Afatinib in Previously Untreated Metastatic NSCLC With Nonresistant EGFR Mutations


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

On January 12, 2018, afatinib (Gilotrif) was approved for a broadened indication in the first-line treatment of patients with metastatic non–small cell lung cancer (NSCLC) with tumors that have nonresistant epidermal growth factor receptor (EGFR) mutations as detected by a U.S. Food and Drug Administration–approved test.1,2 

Approval was based on the finding of durable responses with afatinib in a subgroup of 32 patients with metastatic NSCLC harboring nonresistant EGFR mutations (S768I, L861Q, or G719X) other than exon 19 deletions or exon 21 L858R substitutions who were enrolled in 1 of 3 clinical trials (LUX-Lung 2, LUX-Lung 3, or LUX-Lung 6).2 Nonresistant EGFR mutations were identified using Sanger sequencing or the therascreen® EGFR RGQ PCR Kit. EGFR mutations included in the nonresistant subgroup showed inhibition of cellular proliferation in EGFR-mutant dependent cell lines at clinically relevant concentrations of afatinib. All patients in the subgroup received oral afatinib at 40 mg or 50 mg once daily. 

Among the 32 patients, the median age was 60.5 years (range = 32–79 years); 66% were female; 97% were Asian; all had an Eastern Cooperative Oncology Group performance status of 0 or 1; smoking status was never in 66%, former in 28%, and current in 6%; 97% had stage IV disease; and 88% had received no prior systemic therapy for advanced or metastatic disease. 

The confirmed overall response rate on independent radiology review was 66%. Among the 21 responders, 52% had a response duration of at least 12 months, and 33% had a response duration at least 18 months. 

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. Certain mutations in EGFR, including nonresistant mutations in its kinase domain, can result in increased autophosphorylation of the receptor, leading to receptor activation, sometimes in the absence of ligand binding, and can support cell proliferation in NSCLC. 

Nonresistant mutations are defined as those occurring in exons constituting the kinase domain of EGFR that lead to increased receptor activation with efficacy predicted by clinically meaningful tumor shrinkage with the recommended dose of afatinib or inhibition of cellular proliferation or EGFR tyrosine kinase phosphorylation at concentrations of afatinib sustainable at the recommended dosage, according to validated methods. The most commonly found such mutations are exon 21 L858R substitutions and exon 19 deletions. Afatinib exhibits inhibition of autophosphorylation and proliferation of cell lines expressing wild-type EGFR and in those expressing selected EGFR exon 19 deletion mutations, exon 21 L858R mutations, or other less common nonresistant mutations, at afatinib concentrations achieved in patients. In addition, afatinib inhibits proliferation of cell lines overexpressing HER2. Treatment with afatinib resulted in the inhibition of tumor growth in nude mice implanted with tumors overexpressing wild-type EGFR or HER2 and in an EGFR L858R/T790M double-mutant model.

OF NOTE

Afatinib carries warnings/precautions for diarrhea, bullous and exfoliative skin disorders, interstitial lung disease, hepatic toxicity, keratitis, and embryofetal toxicity.

 

How It Is Used 

PATIENTS SHOULD be selected for first-line treatment in the current expanded indication on the basis of the presence of nonresistant EGFR mutations in tumor specimens. The recommended dose of afatinib is 40 mg once daily until disease progression or intolerance. The recommended dose in patients with severe renal impairment is 30 mg once daily. 

Afatinib should be withheld for adverse events of ≥ grade 3; diarrhea of ≥ grade 2 or persisting for ≥ 2 consecutive days while on antidiarrheal medication; cutaneous reactions of grade 2 that last > 7 days or are intolerable; and renal impairment of grade ≥ 2. Treatment can be resumed when the adverse reaction fully resolves, returns to baseline, or improves to grade 1; treatment should be resumed at a dose reduced by 10 mg/d. 

Afatinib should be permanently discontinued for life-threatening bullous, blistering, or exfoliative skin lesions; confirmed interstitial lung disease; severe drug-induced hepatic impairment; persistent ulcerative keratitis; symptomatic left ventricular dysfunction; and severe or intolerable adverse reactions occurring at a dose of 20 mg/d. 

The afatinib dose should be reduced by 10 mg/d if not tolerated in patients requiring therapy with a P-glycoprotein (P-gp) inhibitor (eg, ritonavir, cyclosporine A, ketoconazole, erythromycin, verapamil, quinidine, amiodarone) and increased as tolerated by 10 mg/d in those requiring a P-gp inducer (eg, rifampicin, carbamazepine, phenytoin, phenobarbital, St. John’s wort). The previous dose can be resumed after discontinuation of the P-gp inhibitor as tolerated and at 2 to 3 days after discontinuation of the P-gp inducer. 

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 www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

Safety Profile 

THE MOST COMMON adverse events of any grade reported in patients receiving afatinib (≥ 20%) across clinical trials have been diarrhea, rash/acneiform dermatitis, stomatitis, paronychia, dry skin, decreased appetite, nausea, vomiting, and pruritus. 

Afatinib carries warnings/precautions for diarrhea, which may result in dehydration and renal failure; bullous and exfoliative skin disorders (severe lesions observed in 0.2% of patients); interstitial lung disease (observed in 1.6% of patents); hepatic toxicity (fatal in 0.2% of patients); keratitis (observed in 0.7% of patients); and embryofetal toxicity. Patients should have periodic liver function testing. Women should be advised to use effective contraception and not to breastfeed while receiving afatinib. ■

REFERENCES 

1. U.S. Food and Drug Administration: FDA broadens afatinib indication to previously untreated, metastatic NSCLC with other non-resistant EGFR mutations. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ ApprovedDrugs/ucm592558.htm. Accessed April 30, 2018. 

2. Gilotrif (afatinib) tablets prescribing information, Boehringer Ingelheim Pharmaceuticals, Inc, January 2018. Available at https://www.accessdata.fda. gov/drugsatfda_docs/label/2018/201292s014lbl.pdf. Accessed April 30, 2018.


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