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Disclosure/Disclaimer. The Molecular Basis of Lung Cancer slide presentation is not an independent educational program, and no CME credits will be provided. This program is not intended to promote any cancer agent or class approved by the FDA/EMA or currently under clinical development.

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  1. Disclosure/Disclaimer • The Molecular Basis of Lung Cancer slide presentation is not an independent educational program, and no CME credits will be provided. • This program is not intended to promote any cancer agent or class approved by the FDA/EMA or currently under clinical development. • The contents of this slide presentation are owned solely by Genentech; any unauthorized uses are prohibited. • This program is presented on behalf of Genentech and the information presented is consistent with FDA guidelines. • The following slides are selected samples from a complete presentation. They are for educational purposes only. BIO0002078200 1

  2. Angiogenesis is a function of multiple signals from multiple cell types Endothelial cell O2 Nutrients Notes Pericyte PDGF, TGFβ Angiogenesis is a vital process in the progression of cancer from small, localized neoplasms to larger and potentially metastatic tumors. Angiogenic vessels deliver oxygen, nutrients, and survival factors to cancer cells.1,2 References: 1.Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J ClinOncol. 2005;23:1011-1027. 2.Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003;3:401-410. VEGF, Ang-2, bFGF Paracrinefactors Tumor cell PDGF=platelet-derived growth factor; TGFβ=transforming growth factor beta; VEGF=vascular endothelial growth factor; Ang-2=angiopoietin; bFGF=basic fibroblast growth factor. 2

  3. Types of ALK resistance in ALK+ NSCLC Separate oncogene driver as a new tumor clone Second oncogene driver in the same tumor cell Primary mutation Second oncogene (partially ALK dependent) Primary mutation Separate oncogene (ALK independent) • ALK=anaplasticlymphoma kinase; NSCLC=non-smallcelllung cancer. • Camidge DR, Doebele RC. Nat Rev Clin Oncol. 2012;9:268-277. 3

  4. EGFR variant III deletions SCC (5%) Substitutions NSCLC (5%) Deletions NSCLC (45%) Catalytic domain L858R NSCLC (45%) Constitutive EGFR-mediated signaling is a major pathogenic mechanism of NSCLC • Exon 19-21 mutations account for 90% of EGFR mutations • These mutations increase survival signaling through AKT and STAT but not MAPK proliferation signaling • As a result, the tumor cell is dependent on survival signaling • T790M is associated with resistance • Secondary mutation: • T790M, ATP-binding pocket • Occurs only after primary activating mutation EGFR=epidermal growth factor receptor; NSCLC=non-small cell lung cancer; MAPK=mitogen activated protein kinase; ATP=adenosine triphosphate. Gazdar AF, et al. Trends Mol Med. 2004;10:481-486. 4

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