1. Non-Small Cell Lung Cancer Genetic Predictors Sacha Rothschild, MD PhD Medical Oncology

2. The genomic evolution of lung adenocarcinoma 28.11.2013NSCLC Symposium St. Gallen - Genetic Predictors Pao et al. Lancet Oncol 2011; Pao and Hutchinson. Nat Med 2012

3. Survival of patients with oncogenic drivers – targeted therapy vs. no targeted therapy 28.11.2013NSCLC Symposium St. Gallen - Genetic Predictors Kris et al. Abstract PL03-07

4. Mutations in the EGFR tyrosine kinase domain 28.11.2013NSCLC Symposium St. Gallen - Genetic Predictors Pao W, et al. PNAS 2004; Paez J, et al. Science 2004

5. EGFR-TKIs vs. Chemotherapy as first-line therapy AuthorStudyN (EGFR mut. +)EGFR-TKIORRMedian PFS Mok 1 IPASS261Gefitinib71.2% vs. 47.3%9.8 vs. 6.4 months Lee 2 First-SIGNAL42Gefitinib84.6% vs. 37.5%8.4 vs. 6.7 months Mitsudomi 3 WJTOG 3405177Gefitinib62.1% vs. 32.2%9.2 vs. 6.3 months Maemondo 4 NEJGSG002228Gefitinib73.7% vs. 30.7%10.8 vs. 5.4 months Zhou 5 OPTIMAL154Erlotinib83% vs. 36%13.1 vs. 4.6 months Rosell 6 EURTAC175Erlotinib58% vs. 15%9.7 vs. 5.2 months Yang 7 LUX-Lung 3345Afatinib56.1% vs. 22.6%11.1 vs. 6.9 months 28.11.2013NSCLC Symposium St. Gallen - Genetic Predictors 1 Mok et al. NEJM 2009; 2 Lee et al. WCLC 2009; 3 Mitsudomi et al. Lancet Oncol 2010; 4 Maemondo et al. NEJM 2010; 5 Zhou et al. ESMO 2010; 6 Rosell et al. Lancet Oncol 2012; 7 Yang et al. ASCO 2012; abstract LBA7500 7 randomized trials confirming the role of first-line EGFR-TKI in patients with EGFR-mutated adenocarcinoma

6. Mechanisms of Resistance to EGFR kinase inhibitors in EGFR mutant NSCLC 28.11.2013NSCLC Symposium St. Gallen - Genetic Predictors Yu HA, et al. Clin Cancer Res 2013;19:2240-7

7. EML4-ALK translocations in NSCLC 28.11.2013NSCLC Symposium St. Gallen - Genetic Predictors Soda M et al. Nature 2007; 448:561-566. Koivunen et al. CCR 2008 EML4-ALK frequency: ~ 4% Primarily in adenocarcinoma More common in younger patients More common in never-smokers

8. PROFILE 1007 – PFS by independent radiologic review 28.11.2013NSCLC Symposium St. Gallen - Genetic Predictors Median PFS: 7.7 vs. 3.0 months Shaw AT, et al. NEJM 2013;368:2385-94

9. ALK-inhibitor resistance mechanisms in ALK- positive NSCLC 28.11.2013NSCLC Symposium St. Gallen - Genetic Predictors Doebele RC, et al. Clin Cancer Res 2012;18:1472-82; Shaw AT, et al. ASCO 2013; abstract 8010

10. ROS1 Receptor tyrosine kinase of the insulin receptor family 1-2% of lung adenocarcinoma specimens harbor ROS1 fusion abnormality More common in never-smokers and Asian patients ROS1 fusion with the transmembrane solute carrier protein SLC34A2 results in a constitutive kinase activity in a NSCLC cell line 28.11.2013NSCLC Symposium St. Gallen - Genetic Predictors Rikova, et al. Cell 2007; Takeuchi, et a. Nat Med 2011; Bergethon, et al. JCO 2012; Oxnard et al. J Clin Oncol 2013

11. Crizotinib in ROS1 positive NSCLC – a phase II study 28.11.2013NSCLC Symposium St. Gallen - Genetic Predictors Ou et al. Abstract O16.07

12. RAS signalling networks 28.11.2013NSCLC Symposium St. Gallen - Genetic Predictors Kamaub and Weinberg, Nat Rev 2008