The Evolving Treatment Landscape in NSCLC
Barbara Melosky, MD Outline of Talk Highlight targeted agents that have improved patient clinical outcomesin the treatment of NSCLC Provide a brief overview of current advances in the treatment ofNSCLC NSCLC: Genetic Heterogeneity and Driver Mutations
Traditional, Histological View Lung Cancer Mutation Consortium (LCMC) Adenocarcinoma 22% 17% 2% 7% 3% Mutation found in 54% of tumors 97% mutually exclusive Kris MG et al. ASCO Abstract CRA7506. Impact of Targeted Agents in the Treatment of NSCLC
Patients with an oncogenic driver mutation who did and did not receivetargeted therapy, and patients without an oncogenic driver Kris MG et al. JAMA. 2014;311:1999. Overview Targeted Agents in the Treatment of NSCLC EGFR Mutations 1.Bunn PA. Current status of advanced lung cancer therapy. Presented at: 13th International Lung Cancer Congress; July 19-22, 2012; Huntington Beach, CA. 2.Pao W, Hutchinson KE. Chipping away at the lung cancer genome. Nat Med. 2012;18: Molecular profiling of lung cancer. My Cancer Genome website.Accessed September 19, 2012. 3.Sos ML, Thomas RK. Genetic insight and therapeutic targets in squamous-cell lung cancer [published online ahead of print January 23, 2012]. Oncogene. 2012:1-4. doi: /onc ErbB Receptors and Mutations in NSCLC
Impaired TK domain No known ligand EGFR (ErbB1) Mutation frequency in NSCLC: 10%of white and 50% of Asian patients2 HER2 (ErbB2) Lacks a ligand-binding domain Uncommonly mutated in NSCLC(2%-4%)3,4 ErbB3 Heterodimer with HER2 is most potent5 ErbB4 Role in dysregulation of ErbB signalling increasingly recognised6 Adapted from Yarden et al ErbB Family required for essential functions in healthy tissues. Dysregulated in a range of tumours.1 Yarden et al. Nat Rev Cancer. 2012;12:553; 2. Hirsch et al. Lancet Oncol. 2009;10:432; 3. Stephens et al. Nature. 2004;431:525; 4. Shigematsu et al. Cancer Res. 2005;65:1642; 5. Hellyer et al. J Biol Chem. 2001;276:42153; 6. Rudloff et al. Cell Cycle. 2010;9:1487. ErbB Family in the Development of NSCLC
Ligand binding and receptor dimerization lead to activation of proliferation and survival pathways Homodimer Heterodimer Activation of downstream signalling pathways Adapted from Yarden and Pines. Nat Rev Cancer. 2012;12:553; Hynes and Lane. Nat Rev Cancer. 2005;5:341. EGFR Activating Mutations
19 and 21 Mutations: 90% T790 L858R Pao W et al. PNAS. 2004;101: T790M Mutation Blocks TKI Binding
T790 codes for the binding pocket Gefitinib, a First-Generation EGFR-Targeted TKI,in the Treatment of NSCLC: IPASS
Gefitinib 250 mg/day n=609 R A N D O M I S E Asian patients with advanced NSCLC(histologically confirmed stage IIIB or IV) No prior systemic therapy Never or light former smoker WHO PS: 0-2 N=1217 1:1 Carboplatin/paclitaxel Q3 wks n=608 Primary endpoint: PFS Mok TS et al. N Engl J Med. 2009;361: IPASS: PFS Median PFS in EGFR-mutation+ patients (months)
Gefitinib: 9.5 months Chemotherapy: 6.3 months HR 0.48, 95% CI ; P