Revue de Pharmacovigilance

Abstrait

Tyrosine Kinase Inhibitors for EGFR Gene Mutation-Positive Non-SmallCell Lung Cancers: An Update for Recent Advances in Therapeutics

Clement Chung

The presence of activating gene mutations in the epidermal growth factor receptor (EGFR) of non-small cell lung cancer (NSCLC) patients is predictive (improved progression-free survival and improved response rate) when treated with small molecule tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib and afatinib. The two most common mutations that account for greater than 85% of all EGFR gene mutations, are in-frame deletions in exon 19 (LREA deletions) and point mutations in exon 21 (L858R). Exon 18 mutations occur much less frequently at about 4% of all EGFR gene mutations. Together, deletion19 and L858R gene mutations are present in about 10% of Caucasian patients and 20–40% of Asian patients with NSCLC. T790M gene mutation at exon 20 is associated with acquired resistance to EGFR TKIs. Early studies showed that activating EGFR gene mutations are most common in patients with adenocarcinoma histology, women, never smokers and those of Asian ethnicity. A recent multi-center phase III trial suggested that frontline EGFR TKI therapy with afatinib is associated with improved progressionfree survival compared to chemotherapy regardless of race. Moreover, guidelines suggest EGFR testing should be conducted in all patients with lung adenocarcinoma or mixed lung cancers with an adenocarcinoma component), regardless of characteristics such as smoking status, gender, or race. The success of targeted therapies in NSCLC patients has changed the treatment paradigm in metastatic NSCLC. However, despite a durable response of greater than a year, resistance to EGFR TKIs inevitably occurs. This mini-review describes the clinically significant EGFR gene mutations and the efficacy of small molecule EGFR TKIs as targeted therapies for these gene mutations. Therapeutic strategies to overcome resistance, including selected emerging and novel therapies are discussed.