Non-Small Cell Lung CancerGenetic Predictors

Sacha Rothschild, MD PhDMedical 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