Targeting oncogenic drivers in lung cancer: celebrating a decade of progress
In the past decade, remarkable progress was achieved in the field of targeted therapy for patients with advanced non-small cell lung cancer and oncogenic driver mutations. From a clinical point of view, it all began in 2004, when three groups independently discovered the predictive role of activating epidermal growth factor receptor (EGFR) mutations for EGFR tyrosine kinase inhibitors. Five years later, the promise of “targeted therapy beats chemotherapy” was fulfilled for the first time in thoracic oncology, when the pivotal IPASS trial demonstrated superior activity of gefitinib compared with first-line chemotherapy in patients with activating EGFR mutations. This was confirmed by a number of follow-on trials with different EGFR inhibitors, including erlotinib and afatinib. In 2007, EML4-ALK fusion in lung cancer was discovered, leading to the rapid clinical development of crizotinib. Again, the pivotal PROFILE trials demonstrated superiority of crizotinib over first- and second-line chemotherapy in patients with ALK rearrangement. Today, clinical research is focused on next generation ALK and EGFR inhibitors with improved activity in the central nervous system and against tumors with secondary resistance mutations. In clinical routine, frontline targeted therapy is considered a new standard-of-care in patients with tumors harboring EGFR or ALK aberrations.