Afatinib and lung cancer

Abstract

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) have an established role in the treatment of non-small-cell lung cancer (NSCLC). First-generation reversible ATP-competitive EGFR-TKIs are approved for the initial treatment of patients with EGFR mutation-positive advanced NSCLC. Afatinib is an irreversible second-generation EGFR-TKI with potent preclinical activity against EGFR (wild type and mutant), HER2, HER4 and EGFR-mutant NSCLC with acquired resistance to reversible EGFR-TKI. LUX-Lung 3 trial demonstrated superiority of afatinib to cisplatin and pemetrexed in the frontline treatment of treatment-naïve patients with advanced adenocarcinoma of the lung and EGFR mutation. Based on these results, afatinib was recently approved for the first-line treatment of NSCLC patients with EGFR mutation. This article summarizes current status of preclinical and clinical development of afatinib in NSCLC.

Keywords::

• afatinib
• EGFR
• erlotinib
• gefitinib
• NSCLC

Financial & competing interests disclosure

N Sharma has received research funding from Incuron Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Despite significant advancements in understanding the molecular underpinnings of lung cancer, survival and quality of life remains poor for most patients. There is great need to develop more effective and less toxic agents to target-specific molecular pathways.

• Non-small-cell lung cancer (NSCLC) is now recognized as a broad entity with several genotypically distinct subgroups for which the role of targeted therapy is increasingly being realized. EGFR pathway has central role in NSCLC and extensive research in last decade led to discovery of activating EGFR mutations in some patients with dramatic responses to first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI).

• First-generation reversible ATP-competitive EGFR-TKI (erlotinib and gefitinib) are approved for the initial treatment of patients with EGFR mutation-positive advanced NSCLC. Acquired resistance to reversible EGFR-TKI is common and involves a second site mutation in exon 20 (T790M) in approximately 50% of cases.

• Afatinib is an irreversible second-generation EGFR-TKI with activity against multiple EGFR members (HER1, HER2, HER4) and EGFR-mutant NSCLC with acquired resistance to reversible EGFR-TKI. LUX-Lung 3 trial demonstrated superiority of afatinib to cisplatin and pemetrexed in the frontline treatment of EGFR mutation-positive advanced NSCLC. Based on these results, afatinib was recently approved for the first-line treatment of this patient population.

• Afatinib is generally well tolerated in most patients, although side effects are common, particularly diarrhea and skin rash. It improved quality of life compared with first-line treatment with chemotherapy in EGFR mutation-positive advanced NSCLC patients.

• Pooled analysis of LUX-Lung 3 and 6 trials showed significant overall survival benefit of afatinib over chemotherapy for the frontline treatment of NSCLC patients with common EGFR mutations (Del19 and L858R).

• Afatinib as a single agent has no significant activity after failure of frontline EGFR-TKI. Combination of afatinib and cetuximab has demonstrated promising results in the ongoing clinical trials of EGFR mutation-positive NSCLC patients who developed acquired resistance after treatment with reversible EGFR-TKI.

Notes