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Lung Cancer 2011 PowerPoint Presentation

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Slide 1 - EML4-ALK: Oncogene Addiction Meets Personalized Medicine Thomas J Lynch, MD Jonathan and Richard Sackler Professor of Internal Medicine Director, Yale Cancer Center Physician-in-Chief, Smilow Cancer Hospital
Slide 2 - Disclosure Slide
Slide 3 - NCI SEER Cancer Statistics, WHO Fact Sheet Lung Cancer 2011 USA 190,000 cases of lung cancer 165,000 deaths 165,300 cases of NSCLC 115,000 cases of adenocarcinoma 28,500 cases of lung cancer in never smokers Global 1.4 million deaths from lung cancer
Slide 4 - Cancer 2011 Cancer is a disease caused by abnormal genes that “drive” either excessive cell growth or inadequate cell destruction Imbalance of growth and death signals leads to growth of cancer cells into tumors Tumors then proceed to grow and metastasize Understanding which genes drive which cancers will provide a “roadmap” to curing cancer
Slide 5 - MacConall LE and Garraway LA. J Clin Oncol 2010;28:5219-28. Major Classes of Genomic Alterations That Give Rise to Cancer Point mutations Copy number alterations Deletions Amplifications Translocations Examples: BCR-ABL, EML4-ALK
Slide 6 - 2011: Lung Adenocarcinoma —Multiple Molecular Subsets Courtesy William Pao Adeno Squam Large Small KRAS Unknown EGFR HER2 BRAF ALK fusion PIK3CA MEK1 ROS fusion PDGFR amp
Slide 7 - Adeno Squam Large Small KRAS Unknown EGFR HER2 ALK fusion 2011: Never Smoker Lung Adenocarcinoma (US) — Almost All Molecular Subsets Defined! Pham D et al. J Clin Oncol 2006;24(11):1700. Stephens P et al. Nature 2004;431(7008):525. Shaw AT et al. J Clin Oncol 2009;27(26):4247. Riely GJ et al. Clin Cancer Res 2008;14(18):5731.
Slide 8 - With permission from Kwak EL et al. N Engl J Med 2010;363:1693-703. Copyright © 2010 Massachusetts Medical Society.
Slide 9 - EML4-ALK Fusion Gene in NSCLC (Non-Small Cell Lung Cancer) Soda M et al. Nature 2007;448;561.
Slide 10 - Soda M et al. Nature 2007;448:561-567. EML4-ALK Is a Potent “Oncogenic” Driver Expression plasmids generated for wild-type EML4 and ALK, wild-type and mutant EML4-ALK, and v-Ras were introduced into mouse 3T3 fibroblasts. In vitro cell transformation and in vivo tumor formation in mice observed with only EML-4ALK, NPM-ALK or v-Ras expressing cells. Inhibition of ALK leads to dramatic in vivo tumor regression.
Slide 11 - PIP2 PLC-Y IP3 MEK RAS ErK S6K mTOR STAT3/5 BAD PI3K ALK Pathway 1. Inamura K et al. J Thorac Oncol 2008;3:13–17. 2. Soda M et al. Proc Natl Acad Sci USA 2008;105:19893–19897.Figure based on: Chiarle R et al. Nat Rev Cancer 2008;8(1):11–23; Mossé YP et al. Clin Cancer Res 2009;15(18):5609–5614. * Subcellular localization of the ALK fusion gene, while likely to occur inthe cytoplasm, is not confirmed.1,2 Translocation Or ALK ALK fusion protein* Tumor cellproliferation Inversion Cell survival AKT
Slide 12 - 1 Shaw AT et al. J Clin Oncol 2009;27(26):4247-4253.With permission from Bang Y et al. Proc ASCO 2010;Abstract 3. FISH = fluorescence in situ hybridization * Assay is positive if rearrangements can be detected in ≥15% of cells FISH Assay for ALK Rearrangement*
Slide 13 - Shaw AT et al. J Clin Oncol 2009;27(26):4247-53. Clinical Features and Outcome of Patients withNon-Small Cell Lung Cancer Who Harbor EML4-ALK 141 pts screened for ALK fusions, 13% positive M>F, young, non-smokers No overlap between EGFR and Kras mutants Refractory to EGFR TKIs Typical chemo responses (not increased as with EGFR mutations) Signet ring cells are commonly found in EML4-ALK-positive tumors Alice T. Shaw, Beow Y. Yeap, Mari Mino-Kenudson, Subba R. Digumarthy, Daniel B. Costa, Rebecca S. Heist, Benjamin Solomon, Hannah Stubbs, Sonal Admane, Ultan McDermott, Jeffrey Settleman, Susumu Kobayashi, Eugene J. Mark, Scott J. Rodig, Lucian R. Chirieac, Eunice L. Kwak, Thomas J. Lynch, and A. John Iafrate
Slide 14 - Shaw AT et al. J Clin Oncol 2009;27:4247–4253. Platinum-based chemotherapy EGFR TKI Patients with ALK-Positive NSCLC Do Not Appear to Respond to EGFR TKIs * WT/WT = wild type: no ALK fusion or EGFR mutation
Slide 15 - Selectivity findings Crizotinib – ALK and c-MET inhibition at clinically relevant dose levels Crizotinib – low probability of pharmacologically relevant inhibition of any other kinase at clinically relevant dose levels Cellular kinase selectivity of crizotinib Crizotinib (PF-02341066) Crizotinib Selectivity Profile 13 kinase “hits” <100x selective for c-MET
Slide 16 - Cohort 2 (n=4) 100 mg QD Cohort 3 (n=8) 200 mg QD Cohort 4 (n=7) 200 mg BID Cohort 5 (n=6) 300 mg BID Cohort 6 (n=9) 250 mg BIDMTD/RP2D Part 2: Molecularly enriched cohorts (ALK and c-MET) Enrolling patients with ALK-positive NSCLC after preliminary observation of impressive activity in a few patients Data from database April 7, 2010 Data presented for 82 patients Phase II target accrual (open): 400 Part 1: Dose escalation Crizotinib: First-in-Human/Patient Trial 1 DLT: grade 3 ALTelevation 2 DLTs: grade 3 fatigue Cohort 1 (n=3) 50 mg QD ALT = alanine aminotransferase With permission from Kwak EL et al. ASCO 2009;Abstract 3509.
Slide 17 - Pre-treatment After 2 cycles crizotinib Kwak EL et al. N Engl J Med 2010;363:1693-703. Copyright © 2010 Massachusetts Medical Society.
Slide 18 - 60 40 20 0 –20 –40 –60 –80 –100 Progressive disease Stable disease Confirmed partial response Confirmed complete response Maximum change in tumor size (%) –30% Tumor Responses to Crizotinib for Patients with ALK-positive NSCLC *Partial response patients with 100% change have non-target disease present * Kwak EL et al. N Engl J Med 2010;363:1693-703. Copyright © 2010 Massachusetts Medical Society.
Slide 19 - Median PFS Has Not Been Reached 70% of Patients in Follow-up for PFS 1.00 0.75 0.50 0.25 0.00 Progression-free survival probability 0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 Progression-free survival (months) PFS probability at 6 months: 72% (95% CI: 61, 83%)  Median follow-up for PFS: 6.4 months (25–75% percentile: 3.5–10 months) 95% Hall-Wellner confidence bands Kwak EL et al. N Engl J Med 2010;363:1693-703. Copyright © 2010 Massachusetts Medical Society. PFS
Slide 20 - Current Crizotinib Clinical Trials PROFILE 1007: NCT00932893; PROFILE 1005: NCT00932451 Key entry criteria Positive for ALK by central laboratory 1 prior chemotherapy (platinum-based) N=318 PROFILE 1007 Crizotinib 250 mg BID (N=250) administered on a continuous dosing schedule Key entry criteria Positive for ALK by central laboratory Progressive disease in Arm B of study A8081007 >1 prior chemotherapy PROFILE 1005 RANDOMIZE N=250 Crizotinib 250 mg BID (n=159) administered on a continuous dosing schedule Pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 (n=159) infused on day 1 of a 21-day cycle
Slide 21 - Molecular Profiling
Slide 22 - Kris MG et al. Proc ASCO 2011;Abstract CRA7506. Identification of Driver Mutations in Tumor Specimens from 1,000 Patients with Lung Adenocarcinoma: The Lung Cancer Mutation Consortium (LCMC)
Slide 23 - Kris MG et al. Proc ASCO 2011;Abstract CRA7506. Lung Cancer Mutation Consortium: Patients and Study Plan Use data to select therapy (erlotinib with EGFR mutation) Recommended clinical trial of agent specific for target Report to LCMC virtual database Mutational analysis CLIA-certified lab at LCMC site: KRAS, EGFR, EML4-ALK, BRAF, HER2, PIK3CA, NRAS, MEK1, AKT1, MET amplification Report to physician 1,000 patients Stage IV ECOG PS 0-2 Lung adenocarcinoma Sufficient tissue (paraffin) Informed consent Central confirmation of adenocarcinoma diagnosis (1 slide)
Slide 24 - Lung Cancer Mutation Consortium:LCMC Protocols Linked to Specific Molecular Lesions Detected (I)
Slide 25 - Lung Cancer Mutation Consortium:LCMC Protocols Linked to Specific Molecular Lesions Detected (II)
Slide 26 - Kris MG et al. Proc ASCO 2011;Abstract CRA7506. Lung Cancer Mutation Consortium: Using LCMC Data to Guide Care – MSKCC Patients 121 Enrolled 102 Multiplex mutation testing and/or FISH completed 60 (59%) Driver mutations found 31 (30%) Received therapy targeted to specific mutation 19 – Erlotinib as initial therapy 16 – Clinical trial of agent for identified mutation
Slide 27 - Conclusions In 516 tumor samples analyzed by IHC and FISH, 54% were positive for a driver mutation. Mutational status information is being used in real time to select erlotinib as initial therapy and direct patients to linked trials.
Slide 28 - Schema of personalized medicine. Originally published by the American Society of Clinical Oncology. MacConaill LE, Garraway LA. J Clin Oncol 2010;28:5219-5228.
Slide 29 - Genome Statistics 29,000 human genes Average gene 3,000 bases but wide variation exists 99.9% of our bases are exactly the same from person to person Functions are unknown for 50% of the discovered genes
Slide 30 - Advances in massively parallel technologies have dramatically reduced the cost of sequencing Originally published by the American Society of Clinical Oncology. MacConaill LE, Garraway LA. J Clin Oncol 2010;28:5219-5228. Cost Per Base of DNA (US $) 100 10 1 0.1 0.01 0.001 0.0001 1E-05 1E-06 1E-07 1E-08 1E-09 1E-10 1975 1980 1985 1990 1995 2000 2005 2010 2015 2020 2025 Years US $/base pair US $/IPS (Moore’s Law)
Slide 31 - Progress in Sequencing the Human Genome 2000 12 years 1,800,000,000 USD 2010 12 days 20,000 USD 2011 5 days 5,000 USD
Slide 32 - Yale Genome Statistics Human genome 3.2 billion bases or 3.2 Gbases September 2010 Yale sequences 1.8 trillion bases or 1,800 Gbases September 2010 Yale sequenced the equivalent of 562 human genomes! January 2011 Yale sequenced 1,300 human genomes!
Slide 33 - 2008: EGFR and Ras mutation testing routine 2009: Molecular genotyping — snapshot 2010: Whole genome sequencing begins experimentally 2012: Routine WGS available to patients Will we be ready? Post-Genome World
 

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