1. Copyright © 2011 Research To Practice. All rights reserved. Faculty Meet The Professors Oncologist and Nurse Investigators Consult on Challenging Patient Cases in Non-Small Cell Lung Cancer Saturday, November 13, 2010 6:30 AM – 8:00 AM Peabody Orlando Hotel Moderator Neil Love, MD Mark A Socinski, MD Michelle M Turner, MS, CRNP Beth Eaby-Sandy, MSN, CRNP, OCN Rogerio C Lilenbaum, MD

2. Copyright © 2011 Research To Practice. All rights reserved. Agenda Module 1 Biomarker- and Histology-Guided Treatment of NSCLC: Ms Eaby-Sandy Module 2 Current Options for Adjuvant Systemic Treatment of NSCLC: Ms Turner Module 3 The Use of EGFR Tyrosine Kinase Inhibitors in NSCLC and Relevance of EGFR Tumor Mutations: Ms Eaby-Sandy Module 4 Chemobiologic Management of Advanced NSCLC: Ms Turner Panel Discussion and Response to Audience Questions

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5. Temel JS et al. N Engl J Med 2010;363(8):733-42.

6. Copyright © 2011 Research To Practice. All rights reserved. Case 1 (Ms Eaby-Sandy) A 71-year-old woman and never smoker with EGFR wild-type metastatic NSCLC receives six cycles of pemetrexed/carboplatin/ bevacizumab followed by maintenance pemetrexed/bevacizumab but then experiences disease progression. Assay of the tumor is positive for the EML4-ALK mutation, and she is currently participating in a clinical trial of crizotinib.

7. Copyright © 2011 Research To Practice. All rights reserved.

9. KRAS Unknown EGFR HER2 BRAF ALK fusion PIK3CA MEK1 ROS fusion PDGFR amp Adeno Squam Large Small Courtesy of William Pao, AAAS-FDLI Colloquium on Personalized Medicine, 2009. Lung Cancer Histologic and Molecular Subsets

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14. Sandler A et al. N Engl J Med 2006;355:2542-50. Reck M et al. J Clin Oncol 2009;27(8):1227-34. Crinò L et al. Lancet Oncol 2010;11:733-40.

15. Copyright © 2011 Research To Practice. All rights reserved. Faculty Meet The Professors Oncologist and Nurse Investigators Consult on Challenging Patient Cases in Non-Small Cell Lung Cancer Saturday, November 13, 2010 6:30 AM – 8:00 AM Peabody Orlando Hotel Moderator Neil Love, MD Mark A Socinski, MD Michelle M Turner, MS, CRNP Beth Eaby-Sandy, MSN, CRNP, OCN Rogerio C Lilenbaum, MD

16. Copyright © 2011 Research To Practice. All rights reserved.

17. Patel JD et al. J Clin Oncol 2009;27(20):3284-9.

18. Copyright © 2011 Research To Practice. All rights reserved. Patel JD et al. J Clin Oncol 2009;27(20):3284-9. Efficacy Endpoints Median progression-free survival7.8 mos Median overall survival14.1 mos Objective response rate55% Select Adverse EventsGrade 3Grade 4 Diverticulitis 1 6%2% Thrombocytopenia0%8% Neutropenia4%0% Venous thrombosis4%2% 1 One case of Grade IV diverticulitis with bowel perforation Pem/Carbo/Bev with Maintenance Pem/Bev as First-Line Therapy for Nonsquamous NSCLC (N = 49)

19. Copyright © 2011 Research To Practice. All rights reserved. POINTBREAK Phase III Trial Pemetrexed (Pem)/Carboplatin (C)/Bevacizumab (Bev)  Maintenance Pem/Bev versus Paclitaxel/C/Bev  Maintenance Bev in Patients with NSCLC www.ClinicalTrials.gov, November 2010. Eligibility Stage IIIB or IV nonsquamous NSCLC R Pemetrexed + Carboplatin + Bevacizumab Target accrual = 900 Paclitaxel + Carboplatin + Bevacizumab Maintenance Pemetrexed + Bevacizumab Maintenance Bevacizumab

20. Copyright © 2011 Research To Practice. All rights reserved. Pirker R et al. Lancet 2009;373(9674):1525-31.

21. Copyright © 2011 Research To Practice. All rights reserved. Pirker R et al. Lancet 2009;373(9674):1525-31. Efficacy Parameter Cetux + CV (n=557) CV (n=568) Hazard Ratio p-value Median overall survival All patients Nonsquamous Squamous 11.3 mos 12.0 mos 10.2 mos 10.1 mos 10.3 mos 8.9 mos 0.87 0.94 0.80 0.044 Median progression-free survival4.8 mos 0.940.39 Overall response rate36%29%—0.010 FLEX: Efficacy Outcomes EGFR expression-positive by IHC (>1 positive tumor cell)

22. Copyright © 2011 Research To Practice. All rights reserved. Case 1 (Ms Eaby-Sandy) A 71-year-old woman and never smoker with EGFR wild-type metastatic NSCLC receives six cycles of pemetrexed/carboplatin/ bevacizumab followed by maintenance pemetrexed/bevacizumab but then experiences disease progression. Assay of the tumor is positive for the EML4-ALK mutation, and she is currently participating in a clinical trial of crizotinib.

23. Copyright © 2011 Research To Practice. All rights reserved. Kwak EL et al. N Engl J Med 2010;363(18):1693-703.

24. Copyright © 2011 Research To Practice. All rights reserved. Crizotinib Inhibition of the ALK Signaling Pathway Bang Y et al. Proc ASCO 2010;Abstract 3. ALK Tumor cell proliferation Cell survival PI3K BAD AKT STAT3/5 mTOR S6K RAS MEK ErK PLC- Y PIP 2 IP 3 Crizotinib

25. Copyright © 2011 Research To Practice. All rights reserved. Best Response to Crizotinib in Patients with ALK-Positive Advanced NSCLC Kwak EL et al. N Engl J Med 2010;363(18):1693-703. © 2010. Massachusetts Medical Society. All rights reserved. Patient No. Percent Change from Baseline Disease progression Stable disease Partial response Complete response -30%

26. Copyright © 2011 Research To Practice. All rights reserved. Grade 3/4 Adverse Events Adverse Event (AE) Grade 3Grade 4 ALT elevation5%1% AST elevation 6%0% Lymphopenia2%0% Hypophosphatemia1%0% Neutropenia1%0% Hypoxia1%0% Pneumonitis1%0% Pulmonary emoblism1%0% Kwak EL et al. N Engl J Med 2010;363(18):1693-703.

27. Copyright © 2011 Research To Practice. All rights reserved. Case 1 (Ms Eaby-Sandy) A 71-year-old woman and never smoker with EGFR wild-type metastatic NSCLC receives six cycles of pemetrexed/carboplatin/ bevacizumab followed by maintenance pemetrexed/bevacizumab but then experiences disease progression. Assay of the tumor is positive for the EML4-ALK mutation, and she is currently participating in a clinical trial of crizotinib.

28. Copyright © 2011 Research To Practice. All rights reserved. Case 2 (Ms Turner) A 61-year-old man with Stage II NSCLC received adjuvant docetaxel/cisplatin and bevacizumab on the ECOG-E1505 clinical trial and completed one year of maintenance bevacizumab in early 2010. The patient is now found on imaging to have a solitary metastasis in the adrenal gland.

29. Copyright © 2011 Research To Practice. All rights reserved.

34. Chemotherapy Adjuvant chemotherapy (vinorelbine + cisplatin OR docetaxel + cisplatin OR gemcitabine + cisplatin OR pemetrexed + cisplatin) Chemotherapy + bevacizumab Adjuvant chemotherapy (as described above) with bevacizumab on d1 q3wk x 1y Eligibility (Target accrual = 1,500) Resection within the past six to 12 weeks ECOG PS 0 - 1 No history of CVA or TIA History of myocardial infarction or angina acceptable if no evidence of active disease within the past 12 months * Patients are stratified according to type of chemotherapy, stage, histology and gender. ECOG-E1505: A Phase II Study of Adjuvant Chemotherapy with or without Bevacizumab for Stage IB-IIIA NSCLC R*R* www.ClinicalTrials.gov, November 2010.

35. Copyright © 2011 Research To Practice. All rights reserved.

37. Bria E et al. Lung Cancer 2009;63(1):50-7.

38. Copyright © 2011 Research To Practice. All rights reserved. Magnitude of Benefit of Adjuvant Chemotherapy for NSCLC: A Meta-analysis of Randomized Clinical Trials Meta-analysis of 12 Phase III trials (from 1994-2007), and an individual patient meta-analysis were conducted to determine if cisplatin-based chemotherapy improves survival over surgery (seven subpopulations examined, n = 7,334). Absolute benefit and the number of patients treated for one patient to benefit (NNT) were evaluated for magnitude of benefit. Bria E et al. Lung Cancer 2009;63(1):50-7. Results from Pooled Data Adjuvant Chemotherapy vs. Surgery OnlyRelative BenefitAbsolute BenefitNNT Overall survival (n = 7,334)7%-12%2.5%-4.1%24-39 Disease-free survival (n = 6,396)11%-12%4.2%-4.6%22-24

39. Copyright © 2011 Research To Practice. All rights reserved. What patient education information do you consider essential in a patient with non-small cell lung cancer about to begin treatment with…. Adjuvant cisplatin/paclitaxel

40. Copyright © 2011 Research To Practice. All rights reserved. Pfannschmidt J, Dienemann H. Lung Cancer 2010;69(3):251-8.

41. Copyright © 2011 Research To Practice. All rights reserved. Surgical Treatment of Oligometastatic NSCLC: Analysis of Retrospective Cases Series Site of Metastasis5-Year Survival Satellite nodules28% Ipsilateral nodules21% Brain metastasis11% - 30% Adrenal metastasis 26% Pfannschmidt J, Dienemann H. Lung Cancer 2010;69(3):251-8.

42. Copyright © 2011 Research To Practice. All rights reserved. Case 3 (Ms Eaby-Sandy) A 71-year-old man with EGFR-mutated metastatic NSCLC and limited family support begins front-line therapy with erlotinib 150 mg daily. Significant side effects require dose reduction to 100 mg, which he is now tolerating well.

43. Copyright © 2011 Research To Practice. All rights reserved.

45. Epidermal Growth Factor Receptor (EGFR) Mutations

46. Copyright © 2011 Research To Practice. All rights reserved. EGFR Signaling Adapted by permission from Macmillan Publishers Ltd. (Arteaga CL. HER3 and mutant EGFR meet MET. Nat Med 13:675-7), copyright 2007.Nat Med

47. Copyright © 2011 Research To Practice. All rights reserved. Adapted by permission from Macmillan Publishers Ltd. (Arteaga CL. HER3 and mutant EGFR meet MET. Nat Med 13:675-7), copyright 2007.Nat Med EGFR-TKI Mechanism of Action

48. Copyright © 2011 Research To Practice. All rights reserved. Adapted by permission from Macmillan Publishers Ltd. (Arteaga CL. HER3 and mutant EGFR meet MET. Nat Med 13:675-7), copyright 2007.Nat Med Resistance Mechanisms

49. Copyright © 2011 Research To Practice. All rights reserved. Mok TS et al. N Engl J Med 2009;361(10):947-57.

50. Copyright © 2011 Research To Practice. All rights reserved. Efficacy of Gefitinib vs C/P in East Asian Patients with NSCLC Objective Response Rate (ORR) GefitinibC/PP-value Intent-to-treat population (n = 609; 608) 43.0%32.2%<0.001 EGFR mutation-positive (n = 132; 129)71.2%47.3%<0.001 EGFR mutation-negative (n = 91; 85)1.1%23.5%0.001 Progression-Free Survival (PFS)Hazard RatioP-value Intent-to-treat population0.74<0.001 EGFR mutation-positive0.48<0.001 EGFR mutation-negative2.85<0.001 Mok TS et al. N Engl J Med 2009;361(10):947-57.

51. Copyright © 2011 Research To Practice. All rights reserved. www.ClinicalTrials.gov, November 2010. Wakelee H et al. Oncologist 2007;12(3):331-7. RADIANT Trial: A Phase III Study of Erlotinib or Placebo with or without Adjuvant Chemotherapy for Patients with Resected, EGFR-Positive NSCLC Eligibility Resected Stage IB to IIIA EGFR-positive by FISH or IHC  4 cycles of platinum-based chemotheraphy (optional) Erlotinib 150 mg daily x 2 years Observation Protocol IDs: OSI-774-302, NCT00373425 Target accrual: 945 (Open) * Stratified by histology (squamous versus other), gender, age, EGFR status, smoking status and adjuvant chemotherapy 2:1 R*R*

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53. Skin Rash from Tyrosine Kinase Inhibitors Ricciardi S et al. Clin Lung Cancer 2009;10(1):28-35. Most frequent dermatologic side effect reported is acneiform eruption. Affects mainly face, upper chest and/or back Also known as acne, acneiform skin reaction/rash, follicular rash and maculopapular skin rash.

54. Copyright © 2011 Research To Practice. All rights reserved. Case 3 (Ms Eaby-Sandy) A 71-year-old man with EGFR-mutated metastatic NSCLC and limited family support begins front-line therapy with erlotinib 150 mg daily. Significant side effects require dose reduction to 100 mg, which he is now tolerating well.

55. Copyright © 2011 Research To Practice. All rights reserved. Incidence of Acneiform Eruption During Therapy with Epidermal Growth Factor Receptor Inhibitors Ricciardi S et al. Clin Lung Cancer 2009;10(1):28-35. EGFR InhibitorIncidence of Acneiform Eruption Erlotinib79% (10.4% >Grade 3) Cetuximab80% (18% >Grade 3) Gefitinib53% (1.6% >Grade 3) Panitumumab70%-100% (<10% severe) Matuzumab64% (0% >Grade 3)

56. Copyright © 2011 Research To Practice. All rights reserved. Case 3 (Ms Eaby-Sandy) A 71-year-old man with EGFR-mutated metastatic NSCLC and limited family support begins front-line therapy with erlotinib 150 mg daily. Significant side effects require dose reduction to 100 mg, which he is now tolerating well.

57. Copyright © 2011 Research To Practice. All rights reserved. Case 4 (Ms Turner) A 71-year-old man underwent concurrent docetaxel/carboplatin and radiation therapy in 2003 for localized NSCLC with positive margins. A biopsy of new pulmonary nodules in 2008 showed poorly differentiated adenocarcinoma. Paclitaxel/carboplatin/bevacizumab was administered but had to be discontinued because of toxicity issues.

58. Copyright © 2011 Research To Practice. All rights reserved. What patient education information do you consider essential in a patient with non-small cell lung cancer about to begin treatment with…. carboplatin/pemetrexed/bevacizumab

59. Copyright © 2011 Research To Practice. All rights reserved. Case 4 (Ms Turner) A 71-year-old man underwent concurrent docetaxel/carboplatin and radiation therapy in 2003 for localized NSCLC with positive margins. A biopsy of new pulmonary nodules in 2008 showed poorly differentiated adenocarcinoma. Paclitaxel/carboplatin/bevacizumab was administered but had to be discontinued because of toxicity issues.

60. Copyright © 2011 Research To Practice. All rights reserved. Eligibility Unresectable nonsquamous Stage III NSCLC Standard-dose radiotherapy + chemo  consolidation chemo www.ClinicalTrials.gov, November 2010. RTOG-0617: A Phase III Trial of High-Dose (74 Gy) or Standard-Dose (60 Gy) Radiation Therapy Plus Chemotherapy High-dose radiotherapy + chemo  consolidation chemo Standard-dose radiotherapy + chemo and cetuximab  consolidation chemo and cetuximab High-dose radiotherapy + chemo and cetuximab  consolidation chemo and cetuximab R

61. Copyright © 2011 Research To Practice. All rights reserved. Randomized, Double-Blind, Placebo-Controlled Multicenter Phase II Study of the Efficacy and Safety of Apricoxib in Combination With Either Docetaxel or Pemetrexed in NSCLC Apricoxib 100 mg PO qd + docetaxel or pemetrexed q3 wks Placebo PO qd + docetaxel or pemetrexed q3 wks Protocol IDs: UMGCC 0822 (Open)Target Accrual: 130 Eligibility: Stage IIIb (pleural effusion) or IV NSCLC; progression after 1 prior platinum-based chemo; received prior erlotinib R www.ClinicalTrials.gov, November 2010.

62. Copyright © 2011 Research To Practice. All rights reserved.