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Incorporating Novel Data in the Molecular Features of Lung Cancer Into the Treatment Paradigm

In association with Translational Research in Oncology. Incorporating Novel Data in the Molecular Features of Lung Cancer Into the Treatment Paradigm.

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Incorporating Novel Data in the Molecular Features of Lung Cancer Into the Treatment Paradigm

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  1. In association with Translational Research in Oncology Incorporating Novel Data in the Molecular Features of Lung Cancer Into the Treatment Paradigm Bruce Johnson, MDProfessor of Medicine Department of MedicineHarvard Medical SchoolProgram DirectorLowe Center for Thoracic OncologyDana-Farber Cancer InstituteBoston, Massachusetts This program is supported by educational grants from

  2. About These Slides • Our thanks to the presenters who gave permission to include their original data • Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent • These slides may not be published or posted online without permission from Clinical Care Options DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

  3. Program Faculty Program Director Dennis J. Slamon, MD, PhD TRIO ChairmanChief, Division of Hematology/OncologyDavid Geffen School of Medicine at UCLALos Angeles, California Faculty Bruce Johnson, MD Professor of MedicineDepartment of MedicineHarvard Medical SchoolProgram DirectorLowe Center for Thoracic OncologyDana-Farber Cancer InstituteBoston, Massachusetts

  4. Faculty Disclosures Bruce Johnson, MD, has disclosed that he has received consulting fees from Acceleron, AstraZeneca, Chugai, Genentech, Millennium, and Pfizer; has ownership interest (equity) in Celgene; and has received postmarketing royalties from Genentech for EGFR testing. Dennis J. Slamon, MD, PhD, has disclosed that he has received consulting fees from Genentech, GlaxoSmithKline, and Roche.

  5. Incorporating Novel Data in the Molecular Features of Lung Cancer Into the Treatment Paradigm • EGFR mutation testing in initial assessment and treatment of lung cancer • ALK rearrangements and their role in therapeutic selection • MET as a therapeutic target in NSCLC • Subpopulations of NSCLC patients who may be effectively treated with HDAC inhibitors

  6. Woman With Adenocarcinoma Treated With Gefitinib January 2002 October 2004

  7. Epidermal Growth Factor Receptor Mutations 13 of 14 patients with response to gefitinib had EGFR mutation Lynch TJ, et al. N Engl J Med. 2004;350:2129-2139. Paez JG, et al. Science. 2004;304:1497-1500.

  8. Incorporating Novel Data in the Molecular Features of Lung Cancer Into the Treatment Paradigm Paez JG, et al. Science. 2004;304:1497-1500.

  9. EGFR-Mutant NSCLC Cell Lines Are Dependent on EGFR for Their Survival 30 25 Control Gefitinib 20 15 Apoptosis (%) 10 5 0 A549 HI666 H3255 DFCILU-011 Tracy S, et al. Cancer Research. 2004;64:7241-7244.

  10. Gefitinib vs Combination Chemotherapy for NSCLC With Mutated EGFR • Sample size was calculated to be 320 in total (alpha = 5%, power = 80%) to confirm the superiority of arm A (HR: 0.69) • Interim analysis to investigate PFS was planned 4 mos after 200 patients were entered Gefitinib (n = 160) • NSCLC with sensitive EGFRmutations • Stage IIIb/IV • No previous chemo • PS 0-1 • 20-75 yrs of age • Primary endpoint • PFS • Secondary endpoints • OS • Response • Adverse events • QoL R Balanced: institution sex stage CBDCA + TXL (n = 160) Maemondo M, et al. N Engl J Med. 2010;362:2380-2388.

  11. Gefitinib vs Combination Chemotherapy: PFS 100 Gefitinib: median PFS 10.8 mos Chemotherapy: median PFS 5.4 mos HR: 0.30 (95% CI: 0.22-0.41; P < .001) 80 60 PFS (%) 40 Gefitinib(n = 114) Standard chemotherapy(n = 110) 20 P < .001 0 0 3 6 9 12 15 18 21 24 27 Mos Since Randomization Maemondo M, et al. N Engl J Med. 2010;362:2380-2388.

  12. Prospective Clinical Trials in Japan and China: EGFR-TKIs vs Chemotherapy *12-mo rate of PFS. 1. Mitsudomi T, et al. ASCO 2012. Abstract 7521. 2. Maemondo M, et al. N Engl J Med. 2010;362:2380-2388. 3. Zhou C, et al. Lancet Oncol. 2011; 12:735-742.

  13. Incorporating Novel Data in the Molecular Features of Lung Cancer Into the Treatment Paradigm Unknown EGFR KRAS MET Amplification ALK PIK3CA MEK1 ERBB2 Amplification ERBB2 BRAF

  14. Potential “Druggable” Molecular Targets? Emerging “Druggable” Targets in NSCLC-Squamous Subtype Lung Cancer Molecular Consortium Lung Adenocarcinomas No mutationdetected KRAS22% AKT1 NRAS EGFR17% MEK1 EML4-ALK7% MET AMP HER2 PIK3CA 2% BRAF 2% Doublemutants 3% Mutations found in 54% (280/516) Kris MG, et al. ASCO 2011. CRA7506. Johnson BE, et al. IASLC WCLC 2011. Abstract O16.01 Hammerman P, et al. IASLC WCLC 2011. Abstract PRS.1

  15. Incorporating Novel Data in the Molecular Features of Lung Cancer Into the Treatment Paradigm • EGFR mutation testing in initial assessment and treatment of lung cancer • ALK rearrangements and their role in therapeutic selection • MET as a therapeutic target in NSCLC • Subpopulations of NSCLC patients who may be effectively treated with HDAC inhibitors

  16. ALK Rearrangement in NSCLC Identification of the Transforming EML4-ALK Fusion Gene in NSCLC Soda M, et al. Nature. 2007;448:561-566.

  17. ALK Inhibitor TAE684 Affects Growth of EML4-ALK–Containing NCI-H3122 Cells in Vivo 3500 ControlErlotinibTAE684 10 mpkTAE684 25 mpk 3000 2500 2000 Mean Tumor Volume 1500 1000 500 0 0 4 7 11 15 18 21 25 28 32 35 39 42 46 49 53 Days Koivunen JP, et al. Clin Cancer Res. 2008;14:4275-4283.

  18. 72-Yr-Old Woman With ALK-Positive NSCLC Treated With Crizotinib July 2009 January 2012

  19. Survival of ALK-Positive NSCLC Patients Treated With Crizotinib 100 Median OS: not reached 1-yr OS: 74%; 2-yr OS: 54% 61% of patients in follow-up for OS with median follow-up of 18 mos 80 74% 60 OS From First Crizotinib Dose (%) From first crizotinib dose 54% 40 20 0 0 1 2 3 4 Yrs Shaw AT, et al. Lancet Oncol. 2011;12:1004-1012.

  20. Study A8081007: Phase 3 Study ofCrizotinib vs Pemetrexed or Docetaxel RANDOMIZE • Key Entry Criteria • Positive for ALK gene translocation • Brain mets allowed • 1 previous chemo(platinum based)(N = 318) Crizotinib (n = 159) Pemetrexed or Docetaxel(n = 159)

  21. 50-Yr-Old Woman With ALK-Positive NSCLC Treated With Crizotinib December 2010 May 2011

  22. 50-Yr-Old Woman With ALK-Positive NSCLC Treated With Crizotinib September 2011 April 2012

  23. ALK-Positive Timeline EML4-ALK chromosomal rearrangements reported in NSCLC[1] Crizotinib antitumor activity in advanced cancers with EML4-ALK rearrangement[4] FDA approves crizotinib for treatment of ALK+ NSCLC[6] 2011 2007 2009 2008 2010 Preclinical studies document antitumor activity of ALK inhibitors in lung cancer cell lines and xenografts[2,3] Crizotinib produces a response in 47/82 ALK+ patients and a 6-month PFS of 72%[5] 1. Soda M, et al. Nature. 2007;448:561-566. 2. McDermott U, et al. Cancer Res. 2008;68:3389-3395. 3. Koivunen JP, et al. Clin Cancer Res. 2008;14:4275-4283. 4. Kwak EL, et al. ASCO 2009. Abstract 3509. 5. Kwak EL, et al. N Engl J Med. 2010;363:1693-1703. 6. US Food and Drug Administration.

  24. Lung Adenocarcinoma: 2012 Unknown EGFR KRAS MET Amplification ALK PIK3CA MEK1 ERBB2 Amplification ERBB2 BRAF

  25. Incorporating Novel Data in the Molecular Features of Lung Cancer Into the Treatment Paradigm • EGFR mutation testing in initial assessment and treatment of lung cancer • ALK rearrangements and their role in therapeutic selection • MET as a therapeutic target in NSCLC • Subpopulations of NSCLC patients who may be effectively treated with HDAC inhibitors

  26. Incorporating Novel Data in the Molecular Features of Lung Cancer Into the Treatment Paradigm • Rationale for targeting MET • MET is amplified, mutated, overexpressed in many tumors • MET expression is associated with a worse prognosis in many cancers including NSCLC • MET activation is implicated in resistance to erlotinib/gefitinib in patients with activating EGFR mutations • MetMAb (onartuzumab): • 1-armed format designed to prevent HGF-mediated stimulation of pathway • Preclinical activity across multiple tumor models Spigel DR, et al. ASCO 2011. Abstract 7505.

  27. Phase II Randomized OAM4558g Study: Erlotinib ± MetMAb (Onartuzumab) in Stage IIIB/IV NSCLC Stratified by tobacco use, performance score, histology Primary objective • PFS in overall ITT population Other key objectives • OS in “MET-high” patients • OS in overall ITT patients Arm A Erlotinib 150 QD PO + Onartuzumab 15 mg/kg IV q3w (n = 64) Patients with stage IIIB/IV NSCLC who failed first- or second-line treatment, ECOG PS 0-2 (n = 128) Arm B Erlotinib 150 QD PO + Placebo IV q3w (n = 64) PD • Enrollment from 3/2009 to 3/2010 • Data cutoff: June 8, 2010 Addition of Onartuzumab* (n = 23) *If eligible. Spigel D, et al. ASCO 2011. Abstract 7505.

  28. Development of MET IHC as a Diagnostic • Intensity of MET staining on tumor cells scored on 0-3+ scale • Estimated that ~ 50% of patients would have “MET-high” tumors • Met by IHC was assessed after randomization • Tissue was obtained from 100% of patients • 95% of patients had adequate tissue for evaluation of MET by IHC • 54% patients had “MET-high” NSCLC 1+ 2+ 3+ “MET high” was defined prior to unblinding as ≥ 50% tumor cells with a staining intensity of 2+ or 3+ Spigel D, et al. ESMO 2010. Abstract LBA15.

  29. OAM4558g Study of Erlotinib ± MetMAb (Onartuzumab) in Stage IIIB/IV NSCLC: PFS and OS (ITT) • -23 patients from the erlotinib + placebo arm crossed over to MetMAb PFS HR: 1.09 OS HR: 0.8 Placebo + Erlotinib MetMAb + Erlotinib Placebo + Erlotinib MetMAb + Erlotinib 1.0 1.0 Median, mosHR95% CILog-rank P valueEvents, n 2.656 1.090.73-1.62.69 2.248 Median, mosHR95% CILog-rank P valueEvents, n 7.441 0.800.50-1.28.34 8.934 0.8 0.8 0.6 0.6 Probability of Progression Free Probability of Survival 0.4 0.4 0.2 0.2 0 0 0 3 6 9 12 15 18 0 3 6 9 12 15 18 21 TTP (Mos) OS (Mos) mPFS and mOS are consistent with previously reported findings in similar disease setting

  30. 1.0 1.0 0.8 0.8 0.6 0.6 0 3 6 9 12 15 18 0 3 6 9 12 15 18 21 0.4 0.4 0.2 0.2 0.0 0.0 MetMAb Plus Erlotinib in Met Dx+ Patients PFS: HR = 0.53 OS: HR = 0.37 Placebo +erlotinib 1.5 27 MetMAb +erlotinib 2.9 20 Placebo +erlotinib 3.8 26 MetMAb +erlotinib 12.6 16 Median (mo) HR (95% CI) Log-rank p-value No. of events Median (mo) HR (95% CI) Log-rank p-value No. of events 0.37 (0.19–0.72) 0.002 0.53 (0.28–0.99) 0.04 Probability of survival Probability of progression free Time to progression (months) Overall survival (months)

  31. Incorporating Novel Data in the Molecular Features of Lung Cancer Into the Treatment Paradigm • EGFR mutation testing in initial assessment and treatment of lung cancer • ALK rearrangements and their role in therapeutic selection • MET as a therapeutic target in NSCLC • Subpopulations of NSCLC patients who may be effectively treated with HDAC inhibitors

  32. Erlotinib ± Entinostat for Adv NSCLC Progressing on Prior Chemo: Phase II Open-label Extension • Primary endpoint: 4-mo PFS • Secondary endpoints: 6-mo PFS, overall best objective response • Patients > 18 yrs • of age with: • Stage IIIB/ IV NSCLC • PD after 1 or 2 previous chemo or CRT regimen • (N = 132) Erlotinib250 mg/day PO + Entinostat 10 mg/day PO Days 1, 15 of 28-day cycle (n = 67) Option to continue combination therapy If no PD Erlotinib150 mg/day PO + Placebo daily PO Days 1, 15 of 28-day cycle (n = 65) Option of crossing over to combination therapy If no PD Witta SE, et al. J Clin Oncol. 2012;[Epub ahead of print].

  33. Subpopulations of NSCLC Pts Who May Be Effectively Treated With HDAC Inhibitors EGFR Interacting Molecules ATP ErbB3 EGFR E-CAD HDACi x HDAC Snail ZEB1 ECAD AGGTG CACCT ErbB3 Courtesy of Paul Bunn, Jr, MD.

  34. Erlotinib ± Entinostat for Adv NSCLC: PFS and OS in Full Patient Population PFS OS • Erlotinib + entinostat did not improve outcomes in the overall study population vs erlotinib monotherapy Placebo, median OS: 6.7 mosEntinostat, median OS: 8.9 mos HR: 0.85 (95% CI: 0.59-1.23; P = .39 by stratified log-rank test, 2 sided) Placebo, median PFS: 1.88 mosEntinostat, median PFS: 1.97 mos HR: 0.99 (95% CI: 0.68-1.44; P = .98 by stratified log-rank test) 1.00 1.00 0.75 0.75 0.50 0.50 Probability of OS Probability of PFS 0.25 0.25 0 0 0 6 12 18 24 30 0 2 4 6 8 10 12 14 16 Mos Mos PlaceboEntinostat 36/6532/67 12/2617/31 6/143/12 2/61/8 0/32/7 1/21/2 0/00/0 0/00/0 PlaceboEntinostat 30/6524/67 16/3516/40 8/1814/22 5/100/7 0/10/1 Witta SE, et al. J Clin Oncol. 2012;[Epub ahead of print].

  35. Erlotinib ± Entinostat for Adv.NSCLC: Effect of E-cadherin Status on OS and Outcome PFS: E-cadherinHIPatients* OS: E-cadherinHI Patients† • High E-cadherin expression levels at diagnosis correlated with Increased sensitivity to HDACi/EGFR-TKI • Results warrant further biomarker-driven validation Placebo, median PFS: 1.88 monthsEntinostat, median PFS: 3.68 months HR: 0.55 (95% CI: 0.22-1.37; P = .19 by stratified log-rank test) Placebo, median OS: 5.4 mosEntinostat, median OS: 9.4 mos HR: 0.35 (95% CI: 0.13-0.92; P = .03 by stratified log-rank test, 2 sided) 1.00 1.00 0.75 0.75 0.50 PFS (probability) 0.50 Probability of OS 0.25 0.25 0 0 0 2 4 6 8 10 12 14 16 0 6 12 18 24 30 Time (months) Mos PlaceboEntinostat 7/125/14 3/54/9 1/21/4 0/01/2 0/01/1 0/00/0 0/00/0 0/00/0 PlaceboEntinostat 7/124/14 3/54/9 1/13/5 0/00/2 0/00/0 *IHC intensity score +3 †IHC intensity score +3 Witta SE, et al. J Clin Oncol. 2012;[Epub ahead of print].

  36. Subpopulations of NSCLC Patients Who May Be Effectively Treated With HDAC Inhibitor • Erlotinib plus entinostat did not improve the outcomes of patients in overall study population compared with erlotinib monotherapy • High E-cadherin expression levels at time of diagnosis are associated with a increased sensitivity to HDACi/EGFR-TKI inhibition • This may provide rationale for investigating a biomarker-driven validation study

  37. Incorporating Novel Data in the Molecular Features of Lung Cancer Into the Treatment Paradigm • EGFR mutation testing in initial assessment and treatment of lung cancer • ALK rearrangements and their role in therapeutic selection • MET as a therapeutic target in NSCLC • Subpopulations of NSCLC patients who may be effectively treated with HDAC inhibitors

  38. Go Online for More CCO Coverage of Chicago 2012! Capsule Summariesof all the key data, plusCME-certified Slidesetsexploring the clinical implications of these findings Downloadable slides: for use as a study resource or in your noncommericial presentations clinicaloptions.com/oncology

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