The discovery that mutations in the EGFR gene are present in up to 50% of patients with
lung adenocarcinoma, and the development of highly efficacious EGFR
tyrosine kinase inhibitors (TKIs), has revolutionized the way this common
malignancy is treated. Three generations of EGFR TKIs are now approved for use in EGFR mutation-positive
non-small cell lung cancer (NSCLC); the first-generation agents
erlotinib,
gefitinib, and
icotinib; the second-generation ErbB family blockers
afatinib and
dacomitinib; and most recently,
osimertinib, a third-generation EGFR TKI. The second-generation agents have demonstrated impressive efficacy relative to both standard
platinum-based
chemotherapy and first-generation EGFR TKIs, significantly improving response and progression-free and overall survival. Data from real-world studies suggest that
afatinib is as effective and well tolerated in routine clinical practice as it is in clinical studies and is effective in patients with certain uncommon EGFR mutations, patients with
brain metastases, and older patients. Few real-world data are available for
dacomitinib in the first-line setting.
Afatinib and
dacomitinib have similar safety profiles, with
acne/skin dryzness,
diarrhea,
stomatitis, and
paronychia the most common adverse events (AEs) reported in clinical and real-world studies. Numerous studies have shown that tolerability-guided
dose reductions can help manage
afatinib-related AEs without reducing efficacy. As the number of therapeutic options for advanced NSCLC increases, the optimal choice for first-line treatment will be determined by considering patient factors such as the presence of
brain metastases, the type of EGFR mutation, tolerability, and subsequent
therapy options for long-term treatment.