutations. Lung Cancer . 2018; 126:41-47. [PubMed 30527191]
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