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U.S. Department of Health and Human Services

Drugs

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Afatinib

On July 12, 2013, the U. S. Food and Drug Administration approved afatinib (Gilotrif tablets, Boehringer Ingelheim Pharmaceuticals, Inc.), 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 safety and efficacy of afatinib have not been established in patients whose tumors have other EGFR mutations. Concurrent with this action, FDA approved the therascreen EGFR RGQ PCR Kit (QIAGEN) for detection of EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.

 
The approval of afatinib was based on the demonstration of improved progression-free survival (PFS) in a multi-center, international, open-label, randomized (2:1) trial. This trial enrolled 345 patients with metastatic NSCLC whose tumors tested positive for EGFR mutations. Patients were randomized to receive afatinib 40 mg orally once daily (n=230) or 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).
 
Of 345 patients enrolled, 65% were female, the median age was 61 years, 26% were Caucasian, and 72% were Asian.  The majority of patients had a tumor sample with an EGFR mutation categorized as either exon 19 deletion (49%) or exon 21 (L858R) substitution (40%), while the remaining 11% had ‘other’ mutations.
 
A statistically significant prolongation of PFS determined by the IRC was demonstrated for patients assigned to the afatinib treatment arm [HR 0.58 (95% CI: 0.43, 0.78); p < 0.001, stratified log-rank test]. The median PFS was 11.1 months in the afatinib arm and 6.9 months in the chemotherapy arm. Objective response rates were 50.4% and 19.1% in the afatinib and chemotherapy arms, respectively. No statistically significant difference in overall survival between the two arms was demonstrated.  In patients whose tumors have exon 19 deletions or exon 21 (L858R) substitution mutations, the median PFS was 13.6 months in the afatinib arm and 6.9 months in the chemotherapy arm.

 
The most frequent (≥20% incidence) adverse reactions from afatinib were diarrhea, rash/dermatitis acneiform, stomatitis, paronychia, dry skin, decreased appetite and pruritus.
 
Serious adverse reactions were reported in 29% of patients treated with afatinib.  The most frequent serious adverse reactions were diarrhea (6.6%), vomiting (4.8%); and dyspnea, fatigue, and hypokalemia (1.7% each). Fatal adverse reactions in afatinib-treated patients included pulmonary toxicity/ interstitial lung disease (ILD)-like adverse reactions (1.3%), sepsis (0.43%), and pneumonia (0.43%).
 
The recommended dose and schedule for afatinib is 40 mg orally once daily until disease progression or no longer tolerated by the patient. Afatinib should be taken at least one hour before or two hours after a meal.
 
Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/201292s000lbl.pdf
 
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).