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Molecular Profiling and Patient Selection

Molecular Profiling and Patient Selection. Focus on Thoracic Surgery. Marker Driven Pathology Reports - Are they Useful? November 16 , 2012 Bruce E. Johnson, MD Dana-Farber Cancer Institute and Brigham and Women’s Hospital. Derive Post-Marketing Royalties from EGFR Mutation Testing

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Molecular Profiling and Patient Selection

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  1. Molecular Profiling and Patient Selection Focus on Thoracic Surgery Marker Driven Pathology Reports - Are they Useful? November 16 , 2012 Bruce E. Johnson, MD Dana-Farber Cancer Institute and Brigham and Women’s Hospital

  2. Derive Post-Marketing Royalties from EGFR Mutation Testing Paid Consultant to AstraZeneca, Genentech, Pfizer, Chugai, Millenium, Sanofi, and Transgenomics Conflicts

  3. Marker Driven Pathology Reports Role in Adjuvant Therapy • Magnitude of Survival Benefit with Adjuvant Chemotherapy • Potential Markers to Identify Candidates for Adjuvant Chemotherapy • Future Strategies to Improve the Efficacy of Adjuvant Chemotherapy

  4. Woman with Adenocarcinoma Treated with Gefitinib with Exon 19 EGFR Deletion Mutation Woman with a T1bN2MO Squamous Cell Carcinoma of the Lung July 2012

  5. Woman with Adenocarcinoma Treated with Gefitinib with Exon 19 EGFR Deletion Mutation Woman with a T1bN2MO Squamous Cell Carcinoma of the Lung • LEVEL 4R (including FSA): METASTATIC SQUAMOUS CELL CARCINOMA, present in one lymph node (see NOTE). • B. TRISEGMENTAL RESECTION (including FSB): SQUAMOUS CELL CARCINOMA moderately differentiated (2.3 cm in greatest dimension). Tumor does not invade visceral pleura (see NOTE). Bronchial margin of resection is negative for tumor. The tumor is 3.7 cm from the nearest bronchial resection margin. Lymphovascular invasion in lung is identified. Adjacent lung parenchyma with emphysematous change. One (1) lymph node with no tumor present (peribronchial). AJCC Classification (7th edition): pT1b N2 (all parts). July 2012

  6. Lung Adjuvant Cisplatin Evaluation • Meta-analysis reported 2008 • 5 Trials, 4584 patients • Median follow-up more than 5 years • 80% male, median age 59 • Stage IA 8%, IB 30%, II 35%, III 27% • Squamous 49%, Adeno 39%, Other 12% Pignon et al J Clin Oncol. 2008 26:3552

  7. Lung Adjuvant Cisplatin Evaluation PooledAnalysis 5 RCTs (4,584 patients) ALPI BLT IALT JBR.10 ANITA Pignon et al J ClinOncol. 2008 26:3552

  8. Chemotherapy Regimens Lung Adjuvant Cisplatin Evaluation (cisplatin + vinorelbine) Pignon et al J ClinOncol. 2008 26:3552

  9. Chemotherapy Regimens Lung Adjuvant Cisplatin Evaluation (cisplatin + vinorelbine) Pignon et al J ClinOncol. 2008 26:3552

  10. Marker Driven Pathology Reports Role in Adjuvant Therapy • Magnitude of Survival Benefit with Adjuvant Chemotherapy • Potential Markers to Identify Candidates for Adjuvant Chemotherapy • Future Strategies to Improve the Efficacy of Adjuvant Chemotherapy

  11. Marker Driven Pathology Reports Role in Adjuvant Therapy Olaussen et al 2006 355:983

  12. Marker Driven Pathology Reports Role in Adjuvant Therapy • Subset of patients (N = 761) from the 1867 Participating in the International Adjuvant Lung Cancer (IALT) trial. • DNA repair protein expression (XPF, BRCA1, ERCC1, MSH2, p53, PARP1, and ATM) was assessed by immunohistochemistry • 5-year overall survival used binary cut-offs (H score low/high expression). Pierceall et al Ann Oncol. 2012 23:2245

  13. Marker Driven Pathology Reports Role in Adjuvant Therapy Pierceall et al Ann Oncol. 2012 23:2245

  14. Marker Driven Pathology Reports Role in Adjuvant Therapy • Magnitude of Survival Benefit with Adjuvant Chemotherapy • Potential Markers to Identify Candidates for Adjuvant Chemotherapy • Future Strategies to Improve the Efficacy of Adjuvant Chemotherapy

  15. Predictive Markers in Adenocarcinomaof Lung No known genotype

  16. Epidermal Growth Factor Receptor Mutations Paez et al. 2004 13 of 14 Patients with Response to Gefitinib Had EGFR Mutation Lynch et al 2004

  17. Gefitinib versus Combination Chemotherapy Maemondo M NEJM 362:2380, 2010

  18. Progression-Free Survival of NSCLC Patients Treated with Gefitinib versus Combination Chemotherapy Hazard Ratio 0.30; P<0.001 Median 10.8 months for gefitinib Median 5.4 months for chemo Maemondo M NEJM 362:2380, 2010

  19. ALK Rearrangement Soda M, et al. Nature. 2007;448(7153):561-566. 19

  20. 50 YO woman with ALK+ NSCLC Treated with Crizotinib September 2011 September 2012

  21. Efficacy of Crizotinib in Patients with EML4-ALK Rearrangements Kwak et al. 2010 363(18) 1693-1703

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

  23. Primary Endpoint: PFS by Independent Radiologic Review (ITT Population) 100 80 60 Probability of survival without progression (%) 40 Shaw et al ESMO 2012 20 0 0 5 10 15 20 25 Time (months) No. at risk CrizotinibChemotherapy 173 93 38 11 2 0 174 49 15 4 1 0

  24. Marker Driven Pathology Reports Role in Adjuvant Therapy Screen >7000 Patients for EGFR Mutations and ALK Rearrangements Randomize Patients with EGFR mutations to Erlotinib versus Placebo Randomize Patients with ALK Rearrangements to Crizotinib versus Placebo

  25. Marker Driven Pathology Reports Role in Adjuvant Therapy • Magnitude of Survival Benefit with Adjuvant Chemotherapy • Potential Markers to Identify Candidates for Adjuvant Chemotherapy • Future Strategies to Improve the Efficacy of Adjuvant Chemotherapy

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