The next decade of cancer research will continue to focus on identification and effective targeting of somatic driver mutations. The first successfully targeted driver mutation in lung cancer is the mutated epidermal growth factor receptor (EGFR) discovered 8 years ago. Multiple prospective trials for patients with EGFR mutations comparing treatment with gefitinib and erlotinib versus combination chemotherapy have been reported. The prolongation in PFS and decreased toxicity with EGR-TKIs has led to their regulatory approval as initial systemic therapy in patients with non-small-cell lung cancer (NSCLC) and EGFR sensitizing mutations in many countries throughout the world. The second driver mutation successfully targeted is the ALK rearrangement in NSCLC. Five years have past since Dr. Mano et al. discovered a rearrangement between ALK and EML4 in adenocarcinomas of the lung that could transform NIH 3T3 cells. Further research has shown that additional ALK rearrangements can give rise to constitutively activated ALK tyrosine kinase in ∼5% of NSCLC patients. The ALK inhibitor, crizotinib, has been studied in NSCLC patients with prospectively identified ALK rearrangements in a series of phase I, II, and III trials. The prospective clinical studies administering crizotinib to NSCLC with ALK rearrangements have response rates of ∼60%, PFS of ∼10 months, and more than half of the patients are alive 2 years from starting crizotinib. The high response rates, prolongation in PFS and decreased toxicity with crizotinib compared with chemotherapy has led to the regulatory approval of crizotinib as systemic therapy in patients with NSCLC and ALK rearrangements in the United States in August 2011.
The additional driver mutations targeted in NSCLC include KRAS, BRAF, HER2, and PIK3CA mutations, ROS1 and RET rearrangements as well as MET amplification. BRAF has been successfully targeted in melanoma and HER2 amplification in breast cancer. Multiplex genomic characterization efforts are identifying these driver mutations and multi-institutional trials with therapeutic agents directed against these genomic alterations are underway.