Pharmacology Update: Afatinib Tablets (Gilotrif)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Chair, Formulary Committee, Northern
California Kaiser Permanente; and Assistant Professor
of Medicine, University of California, San Francisco.
Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
An irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has been approved for first-line treatment of non-small cell lung cancer (NSCLC) with certain EGFR mutations. Afatinib is marketed by Boehringer Ingelheim Pharmaceuticals as Gilotrif.
Afatinib is indicated as first-line treatment for metastatic NSCLC in tumors with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.1
The recommended dose is 40 mg orally once daily at least 1 hour before a meal or 2 hours after a meal.1 The dose should be reduced by 10 mg if coadministered with a P-glycoprotein inhibitor (e.g., phenytoin, rifampin) and increased by 10 mg if coadministered with a p-glycoprotein inducer (e.g., cyclosporine, itraconazole, erythromycin). Afatinib is available as 20 mg, 30 mg, and 40 mg tablets.
Afatinib is associated with prolongation of progression-free survival (PFS) compared to standard chemotherapy (cisplatin and pemetrexed) as well as better control of cough and dyspnea.1,2,3 Afatinib is an irreversible tyrosine kinase inhibitor with increased inhibition of common EGFR-activating mutations compared to reversible inhibitors such as erlotinib and gefitinib.4 Afatinib does not interact with the cytochrome P450 isoenzymes.
Afatinib is associated with a higher frequency of diarrhea, rash, stomatitis, and paronychia compared to chemotherapy (cisplatin/pemetrexed) (1,2). Grade 3 severity adverse events ranged from 11 to 15%.
Afatinib irreversibly binds to the kinase domains of EGFR, HER2, and HER4 as well as tyrosine kinase autophosphorylation.1 This results in down regulation of ErbB signaling resulting in inhibition of tumor growth. The efficacy and safety of afatinib were evaluated in 345 treatment-naïve subjects with EGFR mutation positive metastatic NSCLC.1,2 These subjects had Stage IV and Stage III b disease with pleural and/or pericardial effusion. They were randomized (2:1) to afatinib (40 mg daily; n = 230) or up to six cycles of cisplatin 75 mg/m2/pemetrexed (500 mg/m2 × 21 days) (n = 115). Mutation-positive subjects were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian). The primary endpoint was PFS and secondary endpoints were overall survival and tumor response. Median PFS was 11.1 months for afatinib and 6.9 months for cisplatin/pemetrexed (HR, 0.58; 95% confidence interval, 0.43, 0.78; P < 0.001). Subgroup analysis showed that those with exon 19 deletion had the best response (PFS 13.7 vs 5.6). Asians tended to respond better than non-Asians.2 Objective tumor response (complete + partial) was 50.4% for afatinib and 19.1% for cisplatin/pemetrexed. There was no difference in overall survival (50.4% vs 51.2%), although those with exon 19 deletion showed survival benefit. Afatinib delayed the time to deterioration for cough and dyspnea as well as improvement in dyspnea score compared to cisplatin/pemetrexed. Dose reductions were required in 57% of subjects randomized to afatinib. The most common adverse events were diarrhea, rash, paronychia, and stomatitis. The discontinuation rate was 14%. Uncommon but serious adverse events included interstitial lung disease (1.5%) (which appears to be more common in Asians [2.1%]) and left ventricular dysfunction (2.2%).1 In patients previously treated with erlotinib or gefitinib (n 585), the addition of afatinib to best supportive care improved NSCLC-related symptoms compared to placebo.5 In a subgroup analysis with known EGFR mutations (n = 96), PFS favored afatinib vs placebo (4.5 months vs 1 month).4,6
NSCLC is the most common type of lung cancer and exon 19 deletions and exon 21 single amino acid substitutions (L585R) are the most common mutations.4 Approximately 50% of Asians have this mutation compared to 10-15% of Caucasians. Currently, erlotinib is first-line treatment for NSCLC with EGFR exon 19 deletion or exon 21 substitution mutation.4,7 Unfortunately, a significant percentage of patients develop secondary resistance within 9-12 months after initiation of therapy with reversible TKIs.4,8 Afatinib offers a new option as first-line treatment and may have a role in patients who develop resistance to erlotinib. More clinical experience is needed to define the ultimate role of afatinib in NSCLC. The wholesale cost of afatinib 40 mg is $5555 for 30 days compared to $5752 for erlotinib 150 mg.
- Gilotrif Prescribing Information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals; July 2013.
- Sequist LV, 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.
- Yang JC, et al. Symptom control and quality of life in LUX-Lung 3: A phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013;31: 3342-3350.
- Nelson V, et al. Afatinib: Emerging next-generation tyrosine kinase inhibitor for NSCLC. Onco Targets Ther 2013;6:135-143.
- Hirsh V, et al. Symptom and quality of life benefit of afatinib in advanced non-small-cell lung cancer patients previously treated with erlotinib or gefitinib: Results of a randomized phase IIb/III trial (LUX-Lung 1). J Thorac Oncol 2013;8:229-237.
- Miller VA, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): A phase 2b/3 randomised trial. Lancet Oncol 2012;13:528-538.
- http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed September 22, 2013.
- Cadranel J, et al. Therapeutic strategy for advanced EGFR mutant non-small-cell lung carcinoma. Crit Rev Oncol Hematol 2013; Jul 30. [Epub ahead of print.]