Slide 1 ___________________________________ Next Generation Lung - - PDF document

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Vanderbilt-Ingram Cancer Center

Next Generation Lung Cancer Medicine

12th International Lung Cancer Congress 4th 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

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Vanderbilt-Ingram Cancer Center

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

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Vanderbilt-Ingram Cancer Center

Agenda

• 10 year journey in translational lung

cancer research: from empiric to rational treatment

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Vanderbilt-Ingram Cancer Center

Adenocarcinoma Squamous cell carcinoma Large cell carcinoma Small cell carcinoma

Traditional View of Lung Cancer 2000

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Vanderbilt-Ingram Cancer Center

Adenocarcinoma Squamous cell carcinoma Large cell carcinoma Small cell carcinoma

Traditional View of Lung Cancer 2000

Non-small cell lung cancer Small cell lung cancer

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Vanderbilt-Ingram Cancer Center

Adenocarcinoma Squamous cell carcinoma Large cell carcinoma Small cell carcinoma

Traditional View of Lung Cancer 2000

Non-small cell lung cancer Small cell lung cancer “Modern” platinum doublet (carbo/tax) Platinum doublet (cis/etop)

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Vanderbilt-Ingram Cancer Center

Dramatic Response to Gefitinib

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Vanderbilt-Ingram Cancer Center

1 Week Off 3 Weeks Off 6 Weeks Off 21W on Dox H H H H

“Oncogene Addiction” = Achilles‟ Heel

(Mouse Model of Lung Cancer)

Regales et al ‘07

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Vanderbilt-Ingram Cancer Center

Some Mutations Occur in Signaling Proteins („Kinases‟), Leaving Them Stuck in the On Position

Turning these mutant kinases „off‟ can be therapeutically effective

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Vanderbilt-Ingram Cancer Center

K DFG L L Tyrosine kinase

745

K DFG Y Y Y Y TM

718 964

EGF ligand binding autophos GXGXXG

858 LREA 861 Exon: 18 19 20 21 22 23 24

EGFR Mutations Associated with Sensitivity to Gefitinib/Erlotinib

G719A/C L858R deletion L861Q

Lynch et al ’04; Paez et al ‘04; Pao et al ‘04

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Vanderbilt-Ingram Cancer Center

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

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Vanderbilt-Ingram Cancer Center

Evolution of Knowledge About „Driver Mutations‟ in Non-Small Cell Lung Cancer

Pao and Girard ’11

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Spectrum of „Driver Mutations‟ in 52 East Asian Never Smokers with Lung Adenocarcinoma

EGFR mut 78.8% ALK 5.8% HER2 mut 3.8% KRAS mut 1.9% Unknown 9.6% Sun et al ‘10 4 PIK3CA

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Vanderbilt-Ingram Cancer Center

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)

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Melanoma Panel: 297 patients

190/297 (64%) Patients with Mutation 102/297 (34%) No Mutation Identified 5/297 ( 2%) No Results Obtained

Lung Panel: 204 patients

80/204 (39%) Patients with Mutation 124/204 (61%) No Mutation Identified

7/1/10-3/31/11

4 Double Mutants

EGFR Exon 19 del / EGFR-T790M (X2) EGFR-L858R/ EGFR-T790M EGFR-L858R/PIK3CA –E542K

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

Tumor Molecular Profiling Results

BRAF 39% CTNNB1 2% GNA11 2.3% GNAQ 1.7% KIT 4% NRAS 18% Unknown 33% PTEN 0.49% PIK3CA 1.96% MEK1 0.49% ERBB2 1.47% KRAS 19.6% EGFR 13% BRAF 1.47% Unknown 61% + 8 ALK fusions

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Vanderbilt-Ingram Cancer Center

Old Method for Reporting Mutation Results in the Electronic Medical Record

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v

Discrete result for each mutation Detected NOT Detected No Result Gene mutation: REFSEQ KRAS c.183A>C (Q61H)

Mia Levy MD PhD

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Vanderbilt-Ingram Cancer Center

MyCancerGenome: Consortium Science

Contributing editors: 17 Consulting editors: 5 Informatics: 10 Knowledge Management Experts: 4

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Worldwide Reach of MCG

47,575 pageviews TN, CA, MA, NY, TX, IL, PA, MD, FL, NJ US, Germany, UK, Italy, China, Canada, France, Japan, So Korea, Netherlands

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Vanderbilt-Ingram Cancer Center

Day 0 4 months 25 months

Acquired Resistance to EGFR TKIs in Lung Cancer

Growing bone lesion Growing lung lesion Pao et al PLoS Med ‘05

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Vanderbilt-Ingram Cancer Center

Drug Contact Residues Are Commonly Affected (T790M, T854A)

Adapted from Yun et al ‟07; Bean et al „08

92% 4% 4%

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Vanderbilt-Ingram Cancer Center

BIBW-2992 Cetuximab Cetux / BIBW Cetux / BIBW Pretreatment H&E H&E H H H H H H C/L+T C/L+T Pretreatment

Effect of BIBW-2992 + Cetuximab in EGFR T790M Tumor-Bearing Mice

Regales et al „09

pEGFR tEGFR Actin Control C B B+C

N T1 T2 T1 T2 T1 T2 T1 T2

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Study Design

1EGFR G719X, exon 19 deletion, L858R, L861Q; 2Progression of disease (Response Evaluation Criteria in Solid Tumors v1.1)

• n continuous treatment with erlotinib or gefitinib within the last 30 days; 3Amended from original 14-day interval; 4Acquisition 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.

Phase Ib, open-label, multicenter trial in the US and The Netherlands

Stop erlotinib/ gefitinib for ≥72 hours3 Disease progression2 Pathology confirmed NSCLC with EGFR mutation1 OR SD 6 months

• n erlotinib/gefitinib

OR Partial or complete response to erlotinib/gefitinib MTD cohort expanded up to 80 EGFR mutation-positive patients4: 40 T790M+ and 40 T790M– Dose escalation schema 3–6 patients per cohort Afatinib p.o. daily + escalating doses of i.v. cetuximab q 2 weeks Dose levels starting at: afatinib 40 mg + cetuximab 250 mg/m2 Predefined maximum dose: afatinib 40 mg + cetuximab 500 mg/m2 ECOG PS 0-2 Age ≥ 18 years

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Tumor Regression by T790M Mutation Status

at Recommended Dose

Horn et al WCLC ‘11

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Vanderbilt-Ingram Cancer Center

09.21.10 10.18.10 11.15.10 Tumor Shrinkage in First Vanderbilt Patient with EGFR T790M on Phase IB Trial of BIBW2992/Cetuximab Del 19 + T790M Pao, unpublished

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Trials to Overcome Acquired Resistance

Treatment RR (%) Reference EGFR TKI + everolimus Riely et al CCR ‘07 Everolimus 2 Soria et al Ann Oncol ‘09 Neratinib 3 Sequist et al JCO ‘10 IPI-504 4 Sequist et al JCO ‘10 Erlotinib + cetuximab Janjigian et al CCR ‘11 Dasatinib/Erlotinib + dasatinib 0/0 Johnson et al JTO ‘11 XL647 4 Miller et al PASCO ‘08 PF00299804 5 Campbell et al PASCO ‘10 PF00299804 15* (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 PF00299804 + PF02341066 P Erlotinib + AUY922 P

Not all eligibility criteria the same

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Vanderbilt-Ingram Cancer Center

11.08.10 L858R, insufficient to determine if T790M present 01.04.11 05.24.11

Acquired Resistance to Afatinib/Cetuximab

Pao, unpublished

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Modeling Acquired Resistance to BIBW-2992/Cetuximab in vivo

Politi and Pao, unpublished

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Vanderbilt-Ingram Cancer Center

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 genotype- driven clinical trial accrual

• Understanding the biology of disease can lead to

significant improvements in patient outcome and rational approaches to overcome acquired resistance

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Vanderbilt-Ingram Cancer Center

Thank you!

• To Bonnie Addario and the Bonnie Addario

Lung Cancer Foundation

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Acknowledgements – BIBW-2992/Cetuximab Acknowledgements – BIBW-2992/Cetuximab

• Pao Lab (MSKCC)

– Lucia Regales

• Yale

– Katerina Politi

• MSKCC

– Yelena Janjigian – Vincent Miller – Mark Kris – Katerina Politi

• Vanderbilt

– Leora Horn

• Boehringer-Ingelheim

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Acknowledgements

• Pao Lab

– (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

• VICC

– 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

– Ryn Miake-Lye

• MGH

– Dora Dias-Santagata – Darrell Borger –

• A. John Iafrate
• Funding

– NIH/Martell/Kleberg/Anonymous Fnd’n

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Vanderbilt-Ingram Cancer Center

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

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