This presentation based on how will you present your case in front of ODAC meeting with FDA. It shows ability to find the data, guidances,designing of clinical trials, compilation, strategies to make drug readily available by its ability to meet designations like fast track, priority review,orphan drug designation etc.

1. Investigative Drugpresentation toMassachusetts College of Pharmacy and Health ScienceOncologic Drugs Advisory CommitteeApril 12, 2010

2. A review of Tarceva® and a proposal for anInvestigative Drugthird line monotherapy, for patients with advanced NSCLC

4. Patients who live beyond the first stages of the disease have few therapeutic options

5. Many available therapeutic options are toxic intravenous therapies

6. Tarceva® is an oral monotherapeutic option for second and third stage NSCLC

8. http://www.cancer.org/docroot/CRI/content/CRI_2_2_1x_How_Many_People_Get_Non-small_Cell_Lung_Cancer.asp?rnav=cri http://seer.cancer.gov/faststats/selections.php?#Output Lung Cancer is the leading cancer killer in United States Leading cancer killer in men and women in United States (29% of all cancer deaths) 219,440 new cases of lung cancer in 2009 159,390 deaths from lung cancer 5 year survival rate in patients with lung cancer is less than 15.2%

9. Types of lung cancer The two main types of lung cancer are: Small Cell Lung Cancer (SCLC) about 10% of all lung cancer patients are of these type Non Small Cell Lung Cancer (NSCLC) about 80-90% of all lung cancer patients are of these type Other types of tumors include Lung Carcinoid Tumors, whichare slow growing and can be cured by surgery. http://www.cancer.org/docroot/CRI/content/CRI_2_2_1x_What_Is_Non-small_Cell_Lung_Cancer.asp?sitearea=

10. Types of Non Small Cell Lung Cancer (NSCLC) The 3 sub-types of NSCLC differ in size, shape, and chemical composition. Adenocarcinoma: About 40% of lung cancers. Usually found in the outer part of the lung Squamous cell carcinoma: About 25% to 30% of all lung cancers are this kind. Usually develops in the middle of the lungs, near a bronchus. Large-cell (undifferentiated) carcinoma: About 10% to 15% of lung cancers are this type. It can develop in any part of the lung. http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/patient

11. Symptoms of NSCLC Persistent cough Trouble breathing Chest discomfort Wheezing Streaks of blood in sputum Hoarseness Loss of appetite Inexplicable weight loss Fatigue http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/patient

12. How is NSCLC diagnosed? Physical exams Laboratory tests Chest x-ray CT scan PET scan Sputum Cytology Fine-needle Aspiration (FNA) http://emedicine.medscape.com/article/279960-diagnosis

13. Stages of NSCLC Based on severity of Lung Cancer, it is assigned by different stages. Staging will help determine whether cancer has spread within lungs or in the other parts of the body. Stage 0 http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/Patient/page4

14. Stages of NSCLC Based on severity of Lung Cancer, it is assigned by different stages. Staging will help determine whether cancer has spread within lungs or in the other parts of the body. Stage 0 Stage IA & IB http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/Patient/page4 http://www.avastin.com/avastin/patient/lung/learn/stages/index.m

15. Stages of NSCLC Based on severity of Lung Cancer, it is assigned by different stages. Staging will help determine whether cancer has spread within lungs or in the other parts of the body. Stage 0 Stage IA & IB Stage IIA & IIB http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/Patient/page4 http://www.avastin.com/avastin/patient/lung/learn/stages/index.m

16. Stages of NSCLC Based on severity of Lung Cancer, it is assigned by different stages. Staging will help determine whether cancer has spread within lungs or in the other parts of the body. Stage 0 Stage IA & IB Stage IIA & IIB Stage IIIA & IIIB http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/Patient/page4 http://www.avastin.com/avastin/patient/lung/learn/stages/index.m

17. Stages of NSCLC Based on severity of Lung Cancer, it is assigned by different stages. Staging will help determine whether cancer has spread within lungs or in the other parts of the body. Stage 0 Stage IA & IB Stage IIA & IIB Stage IIIA & IIIB Stage IV http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/Patient/page4 http://www.avastin.com/avastin/patient/lung/learn/stages/index.m

18. Treatment Approaches for NSCLC Surgery Radiation Therapy Chemotherapy Targeted Therapy Laser Therapy Photodynamic Therapy Cryosurgery Electrocautery http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/Patient/page4

19. Drug approved for NSCLC treatment Alitma® (pemetrexed) Avastin® (bevacizumab) Gemzar® (gemcitabine) Iressa® (gefitinib) Photofrin® (porfimer) Taxol® (paclitaxel) Taxotere®(docetaxel) Tarceva® (erlotinib) http://www.empr.com/non-small-cell-lung-cancer-nsclc-drug-treatments/article/123617/

20. Tarceva® (erlotinib) – the first EGFR oral targeted agent for NSCLC http://www.roche.com/investors/ ir_update/inv-update-2008-11-14.htm

21. Tarceva® indication Tarceva® is prescribed for patients with advanced-stage non-small cell lung cancer (NSCLC) who have received at least one prior chemotherapy regimen http://www.tarceva.com/patient/taking/how_to_take.jsp

22. Mechanism of Action of Tarceva® Pharmacology Category : Human Epidermal Growth Factor Receptor Type 1/ Epidermal Growth Factor Receptor (HER1/EGFR) tyrosine kinase inhibitor MOA Inhibits the intracellular phosphorylation of tyrosine kinase associated with the epidermal growth factor receptor (EGFR). http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021743s015lbl.pdf http://www.betapharmagroup.com/site/image/egfr.png

23. Chemistry of Tarceva® Active ingredient: Erlotinib hydrochloride Chemical Name: N-(3-ethylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine Chemical Structure

26. Phase II Clinical Trial treatment and population Treatment was taken until disease progression or unmanageable toxicity Median age of the study was 62 years, with 74% of the patients historically smokers 60% of patients were females and 91% were Caucasian http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_StatR.PDF

27. Phase II Clinical Trial showed improved response rates 2 of the patients had complete response (CR) 5 had partial response (PR) The objective response rate was 12.3% (95% CI:5.1-23.7 %) The median overall survival was 8.4 months (95% CI:4.8-13.9 months) http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_StatR.PDF

28. Phase III Clinical Trial Study BR.21 Multicenter, international, randomized, placebo-controlled, double blinded clinical study Designed to compare Tarceva® to a placebo Enrolled 731 patients Conducted in 86 study centers in 17 countries Sites locations included: 1 in USA 27 in Canada 58 (rest of the world) http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_StatR.PDF

29. Study BR.21 requirements Patients ≥ 18 years old with histologically or cytologically confirmed diagnosis of incurable Stage IIIB or IV NSCLC Received one but no more than two prior treatment (one of the treatment had to be a combination of chemotherapy) Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3 Adequate renal and hepatic functions http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_StatR.PDF http://ecog.dfci.harvard.edu/general/perf_stat.html

31. Increase in dosage not permitted

32. Treatment continued until progression of disease or intolerable toxicityhttp://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_StatR.PDF

33. The objective endpoint of the study was to compare the Overall Survival (OS) between the two study arm (Tarceva® vs. Placebo) Secondary endpoints included: Progression-free-survival (PFS) Response Rate Response Duration Quality of life (QoL) OS was BR.21 trial primary endpoint http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_StatR.PDF

34. Tarceva® reduced the risk of death by 27% Efficacy was evaluated by: Periodic assessments of survival and quality of life (QoL) scores Tumor measurement evaluated every 8 weeks Safety assessed in every 4 weeks http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_StatR.PDF

35. Tarceva® efficacy results Eastern Cooperative Oncology Group (ECOG) http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_admincorres.PDF

36. Tarceva® response rate on patients with positive EGFR Evaluation of positive epidermal growth factor receptor (EGFR) (defined as 10% of cells sustaining for EGFR) and negative EGFR Status was determined in 33% patients (238) Tarceva® response rate on positive EGFR was 12% and 3% on negative EGFR http://www.egfr.org/ http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_admincorres.PDF

37. Saturn Study evaluated the effect of EGFR protein and clinical outcome A post marketing Phase III study to evaluate the relationship between EGFR protein expression and clinical outcome: Compared Tarceva® and Placebo as maintenance treatment of patients with locally advanced or metastatic NSCLC following 4 cycles of platinum based chemotherapy 889 patients enrolled in a global, multicenter, randomized, double blinded, placebo-controlled study http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM193921.pdf

38. Saturn divided into 2 study periods The chemotherapy run period Patients received first line platinum based doublet chemotherapy The study period Patients received blinded Tarceva® or Placebo 438 patients received Tarceva ™ 451 patients received a placebo http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM193921.pdf

39. Saturn study requirements Patients with locally advanced Stage IIIB or metastatic (Stage IV) NSCLC Submission of formalin-fixed, paraffin-embedded tumor tissue samples within 3 weeks of starting chemotherapy ECOG performance status of 0-1 before and after chemotherapy Adequate hematopoietic and end-organ function http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM193921.pdf http://ecog.dfci.harvard.edu/general/perf_stat.html

40. PFS was Saturn study primary endpoint The primary objective endpoint for the study was progression-free-survival (PFS) —comparing Tarceva® to Placebo Secondary endpoint was Overall Survival (OS) http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM193921.pdf

41. Saturn study met primary endpoint Demonstrated a significant improvement in assessed PFS in the overall population and with EGFR IHC-positive tumors PFS Improvements 41% in overall population 45% in EGFR IHC-positive population Median PFS was 11.1 weeks in the placebo arm vs. 12.3 weeks in the Tarceva® arm http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM193921.pdf

42. Saturn study time to event results http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM193921.pdf

43. Most adverse events associated with Tarceva® include rash and diarrhea, which are manageable Tarceva® safety concerns

44. A well tolerated, oral agent to maintain tumor regression from chemotherapy and to prolong time to progression for patients with NSCLC Alternative to intravenous maintenance therapy with a high toxicity profile Tarceva® provides an unmet medical need

45. Tarceva® approval process

46. Tarceva® qualifies for Fast Track status For use with a serious disease non small cell lung cancer (NSCLC) Positively impacts survival, quality of life Inhibits disease progression Fills an unmet medical need by showing superior effectiveness to available therapies First EGFR oral targeted agent for NSCLC http://www.roche.com/investors/ ir_update/inv-update-2008-11-14.htm

47. Tarceva® qualifies for a Rolling Review Fast Track status Select group of innovative therapies FDA began reviewing Tarceva®components in January 2004 and ended in July 2004 http://www.accessmylibrary.com/coms2/summary_0286-20139832_ITM, “OSI, Genentech, Roche begin filing Tarceva rolling NDA”, BioWorld Week January 26, 2004

49. Significant treatment advancement

50. Initial submissionhttp://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/SpeedingAccesstoImportantNewTherapies/ucm128291.htm

51. From FDA on November 18, 2004 for treatment of NSCLC after failure of at least 1 chemotherapy regimen Tarceva® approved under the Pilot Program for Continuous Marketing Applications Tarceva® demonstrated an increase in overall survival in advanced NSCLC patients Tarceva® receives approval http://www.osip.com/tarceva

52. Tarceva® application accepted for an sNDA On June 15, 2009, as a first-line maintenance therapy for patients with locally advanced or metastatic NSCLC Acceptance based on double-blind trial, SATURN Delivers effectiveness comparable to chemotherapy Significantly improves QOL without the toxic side effects of chemotherapy such as nausea and vomiting http://www.roche.com/investors/ ir_update/inv-update-2008-11-14.htm

53. Tarceva® reviewed by ODAC Oncologic Drugs Advisory Committee (ODAC) voted against recommending Tarceva® as a “switch” maintenance therapy FDA extended the review action on the sNDA to April 18, 2010 http://cancergrace.org/lung/2009/12/16/odac-says-no-to-maint-erlotinib/ http://www.pharmastrategyblog.com/2010/01/fda-extends-review-period-for-tarceva-application-for-firstline-maintenance-use-in-advanced-nonsmall.html

55. Inhibits tumor growth and blood supply

56. Oral monotherapyhttp://www.nelm.nhs.uk/en/NeLM-Area/News/493764/493843/493847 3-23-10

57. Investigative Drug: Proposed Indication Third line therapy for advanced NSCLC Patients must have been previously treated with 2 prior chemotherapeutic agents Tarceva® is currently the only approved drug for third line therapy http://www.nelm.nhs.uk/en/NeLM-Area/News/493764/493843/493847 3-23-10

59. Study done by Dr. Nicholas Girardi at Centre Hospitalier Universitaire de Besançon in France between 2000-2006

60. 613 patients received first line chemotherapy for advanced NSCLC

61. 173 (28%) went on to receive both second and third line therapyhttp://cancergrace.org/lung/2009/11/24/who-benefits-from-third-line-treatment-for-advanced-nsclc 3-15-10

62. Center for Drug Evaluation & Research (CDER) Office of Oncology Drug Products (OODP) Director: Richard Pazdur, MD Associate for Director of Regulatory Affairs: Glen Jones, Ph. D Division of Drug Oncology Products (DDOP) Director: Robert Justice, MD Deputy Director: Ann Farrell, MD http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm093910.htm5 April 2010

63. CDER Approval Statistics 26 new drugs in 2009 7 biologics 5 priority review http://www.fiercebiotech.com/story/fda-approvals-2009/2010-01-25 4-5-10

64. OODP Statistics 9 total oncology drugs in 2009 3 Accelerated Approval 53 oncology indications approved from July 2005 – December 2007 60 applications in total reviewed 18 indications for new drugs 35 indications for previously approved drugs 9 drugs received accelerated approval 25% of 53 new indications based on overall survival http://www.drugs.com/news/fda-cancer-approval-rate-highlighted-jnci-22743.html 4-4-10

65. Oncologic Drugs Advisory Committee (ODAC) 13 voters One non-voter General, pediatric, hematologic, immunologic and several other oncology specialties represented L.T. Nicole Vesely, Pharm. D., R.Ph., Desingated Federal Official http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/default.htm 4-4-10

66. Previous ODAC meetings March 2003 meeting with Astra Zeneca regarding Iressa™ Confirmatory trial fails to support initial accelerated approval December 2009 meeting with OSI Pharmaceuticals, Inc. regarding Tarceva® Inclusion of EGFR-negative population “Switch Maintenance Therapy” rejected http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4095B2_01_01-AstraZeneca-Iressa.pdf http://cancergrace.org/lung/2009/12/16/odac-says-no-to-maint-erlotinib/ 4-4-10

67. http://www.clinicaltrials.gov 3-20-10

70. Focus on dosing

71. Major focus on hematological effect on patients

72. All regimens continue until disease has progressed or severe toxicity has presentedhttp://www.nelm.nhs.uk/en/NeLM-Area/News/493764/493843/493847 3-23-10

73. Phase II: Safety and Efficacy Primary endpoint: Overall Objective Response Rate (Partial and Complete Responses) Shown to be that of 13.1% 8 month duration of response Improvement over Tarceva Secondary endpoints: Progression-Free Survival (PFS), Overall Survival (OS) Of 250 participants two Grade 5 events due to internal hemorrhage http://www.nelm.nhs.uk/en/NeLM-Area/News/493764/493843/493847 3-23-10 http://www.medscape.com/viewarticle/714841 3-25-10

75. Investigative Drug vs. Tarceva®

76. Randomized double-blinded study in 1,200 patients

77. Improved overall survivalhttp://www.nelm.nhs.uk/en/NeLM-Area/News/493764/493843/493847 3-23-10 http://www.medscape.com/viewarticle/714841 3-25-10

78. Designations Orphan Status? NSCLC affects more than 200,000 people per year Fast Track? Third line therapy for Stage IIIB and IV NSCLC Provides unmet medical need for patients with serious life-threatening condition Applied for Fast Track designation in Phase I T. Class, In-Class Lecture, 1-11-10

79. Investigative Drug Approval Process With fast track designation, priority review and accelerated approval may be offered Priority Review? Has improved objective response rate over Tarceva® Accelerated Approval? Surrogate endpoint of objective response rate in phase II trial reasonably predicts clinical benefit along with 8 month duration of response T. Class, In-Class Lecture, 1-11-10

81. Monotherapy

82. Improved quality of life for patients with third stage NSCLC

84. How many drugs were granted Fast Track status the same year as Tarceva® ? http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/FastTrackApprovalReports/ucm082382.htm

85. Was Tarceva® granted orphan status? No Greater than 200,000 people are diagnosed with NSCLC each year in the US

86. ECOG performance status The Eastern Cooperative Oncology Group (ECOG) is one of the largest clinical cancer research organizations in the United States, and conducts clinical trials in all types of adult cancers. http://ecog.dfci.harvard.edu/

87. Considerations for Future Trials conducted in Asian population in Asian countries vs. Asian population in the U.S. Lower smoking rate in Asian countries than U.S.

88. What is a nonsmoker? A never-smoker is defined as under 100 cigarettes within life http://www3.interscience.wiley.com/journal/123222528/abstract?CRETRY=1&SRETRY=0 3-30-10

89. Pediatric Population Because advanced NSCLC has not shown to affect the pediatric population FDA can waive the requirement to test our investigative drug in children

90. Confidence Interval Expected range of outcome: a range of statistical values within which a result is expected to fall with a specific probability Encarta® World English Dictionary[North American Edition] © & (P) 2009 Microsoft Corporation.All rights reserved. Developed for Microsoft by Bloomsbury Publishing Plc.

91. Hazard Ratio How often a particular event happens in one group compare to how often it happens in another group, over time. In cancer clinical trials it measures survival at any point in a group of patients who have been given a specific treatment compared to a control group given another treatment or a placebo. A hazard ratio of one means that there is no difference in survival between the two groups. A hazard ratio of greater than one or less means that survival was better in one of the groups. http://www.cancer.gov/Templates/db_alpha.aspx?CdrID=618612