Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content. Select slides from the original presentation are omitted where Research To Practice was unable to obtain permission from the publication source and/or author. Links to view the actual reference materials have been provided for your use in place of any omitted slides.

New Agents and Targets in Lung Cancers: HER2, ROS1, KIF5B-RET, and Squamous Cell Carcinomas Mark G Kris Memorial Sloan-Kettering Cancer Center New York, NY

EGF TGF-  Amphiregulin  -cellulin HB-EGFEpiregulin Heregulins HB-EGFHeregulins Tyrosine Kinase Domain ErbB-1 HER1 EGFRErbB-2 HER2 neu ErbB-3HER3ErbB-4HER4 Extracellular Intracellular No Known Ligands The ErbB Family and Ligands

The Required Incomprehensible Pathway Slide Adapted from Yarden and Sliwkowski INPUT LAYE R HIDDEN LAYERS OUTPU T LAYER

Cancer Research 65, , March 1, 2005 © 2005 American Association for Cancer Research Priority ReportsAmerican Association for Cancer Research Somatic Mutations of the HER2 Kinase Domain in Lung Adenocarcinomas Hisayuki Shigematsu 1,9, Takao Takahashi 1, Masaharu Nomura 1, Kuntal Majmudar 1, Makoto Suzuki 5, Huei Lee 6, Ignacio I. Wistuba 7, Kwun M. Fong 8, Shinichi Toyooka 9, Nobuyoshi Shimizu 9, Takehiko Fujisawa 5, John D. Minna 1,2,3 and Adi F. Gazdar 1,4 1 Hamon Center for Therapeutic Oncology Research, Departments of 2 Internal Medicine, 3 Pharmacology, and 4 Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; 5 Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan; 6 Institute of Medical and Molecular Toxicology, Chung Shan Medical University, Taichung, Taiwan; 7 Department of Pathology and Thoracic/Head and Neck Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas; 8 Prince Charles Hospital, Brisbane, Australia; and 9 Department of Cancer and Thoracic Surgery, Graduate School of Medicine and Dentistry, Okayama University, Okayama, Japan

HER2 in Lung Cancer Agents Targeting HER2 n Trastuzumab n Lapatinib

Results with Paclitaxel and Trastuzumab in a Patient with Adenocarcinoma and HER2 Mutation (Exon 20 G776L) Cappuzzo et al NEJM 2006 After 2 months of trastuzumab therapy, chest CT showed a partial response. Disease assessment performed after an additional 2 months showed almost complete disappearance of lung metastases.

HER2 in Lung Cancer Trials of Investigational Agents Targeting HER2 n Dacomitinib (PF ) n Afatinib (BIBW 2992) n Neratinib (HKI 272)

Phase II Trial of BIBW 2992 Lung Adenocarcinoma with Either EGFR or HER2 Mutations Oral BIBW 2992 once-daily Until disease progression or undue toxicity Primary endpoint: RECIST response PI: Jacque de Greve, Belgium Stage IV EGFR or HER2 mutation

Lung Cancer Mutation Consortium Update 4 JAN 2012 MutationNumberPercent KRAS24224% EGFR20820% ALK Rearrangements 728% MET Amplification124% BRAF222% PIK3CA222% HER2141% MEK13<1% NRAS3<1% AKT11< 1% Any Mutation59960%

Lung Cancer Mutation Consortium LCMC protocols linked to specific molecular lesions detected TargetAgentLCMC Lead MEK1GSK P Jänne BRAF (V600E)GSK B Johnson BRAF (not V600E)GSK P Jänne HER2DacomitinibM Kris PIK3CABKM120J Engelman

New Molecular Targets in Lung Cancers in the Last 3 Months TargetAuthorYear Sensitive to Kinase Inhibition? Mutually Exclusive?Incidence ROS1Bergethon2012Yes 2%- 18/1073 KIF5B-RETSeok2011?Yes14%-5/21 HER2 Extracellular Domain Mutations Gruelich In press Yes ?

Carcinoid Large Cell Large Cell Neuroendocrine 5% Using Driver Mutations to Classify and Treat All Lung Cancers

Routine Genotyping of Squamous Cell Lung Cancers SQ-MAP N=28

New Agents and Targets in Lung Cancers: HER2, ROS1, KIF5B-RET, and Squamous Cell Carcinomas Mark G Kris Memorial Sloan-Kettering Cancer Center New York, NY

Saturday, February 11, 2012 Hollywood, Florida Faculty Co-Chairs Rogerio C Lilenbaum, MD Mark A Socinski, MD Co-Chair and Moderator Neil Love, MD Chandra P Belani, MD John Heymach, MD, PhD Pasi A Jänne, MD, PhD Thomas J Lynch Jr, MD Heather Wakelee, MD