1. 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.

4. Tissue Acquisition and Translational Research Models: The Lung Cancer Mutation Consortium and BATTLE Mark G Kris Memorial Sloan-Kettering Cancer Center New York, NY

5. Molecular Profiling Can Explain the Heterogeneity of Lung Adenocarcinomas and Define Targets for Therapy KRAS Lung Adenocarcinomas Pending EGFR BRAF PIK3CA HER2 ALK MEK1METNRAS

6. Lung Cancer Mutation Consortium

7. Patients and Study Plan 1000 patients Stage IV ECOG PS 0-2 Lung Adenocarcinomas Sufficient Tissue (Paraffin) Informed Consent Central Confirmation of Adenocarcinoma Diagnosis (1 slide) Mutational Analysis CLIA-certified lab at LCMC site: KRAS, EGFR, ALK, BRAF, HER2, PIK3CA, NRAS, MEK1, AKT1, MET amplification Use Data to Select Therapy (Erlotinib with EGFR Mutation) Report to Physician Report to LCMC Virtual Database Recommend Clinical Trial of Agent Specific for Target

8. Lung Cancer Mutation Consortium Incidence of Single Driver Mutations Mutation found in 54% (280/516) of tumors completely tested (CI 50-59%) 13 MAY 2011

9. Lung Cancer Mutation Consortium Update 4 JAN 2012 MutationNumberPercent KRAS24224% EGFR20820% ALK Rearrangements728% MET Amplification124% BRAF222% PIK3CA222% HER2141% MEK13<1% NRAS3<1% AKT11< 1% Any Mutation59960%

10. Lung Cancer Mutation Consortium LCMC protocols linked to specific molecular lesions detected (I) TargetAgent(s)LCMC Lead EGFRErlotinib + OSI 906 Erlotinib + MM 121 C Rudin L Sequist KRASTivantinib + Erlotinib GSK1120212 J Schiller P Jänne MET AmplificationCrizotinibR Camidge ALKCrizotinibR Camidge NRASGSK1120212P Jänne

11. Lung Cancer Mutation Consortium LCMC protocols linked to specific molecular lesions detected (II) TargetAgentLCMC Lead MEK1GSK1120212P Jänne BRAF (V600E)GSK2118434B Johnson BRAF (not V600E)GSK1120212P Jänne HER2DacomitinibM Kris PIK3CABKM120J Engelman AKT1

12. Lung Cancer Mutation Consortium LCMC: Conclusions We detected an actionable driver mutation in the majority of individuals with lung adenocarcinomas We use information in real time to select erlotinib as initial therapy and direct patients to linked trials We can quickly add new driver mutations to our multiplexed process in place at 11 sites Our process can be a model for lung and other cancers We will expand the scope of the LCMC under the auspices of the National Lung Cancer Partnership

14. What is BATTLE? Platform for integrated translational research –Clinical trial program –Novel trial design –Biomarker discovery Scientific hypotheses –Real time biopsies are possible to more accurately reflect aberrant signaling pathways of lung cancer –Matching targeted agents with abnormal pathways will improve disease control in lung cancer patients –8-week disease control is an acceptable surrogate for efficacy in patients with pretreated lung cancer

15. Erlotinib Sorafenib Vandetanib Erlotinib + Bexarotene Randomization: Equal  Adaptive Primary end point: 8-week disease control (DC) Umbrella Protocol BATTLE Schema EGFR KRAS/BRAF VEGF RXR/CyclinD1 Core Biopsy Biomarker Profile

16. Biomarker Groups by Molecular Pathway EGFR marker group Mutation Gene copy number, high polysomy/amplification 5 Marker Groups Based on 2005 data Hierarchial-based 1 KRAS/BRAF marker group Mutations (KRAS and BRAF) 2 VEGF marker group VEGF expression VEGFR-2 3 RXR/Cyclin D1 marker group RXR , ,  Cyclin D1 exp/amp 4 Inadequate tissue/no markers present 5 Biomarker analysis performed in Thoracic Molecular Pathology Research Lab

17. BATTLE Results: Disease Control in % (n) EGFRKRASVEGF RXR/ CycD1 None Total Erlotinib 35% (17)14% (7)40% (25)0% (1)38% (8)34% (58) Vandetanib 41% (27)0% (3)38% (16)NA (0)0% (6)33% (52) Erlotinib + Bexarotene 55% (20)33% (3)0% (3)100% (1)56% (9)50% (36) Sorafenib 39% (23)79% (14)64% (39)25% (4)61% (18)58% (98) Total 43% (87)48% (27)49% (83)33% (6)46% (41) 46% (244) Treatments Marker Groups

18. BATTLE Conclusions A feasible, prospective, biopsy-driven study in lung cancer Patients guided to more effective treatments (adaptive design) BATTLE is an alternative to the traditional way to identify biomarkers

19. Sunday, February 12, 2012 Hollywood, Florida Co-Chairs Rogerio C Lilenbaum, MD Mark A Socinski, MD Co-Chair and Moderator Neil Love, MD Faculty Walter J Curran Jr, MD David Jablons, MD Mark G Kris, MD Suresh Ramalingam, MD Alan B Sandler, MD