Erlotinib in First-line Treatment of Metastatic NSCLC with EGFR Exon 19 Deletion or Exon 21 (L858R) Substitution 

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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 May 14, 2013, erlotinib (Tarceva) was approved for first-line treatment of metastatic non–small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.1,2 This indication for erlotinib was approved concurrently with the cobas EGFR Mutation Test, a companion diagnostic test for patient selection. (Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at

The safety and efficacy of erlotinib have not been evaluated in first-line treatment of metastatic NSCLC with EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution. Erlotinib is not recommended for use in combination with platinum-based chemotherapy.

Pivotal Trial

Approval was based on a randomized, multicenter, open-label European trial comparing oral erlotinib (150 mg/d; n = 86) vs platinum-based doublet chemotherapy (n = 88) in patients with metastatic NSCLC whose tumors had EGFR exon 19 deletions or exon 21 (L858R) substitution mutations determined by a clinical trial assay. Tumor samples from 134 patients (69 erlotinib patients and 65 chemotherapy patients) were tested retrospectively by the cobas EGFR Mutation Test.

Patents had a median age of 65 years. The majority of the patients were female (72%), Caucasian (99%), never-smokers (69%), had adenocarcinoma histology (93%), and had ECOG performance status of 1 (53%). On the clinical trial assay, 66% of patients had exon 19 deletions and 34% had the exon 21 L858R substitution. Regimens in the chemotherapy group consisted of cisplatin plus gemcitabine, cisplatin plus docetaxel, carboplatin plus gemcitabine, and carboplatin plus docetaxel.

Median investigator-assessed progression-free survival—the primary endpoint—was 10.4 months in the erlotinib arm and 5.2 months in the platinum-based chemotherapy arm (hazard ratio = 0.34, P < .001). Progression-free survival outcomes were similar on independent review committee analysis and according to cobas EGFR Mutation Test results. A protocol-specified analysis of overall survival conducted at the time of the final analysis of progression-free survival showed no statistically significant difference between the erlotinib and chemotherapy groups (median, 22.9 vs 19.5 months).

At the time of the data cutoff, at least one subsequent treatment had been given to 84% of patients in the chemotherapy group (an EGFR tyrosine kinase inhibitor in 97% of these patients) and to 66% of patients in the erlotinib group. Objective response rates were 65% in the erlotinib group and 16% in the chemotherapy group.

How It Works

Erlotinib reversibly inhibits the kinase activity of EGFR, preventing autophosphorylation of tyrosine residues associated with the receptor and thus inhibiting downstream signaling. EGFR is expressed on the cell surface of both normal and cancer cells. In some tumor cells, signaling through this receptor plays a role in tumor cell survival and proliferation irrespective of EGFR mutation status. The binding affinity of erlotinib for EGFR exon 19 deletions and exon 21 L858R mutations is higher than its affinity for the wild-type receptor. Inhibition of other tyrosine kinase receptors by erlotinib has not been fully characterized.

How It Is Given

The recommended daily dose of erlotinib is 150 mg at least 1 hour before or 2 hours after food. Treatment should continue until disease progression or unacceptable toxicity.

Erlotinib should be discontinued for interstitial lung disease, severe hepatic toxicity that does not improve significantly within 3 weeks, gastrointestinal perforation, severe bullous, blistering, or exfoliating skin conditions, and corneal perforation or severe ulceration. It should be withheld during diagnostic evaluation for possible interstitial lung disease and for severe (grade 3 or 4) renal toxicity, total bilirubin levels greater than three times the upper limit of normal, or transaminases greater than five times upper limit of normal in patients without preexisting hepatic impairment, doubling of bilirubin or tripling of transaminase values in patients with preexisting hepatic impairment or biliary obstruction, persistent severe diarrhea, severe rash, keratitis of grade 3 or 4 or grade 2 lasting more than 2 weeks, and acute/worsening ocular disorders such as eye pain.

The erlotinib dose should be reduced (in 50-mg decrements) if severe adverse reactions occur with concomitant use of a strong CYP3A4 inhibitor (eg, carbamazepine, dexamethasone, phenobarbital). or an inhibitor of both CYP3A4 and CYP1A2 (eg, ciprofloxacin) and when restarting therapy after resolution of dose-limiting toxicity. The dose should be increased (in 50-mg increments) for concomitant use with CYP3A4 inducers (eg, carbamazepine, dexamethasone, and ethosuximide) and for concurrent cigarette smoking. Concomitant use of erlotinib and proton pump inhibitors should be avoided. Erlotinib should be given 10 hours after or at least 2 hours before dosing of H2-receptor antagonists and several hours before or after an antacid.

During erlotinib treatment, patients should be watched for new or progressive pulmonary symptoms (eg, dyspnea, cough, and fever). Patients should undergo monitoring of liver function and renal function as well as electrolytes, particularly if there is risk of dehydration. International normalized ratio (INR) should be monitored in patients taking warfarin or other coumarin-derivative anticoagulants. Women of reproductive potential should be advised of potential risk to the fetus and to use highly effective contraception.

Safety Profile

In the trial supporting approval, the most frequent adverse events of any grade occurring in at least 5% more patients in the erlotinib group were rash (85% vs 2% in chemotherapy group), diarrhea (62% vs 21%), cough (48% vs 40%), and dyspnea (45% vs 30%). The most frequent grade 3 or 4 adverse events in the erlotinib group were rash (14% vs 0%), dyspnea (8% vs 4%), and diarrhea (5% vs 1%). Adverse events caused dose interruptions or reductions in 37% of erlotinib patients and discontinuation in 14%. The most frequent adverse events leading to dose modification were rash (13%), diarrhea (10%), and asthenia (4%).

Erlotinib carries warnings/precautions for interstitial lung disease, renal failure, hepatotoxicity with or without hepatic impairment including hepatic failure and hepatorenal syndrome, gastrointestinal perforation, bullous and exfoliative skin disorders, ocular disorders, hemorrhage in patients taking warfarin, and embryo-fetal toxicity. Risk of myocardial infarction, cerebrovascular accident, and microangiopathic hemolytic anemia is increased in patients receiving erlotinib for pancreatic cancer. ■

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).


1. U.S. Food and Drug Administration: Erlotinib. Available at Accessed May 31, 2013.

2. TARCEVA® (erlotinib) prescribing information, Astellas Pharma US, Inc, and Genentech, Inc, May 2013. Available at Accessed May 31, 2013.