Gilotrif (Afatinib): Second-Generation Tyrosine Kinase Inhibitor Indicated for the First-Line Treatment of Patients with Non–Small-Cell Lung Cancer and EGFR Mutation

Special Feature Fifth Annual Payers' Guide to New FDA Approvals March 2014 Volume 7 - Payers' Guide
Lisa A. Raedler, PhD, RPh
Medical Writer
Download PDF

Lung cancer is one of the most frequently diagnosed cancers, as well as the leading cause of cancer-­related mortality in the United States.1 The American Cancer Society has estimated that more than 159,000 Americans will die from lung cancer in 2013, representing approximately 27% of all cancer deaths.1 Non–small-cell lung cancer (NSCLC), the most common form of the disease, accounts for 85% to 90% of all cases of lung cancer.2 NSCLC encompasses a number of histologies, including adenocarcino­ma, nonsquamous carcinoma, large-cell car­cinoma, sarcomatoid carcinoma, and adenosquamous carcinoma.2

Data from a 2005 retrospective case-control cohort study of more than 2000 patients with lung cancer show that, as can be expected, the cost burden associated with lung cancer is substantial.3 In this study, patients with lung cancer had significantly greater healthcare utilization and costs for hospitalization, emergency department visits, outpatient office visits, radiology procedures, laboratory procedures, and pharmacy-dispensed medications compared with controls (ie, people without any cancer). Approximate adjusted average costs of care across the study period—from diagnosis to death or to a maximum of 2 years—were $45,000 for patients with lung cancer and $2900 for controls.3

A more recent analysis of claims data from an oncology registry associated with a large US commercial health plan has further demonstrated the substantial cost burden associated with NSCLC.4 This study, which was published in 2013, assessed the total cost of treatment for more than 300 patients with advanced NSCLC who were continually enrolled in the plan from diagnosis until death. The average total healthcare costs ranged from approximately $19,000 to more than $167,000 for first-line treatment of NSCLC and from approximately $35,000 to more than $135,000 for second-line treatment. In this analysis, systemic therapy represented 20% to 55% of total costs of first-line treatment, and 22% to 68% of total costs for second-line treatment.4

Traditionally, patients with metastatic NSCLC have been treated with combinations of cytotoxic agents. Although the use of platinum-based “doublet” chemotherapy has improved median overall survival (OS) for patients with advanced NSCLC from 4 or 5 months (for untreated patients) to 8 to 10 months, these doublet therapies are limited by significant toxicities, including myelosuppression, nausea and vomiting, and severe fatigue.5-7

With enhanced knowledge of lung cancer tumor cell biology, targeted agents now offer the opportunity to treat patients with NSCLC using a personalized approach.8 Among North American patients with NSCLC, approximately 10% express mutations in the epidermal growth factor receptor (EGFR).7 Approximately 90% of these EGFR mutations express a deletion at exon 19 or an L858R substitution at exon 21.9,10 Patients whose tumors include either of these 2 classes of EGFR mutations have similar clinical characteristics; they are typically female Asian never-smokers with adenocarcinomas that display bronchioloalveolar features.10

Researchers continue to identify and evaluate medications that target EGFR and other relevant NSCLC mutations. In May 2013, the US Food and Drug Administration (FDA) expanded the indication of erlotinib (Tarceva) to include patients who have not previously received treatment for metastatic NSCLC and whose tumors have a deletion in exon 19 or exon 21 L858R substitution mutations in the EGFR gene as detected by the cobas EGFR Mutation Test.11 The cobas EGFR test was also approved in May 2013. Other novel kinase inhibitors that are being investigated in clinical trials for patients with EGFR mutation–positive NSCLC include dacomitinib, neratinib, pelitinib, and canertinib.8,12

Afatinib: A New Treatment Option for NSCLC

In July 2013, the FDA approved afat­inib (Gilotrif; Boehringer Ingelheim), a tyrosine kinase inhibitor, for the first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.13 This test, known as the therascreen EGFR RGQ PCR Kit (Qiagen, Manchester, United Kingdom), is a companion diagnostic used to determine if a patient’s tumor cells express relevant EGFR mutations.13

The approval of afatinib for the treatment of patients with NSCLC and EGFR mutation was based on the demonstration of efficacy, specifically progression-free survival (PFS), in a phase 3 multicenter clinical trial known as the LUX-Lung 3 trial.13,14

In a recent interview regarding the use of afatinib in patients with metastatic NSCLC, Corey Langer, MD, Director of Thoracic Oncology at the University of Pennsylvania’s Abram­son Cancer Center, stated, “Afatinib, which is an irreversible EGFR inhibitor targeting both human epidermal growth factor receptor 1 (HER1) and HER2, may ultimately have an advantage over erlotinib….Based on my own experience with both agents, I could give one or the other equally to a newly diagnosed [metastatic NSCLC] patient with an EGFR mutation.”15

Mechanism of Action

Afatinib is a pan-HER inhibitor that irreversibly blocks tyrosine kinase autophosphorylation. This results in downregulation of signaling from EGFR1, HER2, ErbB4, and other dimers in the ErbB family.16,17

Dosing and Administration

For first-line patients with NSCLC and EGFR exon 19 deletion mutations or exon 21 (L858R) substitution mutations, the recommended dose of afatinib is 40 mg orally once daily until disease progression or until the drug is no longer tolerated. Afatinib should be taken at least 1 hour before or 2 hours after a meal. Missed doses of afatinib should not be taken within 12 hours of the next dose.16

LUX-Lung 3: A Phase 3 Clinical Trial

In the multicenter LUX-Lung 3 trial that served as the basis for the FDA approval of afatinib, 345 patients with EGFR mutation–positive stage IIIB or IV lung adenocarcinoma were randomly assigned to treatment with afatinib or with the combination of cisplatin plus pemetrexed.14 Patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before 2:1 random assignment to 40-mg oral afat­inib once daily or up to 6 cycles of cisplatin plus pemet­rexed at standard doses administered every 21 days. Maintenance chemotherapy was not permitted. Treatment with afatinib or with cisplatin plus pemetrexed continued until disease progression was observed by the investigators. The trial’s primary end point was PFS as determined by an independent review. Secondary end points included tumor response, OS, adverse events (AEs), and patient-reported outcomes.14

Patient Population
In the LUX-Lung 3 trial, patient dem­ographics and clinical characteristics were balanced between the treatment arms. The patients’ median age was approximately 61 years, and more than 85% of the patients were diagnosed with stage IV adenocarcinoma.14 The majority of patients with EGFR mutation–positive disease enrolled in this trial were East Asian (72%), never-smokers (68%), and women (65%). EGFR mutations were predominantly exon 19 deletions (49%) and L858R point mutations (40%).14

The phase 3 study demonstrated that afatinib is active and safe in newly diagnosed patients with EGFR mutation–positive advanced NSCLC. At the time of data cutoff for the primary end point analysis, patients had been followed for a median of 16.4 months.14 Over that period, 221 disease progression or death events were observed by an independent review.14 As shown in the Figure, the median PFS was significantly prolonged for patients receiving afatinib compared with patients receiving cisplatin and pemetrexed (11.1 vs 6.9 months, respectively; P <.001).14

The difference in PFS outcomes was even more pronounced for patients whose tumors had deletion 19 or L858R EGFR mutations. In those patients, PFS was nearly doubled with afatinib compared with chemother­apy (13.6 vs 6.9 months, respectively; P <.001).14 The PFS findings and other key efficacy end point analyses are summarized in Table 1.14,16

In the phase 3 trial, afatinib was administered for a median of 11 months (16 cycles).14 As assessed on a per-patient basis, the mean overall compliance with afat­inib was 98%. Dose reductions to less than 40 mg daily were necessary for 120 patients (52%). A total of 16 patients (7%) opted to increase the daily dose of afatinib from 40 mg to 50 mg after the first cycle.14

Altogether, 112 patients (49%) receiving afatinib and 53 patients (48%) receiving chemotherapy experienced treatment-related AEs that were grade ≥3 in severity.14 Among patients receiving afatinib, the most common treatment-related AEs were diarrhea, rash, and dryness or irritation of the skin, mucosa, and nails (Table 2). Of these, diarrhea (1.3%) and paronychia (0.9%) resulted in treatment discont­inuation.14 Among patients receiving cisplatin plus pemetrexed, decreased appetite, fatigue, nausea, vomiting, and myelosuppression were the most common AEs. Therapy was discontinued secondary to treatment-related AEs in 8% of patients receiving afatinib and in 12% of patients receiving cisplatin plus pemetrexed.14

Warnings and Precautions

Diarrhea. Diarrhea secondary to afatinib has resulted in dehydration with or without renal impairment, as well as in fatalities. In the LUX-Lung 3 trial, diarrhea occurred in 96% of the patients receiving afatinib (N = 229).16 For 15% of these patients, diarrhea was grade 3 in severity.16 Renal impairment as a consequence of diarrhea occurred in 6.1% of patients treated with afatinib, of which 3 (1.3%) were grade 3.16 For patients who develop grade 2 diarrhea that lasts more than 48 hours or diarrhea that is grade ≥3, afatinib should be withheld until diarrhea resolves to grade ≤1. Afatinib can then be resumed with appropriate dose reduction. Patients should self-administer an antidiarrheal agent, such as loperamide, at the onset of diarrhea and should continue such therapy until loose bowel movements cease for 12 hours.16

Bullous/exfoliative skin disorders. Of the 3865 patients who received afatinib across clinical trials, 6 had grade 3 cutaneous reactions characterized by bullous, blistering, and exfoliating lesions.16 In the LUX-Lung 3 study, 90% had skin reactions (rash, erythema, and acneiform rash), of which 16% were grade 3.16 Of the total patients, 7% experienced grade 1 to 3 hand-foot syndrome (palmar-plantar erythrodysesthesia syndrome).16 Patients who develop life-threatening bullous, blistering, or exfoliating lesions should discontinue using afatinib. In patients who have grade 2 skin AEs that last for more than 7 days, intolerable grade 2 skin reactions, or grade 3 skin reactions, afatinib should be withheld until the reaction resolves to grade ≤1. Afatinib can be resumed with appropriate dose reduction.16

Interstitial lung disease. Interstitial lung disease or interstitial lung disease–like adverse reactions, including lung infiltration, pneumonitis, acute respiratory distress syndrome, or allergic alveolitis, were observed in 1.5% of the 3865 patients who received afatinib across clinical trials.16 The incidence of interstitial lung disease was higher in Asian patients (2.1%) compared with non-Asian patients (1.2%). Among these cases, 0.4% were fatal. In the phase 3 trial, grade ≥3 interstitial lung disease developed in 1.3% of patients receiving afatinib, and resulted in death for 1% of patients. Afatinib should be withheld while patients with suspected interstitial lung disease undergo evaluation, and should be discontinued if a diagnosis of interstitial lung disease is confirmed.16

Hepatic toxicity. Liver test abnormalities occurred in 10.1% of the 3865 patients who received afatinib across clinical trials.16 In 7 patients, this toxicity was fatal. In the LUX-Lung 3 trial, liver test ab­normalities of any grade were observed in 17.5% of afatinib recipients.16

Periodic liver testing should be conducted during treatment with afatinib. Afatinib should be withheld in patients who develop worsening of liver function and in patients who develop severe hepatic impairment.16

Keratitis. Keratitis (ie, acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain, and/or red eye) occurred in 0.8% of 3865 afat­inib recipients across clinical trials.16 Of the patients in the phase 3 afatinib trial, 5 developed keratitis, with 1 patient experiencing grade 3 severity.16

Afatinib should be withheld while patients with suspected keratitis are evaluated. If ulcerative keratitis is confirmed, afatinib treatment should be interrupted or discontinued. Afatinib should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye, as well as in patients who wear contact lenses.16

Embryofetal toxicity. Based on its mechanism of action, afatinib can cause fetal harm when administered during pregnancy. Patients who become pregnant while taking afatinib should be warned about the potential hazard to the fetus.16

Females of reproductive potential should use very effective contraception during treatment with afatinib, and for at least 2 weeks after the last dose of afatinib. Patients taking afat­inib should contact their healthcare providers if they become pregnant or if pregnancy is suspected.16


Lung cancer remains the main cause of cancer-related death in the United States for men and women. The disease is still diagnosed mainly at advanced stages, such that prognosis is poor and long-term survival is rare. Afatinib, the second oral kinase inhibitor approved for the initial treatment of EGFR mutation–positive metastatic NSCLC, has demonstrated improved efficacy with manageable side effects relative to doublet chemotherapy. Afatinib joins erlotinib as the only FDA-approved agents for this subset of patients with NSCLC, offering them another effective alternative to cytotoxic therapy. As a pan-HER inhibitor, afatinib may confer clinical value in other cancers that overexpress EGFR and HER2. In addition to further exploration in NSCLC, investigators are evaluating afat­inib monotherapy, as well as combinations with various cytotoxic and biologic agents, in breast, prostate, head and neck, and esopha­gogastric cancers.18


  1. American Cancer Society. Lung cancer (non-small cell): what are the key statistics about lung cancer? Revised July 12, 2013. non-smallcell/detailedguide/non-small-cell-lung-cancer-key-statistics. Accessed September 23, 2013.
  2. American Cancer Society. Lung cancer (non-small cell): what is non-small cell lung cancer? Revised July 12, 2013. Accessed September 23, 2013.
  3. Kutikova L, Bowman L, Chang S, et al. The economic burden of lung cancer and the associated costs of treatment failure in the United States. Lung Cancer. 2005;50: 143-154.
  4. Henk HJ, Ray S. Treatment patterns and healthcare costs among patients with advanced non-small-cell lung cancer. Lung Cancer Manag. 2013;2:189-197.
  5. Azzoli CG, Giaccone G, Temin S. American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non–Small-Cell Lung Cancer. J Oncol Pract. 2010;6:39-43.
  6. American Cancer Society. Lung cancer (non-small cell): chemotherapy for non-small cell lung cancer. Revised July 12, 2013. non-smallcell/detailedguide/non-small-cell-lung-cancer-treating-chemotherapy. Accessed September 23, 2013.
  7. Villaflor VM, Salgia R. Targeted agents in non-small cell lung cancer therapy: what is there on the horizon? J Carcinog. 2013;12:7.
  8. Hirsh V, Melosky B, Goss G, et al. A personalized approach to treatment: use of EGFR tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer in Canada. Curr Oncol. 2012;19:78-90. Erratum in: Curr Oncol. 2012;19:e228.
  9. Politi K, Zakowski MF, Fan PD, et al. Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors. Genes Dev. 2006;20:1496-1510.
  10. Uramoto H, Mitsudomi T. Which biomarker predicts benefit from EGFR-TKI treatment for patients with lung cancer? Br J Cancer. 2007;96:857-863.
  11. US Food and Drug Administration. Drugs: erlotinib. Updated May 15, 2013. Accessed September 24, 2013.
  12. Landi L, Cappuzzo F. Irreversible EGFR-TKIs: dreaming perfection. Transl Lung Cancer Res. 2013;2:40-49.
  13. US Food and Drug Administration. Drugs: afatinib. Updated July 12, 2013. Accessed September 24, 2013.
  14. Sequist LV, Yang JC, 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. 2013;31:3327-3334.
  15. OncLive TV. Dr. Corey Langer discusses afatinib in EGFR-positive NSCLC. YouTube. August 13, 2013. Accessed September 23, 2013.
  16. Gilotrif (afatinib) tablets [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; July 2013.
  17. Solca F, Dahl G, Zoephel A, et al. Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther. 2012;343:342-350.
  18. Afatinib. Search results. term=afatinib&Search= Search. Accessed September 24, 2013.
Related Items
Welcome to the Tenth Annual Payers’ Guide to New FDA Approvals
March 2019, Vol 12, Tenth Annual Payers' Guide published on April 15, 2019 in FDA Approvals, Payers' Guide
New Indications Approved by the FDA in 2018 for Oncology Drugs
Dalia Buffery, MA, ABD
March 2019, Vol 12, Tenth Annual Payers' Guide published on April 15, 2019 in FDA Approvals, Oncology Overview, Payers' Guide
FDA Approvals of Novel Brand-Name Prescription Drugs in 2018
March 2019, Vol 12, Tenth Annual Payers' Guide published on April 15, 2019 in Drug Updates, FDA Approvals, Payers' Guide
Aimovig (Erenumab-aooe) First CGRP Receptor Antagonist Approved for the Prevention of Migraine in Adults
Lisa A. Raedler, PhD, RPh
March 2019, Vol 12, Tenth Annual Payers' Guide published on April 15, 2019 in Select Drug Profiles, Payers' Guide
Erleada (Apalutamide) First Drug Approved by the FDA for Nonmetastatic Castration-Resistant Prostate Cancer
Loretta Fala
March 2019, Vol 12, Tenth Annual Payers' Guide published on April 15, 2019 in Select Drug Profiles, Payers' Guide
Last modified: April 17, 2014
Copyright © Engage Healthcare Communications, LLC. All rights reserved.