non-small cell lung cancer genetic predictors sacha rothschild, md phd medical oncology
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Non-Small Cell Lung CancerGenetic Predictors
Sacha Rothschild, MD PhD
Medical Oncology
The genomic evolution of lung adenocarcinoma
28.11.2013 NSCLC Symposium St. Gallen - Genetic Predictors
Pao et al. Lancet Oncol 2011; Pao and Hutchinson. Nat Med 2012
Survival of patients with oncogenic drivers – targeted therapy vs. no targeted therapy
28.11.2013 NSCLC Symposium St. Gallen - Genetic Predictors
Kris et al. Abstract PL03-07
Mutations in the EGFR tyrosine kinase domain
28.11.2013 NSCLC Symposium St. Gallen - Genetic Predictors
Pao W, et al. PNAS 2004; Paez J, et al. Science 2004
EGFR-TKIs vs. Chemotherapy as first-line therapy
Author Study N (EGFR mut. +) EGFR-TKI ORR Median PFS
Mok1 IPASS 261 Gefitinib 71.2% vs. 47.3% 9.8 vs. 6.4 months
Lee2 First-SIGNAL 42 Gefitinib 84.6% vs. 37.5% 8.4 vs. 6.7 months
Mitsudomi3 WJTOG 3405 177 Gefitinib 62.1% vs. 32.2% 9.2 vs. 6.3 months
Maemondo4 NEJGSG002 228 Gefitinib 73.7% vs. 30.7% 10.8 vs. 5.4 months
Zhou5 OPTIMAL 154 Erlotinib 83% vs. 36% 13.1 vs. 4.6 months
Rosell6 EURTAC 175 Erlotinib 58% vs. 15% 9.7 vs. 5.2 months
Yang7 LUX-Lung 3 345 Afatinib 56.1% vs. 22.6% 11.1 vs. 6.9 months
28.11.2013 NSCLC Symposium St. Gallen - Genetic Predictors
1Mok et al. NEJM 2009; 2Lee et al. WCLC 2009; 3Mitsudomi et al. Lancet Oncol 2010; 4Maemondo et al. NEJM 2010; 5Zhou et al. ESMO 2010; 6Rosell et al. Lancet Oncol 2012; 7Yang et al. ASCO 2012; abstract LBA7500
7 randomized trials confirming the role of first-line EGFR-TKI in patients with EGFR-mutated adenocarcinoma
Mechanisms of Resistance to EGFR kinase inhibitors in EGFR mutant NSCLC
28.11.2013 NSCLC Symposium St. Gallen - Genetic Predictors
Yu HA, et al. Clin Cancer Res 2013;19:2240-7
EML4-ALK translocations in NSCLC
28.11.2013 NSCLC 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
PROFILE 1007 – PFS by independent radiologic review
28.11.2013 NSCLC Symposium St. Gallen - Genetic Predictors
Median PFS: 7.7 vs. 3.0 months
Shaw AT, et al. NEJM 2013;368:2385-94
ALK-inhibitor resistance mechanisms in ALK-positive NSCLC
28.11.2013 NSCLC Symposium St. Gallen - Genetic Predictors
Doebele RC, et al. Clin Cancer Res 2012;18:1472-82; Shaw AT, et al. ASCO 2013; abstract 8010
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
28.11.2013 NSCLC 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
Crizotinib in ROS1 positive NSCLC – a phase II study
28.11.2013 NSCLC Symposium St. Gallen - Genetic Predictors
Ou et al. Abstract O16.07
RAS signalling networks
28.11.2013 NSCLC Symposium St. Gallen - Genetic Predictors
Kamaub and Weinberg, Nat Rev 2008