INTRODUCTION: The epidermal growth factor receptor (EGFR) is mutated in 15% of 
adenocarcinomas of the lung. In addition, the anaplastic lymphoma kinase (ALK) 
is altered in 8% of adenocarcinomas of the lung. Treatment of EGFR mutant and 
ALK translocation-positive tumors in NSCLC with tyrosine kinase inhibitors (TKI) 
results in a dramatic therapeutic response and has revolutionized therapy. 
Unfortunately, resistance to TKIs invariably develops. Many promising new 
therapies are under investigation to overcome the resistance.
AREAS COVERED: We analyzed the current primary literature and recent national 
meetings to evaluate the clinical characteristics and therapeutic implications 
of relevant treatments for EGFR mutant and ALK-positive NSCLC in the first-line, 
acquired resistance, and adjuvant settings.
EXPERT OPINION: Treatment with EGFR TKIs in the first-line setting of EGFR 
mutant NSCLC results in a significant clinical benefit. Several promising third 
generation EGFR TKIs are being evaluated in Phase II and III trials in the 
acquired resistance setting. Crizotinib is superior to chemotherapy in the 
first-line setting for ALK-positive NSCLC. Ceritinib is effective and approved 
for ALK-positive NSCLC in the acquired resistance setting. Continued 
investigation is needed to develop novel therapies to overcome acquired 
resistance to TKIs.