Expanding the Reach of Targeted Therapy in Lung Cancer

Abstract

Thirteen years have passed since three independent groups discovered the association between epidermal growth factor receptor (EGFR) mutations and sensitivity to EGFRtyrosine kinase inhibitors (TKIs) in approximately 15% of patients with non-small cell lung cancer (NSCLC) in the US and Europe. Prospective randomized trials for previously untreated patients with EGFR mutations treated with either platinum-based chemotherapy or EGFR-TKIs were reported from 2009-2014. A two-fold increase in progression-free survival (PFS) of EGFR-TKIs over combination chemotherapy led to regulatory approval of erlotinib, gefitinib and afatinib as initial therapy for these patients. Those with ALK rearrangements account for 5% of lung cancer patients. Prospective randomized trials for previously untreated patients with ALK rearrangements treated with pemetrexed platinum chemotherapy or ALK inhibitors were reported from 2014-2017. A two-fold increase in PFS of patients treated with ALK inhibitors led to regulatory approval of crizotinib and ceritinib as initial therapy for these patients. Two different large randomized studies of the 2nd generation ALK inhibitor alectinib were reported at ASCO in 2016 and 2017. Patients with ALK rearrangements treated with alectinib have more than a two-fold increase in PFS compared to those treated with 1st generation ALK inhibitor crizotinib. PFS with alectinib now exceeds 2 years. Targeted therapy now extends to rarer events in lung cancer including ROS1 rearrangements and BRAF V600E mutations, each making up 1% of lung cancer patients. Crizotinib and the combination of dabrafenib plus trametinib have been approved for ROS1 rearrangements and V600E BRAF mutations respectively in the US or Europe. The studies show single arm response rates of 60-70% and PFS of 9-11 months leading to their regulatory approval in these rarer subsets. The list of known genomic abnormalities that now make up approximately 22% of lung cancer cases is likely to expand.