Afatinib as First-line Treatment for Metastatic NSCLC with EGFR Exon 19 Deletions or Exon 21 (L858R) Substitution Mutations 

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In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.


On July 12, 2013, afatinib (Gilotrif) was approved for first-line treatment of patients with metastatic non–small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.1,2 The safety and efficacy of afatinib have not been established in patients with tumors carrying other EGFR mutations. FDA concurrently approved the therascreen EGFR RGQ PCR Kit (Qiagen) for detection of EGFR exon 19 deletions and exon 21 (L858R) substitution mutations.

Approval was based on demonstration of improved progression-free survival in an international open-label phase III trial in which 345 patients with EGFR-mutant metastatic NSCLC were randomly assigned to receive oral afatinib at 40 mg once daily (n = 230) or pemetrexed (Alimta)/cisplatin (n = 115).2,3 Overall, 65% of patients were female, the median age was 61 years, 26% were Caucasian, and 72% were Asian.

The majority of patients had either an EGFR exon 19 deletion (49%) or exon 21 (L858R) substitution (40%). Randomization was stratified according to EGFR mutation status (exon 19 deletion vs exon 21 L858R vs “other”) and race (Asian vs non-Asian). The primary endpoint was progression-free survival as assessed by an independent review committee.

After a median follow-up of 16.4 months, median progression-free survival was 11.1 months in the afatinib group and 6.9 months in the chemotherapy group (P < .001). Median progression-free survival among those with exon 19 deletions and L858R mutations was 13.6 months in the afatinib group and 6.9 months in the chemotherapy group (HR = 0.47, P = .001). Objective response rates were 50.4% and 19.1% in the afatinib and chemotherapy groups, respectively. There was no statistically significant difference in overall survival between the two groups. (See page 56 for a comprehensive report on the study.)

How It Works

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 inhibits autophosphorylation and in vitro proliferation of cell lines expressing wild-type EGFR or those expressing EGFR exon 19 deletion mutations or exon 21 L858R mutations.

How It Is Given

The recommended dose of afatinib is 40 mg once daily at least 1 hour before or 2 hours after a meal. Treatment should be withheld for adverse events of grade 3 or higher, persistent diarrhea of grade 2 or higher not responsive to antidiarrheal medication, prolonged or intolerable grade 2 cutaneous reactions, and grade 2 or higher renal dysfunction. Treatment should be resumed at a 10-mg lower dose after resolution of the adverse reaction.

Treatment should be permanently discontinued for life-threatening bullous, blistering, or exfoliative skin lesions, confirmed interstitial lung disease, severe hepatic impairment, persistent ulcerative keratitis, symptomatic left-ventricular dysfunction, and severe or intolerable adverse events occurring at a dose of 20 mg/d. The dose should be increased by 10 mg and decreased by 10 mg in patients requiring concomitant treatment with P-glycoprotein inducers (eg, rifampin, St. John’s wort) and inhibitors (eg, amiodarone, clarithromycin, nicardipine), respectively.

Safety Profile

The most frequent adverse events of any grade with afatinib in the phase III trial were diarrhea (96% vs 23% in chemotherapy group), rash/dermatitis acneiform (90% vs 11%), stomatitis (71% vs 15%), paronychia (58% vs 0%), dry skin (31% vs 2%), decreased appetite (29% vs 55%), and pruritus (21% vs 1%). The most frequent grade 3 or 4 adverse events in afatinib recipients were rash/dermatitis acneiform (16% vs 0%), diarrhea (15% vs 2%), paronychia (11% vs 0%), and stomatitis (9% vs 1%). The trial excluded patients with an abnormal left-ventricular ejection fraction; ventricular dysfunction occurred in 2.2% of afatinib patients (all grade 1 or 2).

Serious adverse events occurred in 29% of afatinib patients, with the most common being diarrhea (7%), vomiting (5%), and dyspnea, fatigue, and hypokalemia (2% each). Adverse events led to dose reduction in 57% of afatinib patients, with the most common reasons being diarrhea (20%), rash/acne (19%), paronychia (14%), and stomatitis (10%), and to discontinuation in 14%, with the most common reasons being diarrhea (1.3%), interstitial lung disease (0.9%), and paronychia (0.9%). Fatal adverse events in afatinib patients included pulmonary toxicity/interstitial lung disease–like adverse events (1.3%), sepsis (0.4%), and pneumonia (0.4%). 

Afatinib carries warnings/precautions for diarrhea, bullous and exfoliative skin disorders (severe lesions observed in 0.15% of patients), interstitial lung disease (observed in 1.5% of patents), hepatic toxicity (fatal in 0.18% of patients), keratitis (observed in 0.8% of patients), and embryofetal toxicity. Patients should have periodic liver function testing. Nursing mothers should discontinue treatment or nursing. ■


1. U.S. Food and Drug Administration: Afatinib. Available at Accessed July 19, 2013.

2. GILOTRIF™ (afatinib) tablets prescribing information, Boehringer Ingelheim Pharmaceuticals, Inc, July 2013. Available at Accessed July 19, 2013.

3. Sequist LV, Yang J-CH, Yamamoto N, et al: Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. July 1, 2013 (early release online).

Report Adverse Events

Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).