SC11.04 Rare Mutations in Lung Cancer

Abstract

“Lung adenocarcinoma” is a genetically heterogenous disease entity, characterized by a wide spectrum of different mutations. Some of these mutations lead to constitutive activation of receptor tyrosine kinases, which can be inhibited by small molecules (tyrosine kinase inhibitors, TKIs). EGFR mutations (2004) and ALK rearrangement (2007) were among the first actionable driver mutations identified in lung adenocarcinomas. Today, several drugs are approved for the treatment of advanced lung adenocarcinomas with EGFR mutations or ALK/ROS1 rearrangement. Combined, these molecular subgroups make up at least 20% of all lung adenocarcinomas or more, depending on the poplulation. Further actionable driver mutations include the genes BRAF, HER2, MET, and RET. These genes are less frequently mutated than EGFR/ALK, nevertheless, rare drivers are clinically relevant because of the availability of targeted therapies approved for other indications in oncology (ALK-lung, HER2-breast, RET-thyroid, and BRAF-melanoma). The discussant will summarize current knowledge about rare driver mutations, with a strong clinical focus. HER2 insertion 20, present in about 1% of lung adenocarcinomas, was initially proposed by Cappuzzo et al as a potential indication for trastuzumab-based therapy.1 Prospective trials with HER2 targeting drugs are currently ongoing. BRAF V600E, present in about 3% of lung adenocarcinomas, was associated with high activity of combined therapy with dabrafenib and trametinib in a prospective phase II trial by Planchard et al.2 Crizotinib, recently approved by the FDA for the treatment of ROS1-NSCLC, is also active in tumors harboring MET exon 14 mutations as demonstrated by Drilon et al.3 Cabozantinib and vandetanib are active in tumors with RET rearrangement as shown by three recent phase II trials.4-6 Entrectinib showed preliminary activity in tumors harboring TRK rearrangement in an early basket Trial.7 These results will be discussed in detail, together with the results of international registries (EUHER2, EURAF, EUROS1 and GLORY).8 Moreover, current treatment recommendations for patients with advanced lung adenocarcinomas and rare driver mutations will be summarized. 1. Cappuzzo et al. N Engl J Med. 2006;354(24):2619-21. 2. Planchard et al. Lancet Oncol. 2016;17(7):984-93. 3. Drilon et al. J Clin Oncol 34, 2016 (suppl; abstr 108) 4. Drilon et al. Cancer Discov. 2013;3(6):630-5. 5. Seto et al. J Clin Oncol 2016;34(suppl; abstr 9012) 6. Lee et al. J Clin Oncol 2016;34(suppl; abstr 9013) 7. Drilon et al. AACR 2016 (abstract CT007) 8. Gautschi et al. WCLC 2016 (abstract 4325). NSCLC, Driver Mutations, Targeted Therapies