Next Generation Lung Cancer Medicine
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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 Nashville, TN
2 Disclosure Information I have the following financial relationships to disclose: Patent licensed to MolecularMD for EGFR T790M testing (got total of $ and no royalties) Consulting for MolecularMD, BMS, AstraZeneca, Symphony Evolution, Clovis Oncology Research funding from Xcovery, Enzon, AstraZeneca, Symphogen
3 Agenda 10 year journey in translational lung cancer research: from empiric to rational treatment
4 Traditional View of Lung Cancer 2000 Adenocarcinoma Squamous cell carcinoma Large cell carcinoma Small cell carcinoma
5 Traditional View of Lung Cancer 2000 Adenocarcinoma Squamous cell carcinoma Non-small cell lung cancer Large cell carcinoma Small cell carcinoma Small cell lung cancer
6 Traditional View of Lung Cancer 2000 Adenocarcinoma Squamous cell carcinoma Large cell carcinoma Non-small cell lung cancer Modern platinum doublet (carbo/tax) Small cell carcinoma Small cell lung cancer Platinum doublet (cis/etop)
7 Dramatic Response to Gefitinib
8 Oncogene Addiction = Achilles Heel H H H H 21W on Dox 1 Week Off 3 Weeks Off 6 Weeks Off (Mouse Model of Lung Cancer) Regales et al 07
9 Some Mutations Occur in Signaling Proteins ( Kinases ), Leaving Them Stuck in the On Position Turning these mutant kinases off can be therapeutically effective
10 EGFR Mutations Associated with Sensitivity to Gefitinib/Erlotinib EGF ligand binding Tyrosine kinase autophos TM K DFG Y Y Y Y GXGXXG K DFG L L Exon: LREA G719A/C deletion L858R L861Q Lynch et al 04; Paez et al 04; Pao et al 04
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
12 Evolution of Knowledge About Driver Mutations in Non-Small Cell Lung Cancer Pao and Girard 11
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 Sun et al 10 EGFR mut 78.8%
14 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)
15 Tumor Molecular Profiling Results 7/1/10-3/31/11 Melanoma Panel: 297 patients 190/297 (64%) Patients with Mutation 102/297 (34%) No Mutation Identified 5/297 ( 2%) No Results Obtained BRAF 39% Unknown 33% 6 Double Mutants NRAS-G13R/CTNNB1-S45P BRAF-V600E/CTNNB1- S45P NRAS-Q61L/CTNNB1 S45P BRAF-V600K/CTNNB1 S45F NRAS-G12C/KIT-K642E BRAF-V600E/CTNNB1 S37C NRAS 18% CTNNB1 2% GNA11 2.3% GNAQ 1.7% KIT 4% Lung Panel: 204 patients 80/204 (39%) Patients with Mutation 124/204 (61%) No Mutation Identified BRAF 1.47% 4 Double Mutants Unknown 61% EGFR Exon 19 del / EGFR-T790M (X2) EGFR-L858R/ EGFR-T790M EGFR-L858R/PIK3CA E542K EGFR 13% KRAS 19.6% PTEN 0.49% ERBB2 1.47% MEK1 0.49% PIK3CA 1.96% + 8 ALK fusions
16 Old Method for Reporting Mutation Results in the Electronic Medical Record
17 v Gene mutation: REFSEQ KRAS c.183a>c (Q61H) Discrete result for each mutation Detected NOT Detected No Result Mia Levy MD PhD
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25 MyCancerGenome: Consortium Science Contributing editors: 17 Consulting editors: 5 Informatics: 10 Knowledge Management Experts: 4
26 Worldwide Reach of MCG US, Germany, UK, Italy, China, Canada, France, Japan, So Korea, Netherlands TN, CA, MA, NY, TX, IL, PA, MD, FL, NJ 47,575 pageviews
27 Acquired Resistance to EGFR TKIs in Lung Cancer Day 0 4 months 25 months Growing bone lesion Growing lung lesion Pao et al PLoS Med 05
28 Drug Contact Residues Are Commonly Affected (T790M, T854A) 92% 4% 4% Adapted from Yun et al 07; Bean et al 08
29 C/L+T Effect of BIBW Cetuximab in EGFR T790M Tumor-Bearing Mice Pretreatment Cetuximab Cetux / BIBW H H H H&E C/L+T Pretreatment H BIBW-2992 H Cetux / BIBW H H&E Control C B B+C N T1 T2 T1 T2 T1 T2 T1 T2 pegfr tegfr Actin Regales et al 09
30 Study Design Phase Ib, open-label, multicenter trial in the US and The Netherlands Pathology confirmed NSCLC with Dose escalation schema 3 6 patients per cohort EGFR mutation 1 OR SD 6 months on erlotinib/gefitinib Disease progression 2 Stop erlotinib/ gefitinib for 72 hours 3 Afatinib p.o. daily + escalating doses of i.v. cetuximab q 2 weeks Dose levels starting at: afatinib 40 mg + cetuximab 250 mg/m 2 OR Partial or complete response to erlotinib/gefitinib ECOG PS 0-2 Age 18 years Predefined maximum dose: afatinib 40 mg + cetuximab 500 mg/m 2 MTD cohort expanded up to 80 EGFR mutation-positive patients 4 : 40 T790M+ and 40 T790M 1 EGFR G719X, exon 19 deletion, L858R, L861Q; 2 Progression of disease (Response Evaluation Criteria in Solid Tumors v1.1) on continuous treatment with erlotinib or gefitinib within the last 30 days; 3 Amended from original 14-day interval; 4 Acquisition of tumor tissue after the emergence of acquired resistance was mandated. i.v.=intravenous; MTD=maximum tolerated dose; NSCLC=non-small cell lung cancer; SD=stable disease.
31 Tumor Regression by T790M Mutation Status at Recommended Dose Horn et al WCLC 11
32 Tumor Shrinkage in First Vanderbilt Patient with EGFR T790M on Phase IB Trial of BIBW2992/Cetuximab Del 19 + T790M Pao, unpublished
33 Trials to Overcome Acquired Resistance Treatment RR (%) Reference EGFR TKI + everolimus 0 Riely et al CCR 07 Everolimus 2 Soria et al Ann Oncol 09 Neratinib 3 Sequist et al JCO 10 IPI Sequist et al JCO 10 Erlotinib + cetuximab 0 Janjigian et al CCR 11 Dasatinib/Erlotinib + dasatinib 0/0 Johnson et al JTO 11 XL647 4 Miller et al PASCO 08 PF Campbell et al PASCO 10 PF * (only 2 pts with EGFR mt) Park et al PASCO 10 Erlotinib + XL184 8** (only 1 pt with EGFR mt) Wakelee et al PASCO 10 Afatinib/placebo 7/0.5 Miller et al PESMO 10 Afatinib + cetuximab >35% Janjigian et al PASCO 11 Erlotinib + peme vs peme P Erlotinib + XL184 vs XL184 P PF PF P Erlotinib + AUY922 P Not all eligibility criteria the same
34 Acquired Resistance to Afatinib/Cetuximab L858R, insufficient to determine if T790M present Pao, unpublished
35 Modeling Acquired Resistance to BIBW-2992/Cetuximab in vivo Politi and Pao, unpublished
36 Summary Cancers are heterogeneous at the molecular level Next-generation cancer medicine is being practiced routinely now MyCancerGenome will enable a genetically-informed approach to cancer medicine and accelerate genotypedriven clinical trial accrual Understanding the biology of disease can lead to significant improvements in patient outcome and rational approaches to overcome acquired resistance
37 Thank you! To Bonnie Addario and the Bonnie Addario Lung Cancer Foundation
38 Acknowledgements BIBW-2992/Cetuximab Pao Lab (MSKCC) Yale Lucia Regales Katerina Politi MSKCC Yelena Janjigian Vincent Miller Mark Kris Katerina Politi Vanderbilt Leora Horn Boehringer-Ingelheim
39 Acknowledgements Pao Lab VICC (Jenny Andrews) Monica Red Brewer (Julie Chmielecki) (MarKeesa Duke) (Laurel Fohn) Katie Hutchinson Darson Lai (Ya-lun Lin) Christine Lovly Helen Pan Nerina McDonald Kadoaki Ohashi (Zengliu Su) Ken Takezawa Paula Woods Paul Yeh Amanda Floyd Ashley Lamb Kim Dahlman Jennifer Pietenpol Pathology (Adriana Gonzalez) Cindy Vnencak-Jones Cheryl Coffin Mike Laposata Sam Santoro Medicine Jeff Sosman David Johnson David Carbone Leora Horn Carlos Arteaga Bioinformatics Mia Levy Dan Masys ScienceDriven MGH Ryn Miake-Lye Dora Dias-Santagata Darrell Borger A. John Iafrate Funding NIH/Martell/Kleberg/Anonymous Fnd n
40 MyCancerGenome Co-Editor-in-Chief: Mia Levy Deputy Editor: Christine Lovly Editors: Carlos Arteaga, Alberto Bardelli, Justin M. Balko, Emily Chan, Christopher Corless, Nicolas Girard, Leora Horn, Vicki Keedy, Marc Ladanyi, Mia Levy, Roger Lo, Christine Lovly, Robert Maki, Ingrid Mayer, Paul Paik, William Pao, Gregory Riely, David Solit, Ben Solomon, Martin Sos, Jeff Sosman, Roman Thomas Informatics: Mik Cantrell, Stacy Cooreman, Vincent Gould, Nathan Johnson, Ashley Lamb, Anna Belle Leiserson, Riyad Naser, Ross Oreto, Scott Sobecki, Mikhail Zemmel And growing! We welcome academic/industry partnerships
Defining Clinically Relevant Molecular Subsets of Cancer
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