Slide 1 ___________________________________ Next Generation Lung Cancer ___________________________________ Medicine 12 th International Lung Cancer Congress ___________________________________ 4 th Annual Addario Lectureship Award Carlsbad, CA August 12, 2011 William Pao, MD, PhD ___________________________________ Ingram Associate Professor of Cancer Research Director, Personalized Cancer Medicine Vanderbilt-Ingram Cancer Center Nashville, TN Vanderbilt-Ingram Cancer Center ___________________________________ ___________________________________ ___________________________________ Slide 2 ___________________________________ Disclosure Information I have the following financial relationships to disclose: ___________________________________ Patent licensed to MolecularMD for EGFR T790M testing (got total of $500.00 and no royalties) Consulting for MolecularMD, BMS, AstraZeneca, Symphony Evolution, Clovis Oncology ___________________________________ Research funding from Xcovery, Enzon, AstraZeneca, Symphogen ___________________________________ Vanderbilt-Ingram Cancer Center ___________________________________ ___________________________________ ___________________________________ Slide 3 ___________________________________ Agenda • 10 year journey in translational lung ___________________________________ cancer research: from empiric to rational treatment ___________________________________ ___________________________________ Vanderbilt-Ingram Cancer Center ___________________________________ ___________________________________ ___________________________________
Slide 4 ___________________________________ Traditional View of Lung Cancer 2000 Adenocarcinoma ___________________________________ Squamous cell carcinoma Large cell ___________________________________ carcinoma Small cell carcinoma ___________________________________ Vanderbilt-Ingram Cancer Center ___________________________________ ___________________________________ ___________________________________ Slide 5 ___________________________________ Traditional View of Lung Cancer 2000 Adenocarcinoma ___________________________________ Squamous cell Non-small cell carcinoma lung cancer Large cell ___________________________________ carcinoma Small cell Small cell lung cancer carcinoma ___________________________________ Vanderbilt-Ingram Cancer Center ___________________________________ ___________________________________ ___________________________________ Slide 6 ___________________________________ Traditional View of Lung Cancer 2000 Adenocarcinoma ___________________________________ “Modern” Squamous cell Non-small cell platinum carcinoma lung cancer doublet (carbo/tax) Large cell ___________________________________ carcinoma Platinum Small cell Small cell doublet lung cancer carcinoma (cis/etop) ___________________________________ Vanderbilt-Ingram Cancer Center ___________________________________ ___________________________________ ___________________________________
Slide 7 ___________________________________ Dramatic Response to Gefitinib ___________________________________ ___________________________________ ___________________________________ Vanderbilt-Ingram Cancer Center ___________________________________ ___________________________________ ___________________________________ Slide 8 ___________________________________ “Oncogene Addiction” = Achilles‟ Heel ___________________________________ H H H H ___________________________________ 21W on Dox 3 Weeks Off 6 Weeks Off 1 Week Off (Mouse Model of Lung Cancer) ___________________________________ Regales et al ‘07 Vanderbilt-Ingram Cancer Center ___________________________________ ___________________________________ ___________________________________ Slide 9 ___________________________________ Some Mutations Occur in Signaling Proteins („Kinases‟), Leaving Them Stuck in the On Position ___________________________________ ___________________________________ ___________________________________ Turning these mutant kinases „off‟ can be therapeutically effective Vanderbilt-Ingram Cancer Center ___________________________________ ___________________________________ ___________________________________
Slide 10 ___________________________________ EGFR Mutations Associated with Sensitivity to Gefitinib/Erlotinib EGF ligand binding Tyrosine kinase autophos ___________________________________ TM K DFG Y Y Y Y 718 745 858 861 964 ___________________________________ GXGXXG K DFG L L Exon: 18 19 20 21 22 23 24 LREA G719A/C deletion L858R L861Q ___________________________________ Lynch et al ’04; Paez et al ‘04; Pao et al ‘04 Vanderbilt-Ingram Cancer Center ___________________________________ ___________________________________ ___________________________________ Slide 11 ___________________________________ Subsets Progress ___________________________________ Year Reference Criteria OS (mos) Notes 1976 Hansen Lung ca 7 SCLC, adeno 2002 Schiller NSCLC 7.9 Platinum dblts 2006 Sandler Non-squamous NSCLC 12.3 Bevacizumab 2009 Mok E Asian never light smoker/adenoca 18.6 Gefitinib arm ___________________________________ 2009 Rosell Spanish EGFR mutant NSCLC 27 Erlotinib 2009 Mitsudomi Japanese EGFR mutant NSCLC 30+ Gefitinib 2010 Maemondo Japanese EGFR mutant NSCLC 30.5 Gefitinib 2010 Janne US EGFR mutant NSCLC 27.6 Erlotinib ___________________________________ Vanderbilt-Ingram Cancer Center ___________________________________ ___________________________________ ___________________________________ Slide 12 Evolution of Knowledge About „Driver ___________________________________ Mutations‟ in Non -Small Cell Lung Cancer ___________________________________ ___________________________________ ___________________________________ Pao and Girard ’11 Vanderbilt-Ingram Cancer Center ___________________________________ ___________________________________ ___________________________________
Slide 13 ___________________________________ Spectrum of „Driver Mutations‟ in 52 East Asian Never Smokers with Lung Adenocarcinoma ___________________________________ Unknown 9.6% KRAS mut 1.9% HER2 mut 3.8% ALK 5.8% ___________________________________ 4 PIK3CA ___________________________________ EGFR mut 78.8% Sun et al ‘10 ___________________________________ ___________________________________ ___________________________________ Slide 14 ___________________________________ Vanderbilt-Ingram Cancer Center Personalized Cancer Medicine Initiative • DETECT: DNA Evaluation of Tumors to ___________________________________ Enhance Cancer Treatment • Goal: to use genotypic information about mutant signaling proteins in tumors to prioritize targeted ___________________________________ therapies for patients – Lung cancer • ~40 mutations in 10 genes – (Melanoma • ~40 mutations in 6 genes) ___________________________________ Vanderbilt-Ingram Cancer Center ___________________________________ ___________________________________ ___________________________________ Slide 15 ___________________________________ Tumor Molecular Profiling Results 7/1/10-3/31/11 Lung Panel: 204 patients Melanoma Panel: 297 patients ___________________________________ 80/204 (39%) Patients with Mutation 190/297 (64%) Patients with Mutation 124/204 (61%) No Mutation Identified 102/297 (34%) No Mutation Identified BRAF 5/297 ( 2%) No Results Obtained 1.47% CTNNB1 ERBB2 2% EGFR 1.47% GNA11 BRAF 13% ___________________________________ 2.3% 39% GNAQ 1.7% KRAS KIT 19.6% Unknown NRAS 4% 61% MEK1 Unknown 18% 0.49% 33% ___________________________________ PIK3CA 1.96% PTEN 6 Double Mutants 4 Double Mutants 0.49% NRAS-G13R/CTNNB1-S45P BRAF-V600E/CTNNB1- S45P NRAS-Q61L/CTNNB1 – S45P EGFR Exon 19 del / EGFR-T790M (X2) + 8 ALK fusions BRAF-V600K/CTNNB1 – S45F EGFR-L858R/ EGFR-T790M NRAS-G12C/KIT-K642E EGFR-L858R/PIK3CA – E542K BRAF-V600E/CTNNB1 – S37C ___________________________________ ___________________________________ ___________________________________
Slide 16 ___________________________________ Old Method for Reporting Mutation Results in the Electronic Medical Record ___________________________________ ___________________________________ ___________________________________ Vanderbilt-Ingram Cancer Center ___________________________________ ___________________________________ ___________________________________ Slide 17 ___________________________________ v ___________________________________ ___________________________________ Gene mutation: REFSEQ KRAS c.183A>C (Q61H) Discrete result for each mutation ___________________________________ Detected NOT Detected No Result Mia Levy MD PhD ___________________________________ ___________________________________ ___________________________________ Slide 18 ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________
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