1. Alimta ® (Pemetrexed) as a Second-Line Treatment for Patients with Non-Small Cell Lung Cancer Presentation to the Oncologic Drugs Advisory Committee Paolo Paoletti, MD Vice President Clinical Research Oncology 27 July 2004 Eli Lilly and Company Version: Modified by: Date: 10/13/03 ID : 001 Content Owner: Informational SubCat: SubSubCat Paoletti Status: Core StudyID

3. List of External Experts Robert Allen, MD University of Colorado, United States Donald Berry, PhD University of Texas, MD Anderson, United States Hilary Calvert, MD University of Newcastle, United Kingdom Scott Emerson, MD, PhD University of Washington, United States Nasser Hanna, MD Indiana University, United States Axel Hanauske, MD, PhD Allgemeines Krankenhaus St Georg, Hamburg, Germany Christian Manegold, MD Thorax Klinik, Heidelberg, Germany Giorgio Scagliotti, MD University of Turin, Torino, Italy ID : 141 Content Owner: Informational List of Experts SubSubCat Paoletti Status: Core StudyID

4. Lilly Team ID : 152 Content Owner: Informational List of Experts SubSubCat Paoletti Status: Core StudyID Medical William John, MD Louis Kayitalire, MD Astra Liepa, PharmD Binh Nguyen, MD, PhD Paolo Paoletti, MD Regulatory Affairs Jeffrey Ferguson Anne Kehely, MD Debasish Roychowdhury, MD John Worzalla Statistics Clet Niyikiza, PhD Sofia Paul, PhD Patrick Peterson, PhD Jim Symanowski, PhD Non-Clinical Studies Ajai Chaudhary, PhD Victor Chen, PhD Vijay Reddy, PhD, DVM Rebecca Wrishko, PhD

11. Alimta in Combination with Cisplatin is Approved in the US for Mesothelioma – 04 February 2004 MST = 12.1 mo HR: 0.77 Log rank p-value = 0.020 MST = 9.3 mo 0 5 10 15 20 25 30 100 Months 75 50 25 0 Method: Kaplan-Meier % Alive Alimta+Cis (n=226) Cis (n=222) ID : 011 Content Owner: Background Approval in Meso SubSubCat Paoletti Status: Core StudyID

14. Non-Small Cell Lung Cancer Second-Line Treatment Version: Modified by: Date: 10/13/03 Frances A. Shepherd, MD, FRCPC Scott Taylor Chair in Lung Cancer Research, Princess Margaret Hospital Professor of Medicine, University of Toronto President, International Association for the Study of Lung Cancer ID : 013 Content Owner: NSCLC SubCat: SubSubCat Shepherd Status: Core StudyID

15. 1997 ASCO Guidelines for NSCLC “… there is no current evidence that either confirms or refutes that 2nd-line chemotherapy improves survival in … patients with advanced NSCLC.”* * Treatment Guidelines For Unresectable NSCLC. JCO 15: 2996-3019, 1997. ID : 138 Content Owner: TAX 317/320 SubCat: SubSubCat Shepherd Status: Core StudyID

16. Monotherapy for Previously Treated Patients With Advanced NSCLC Gemcitabine ID : 138 Content Owner: TAX 317/320 SubCat: SubSubCat Shepherd Status: Core StudyID 6-11 mo. 8-21% 272 Docetaxel 4-10 mo . 0-23% 112 Paclitaxel 4-8 mo . 0-21% 201 3 mo. 0-20% 63 Vinorelbine Median Survival Overall RR N Agent

18. Summary of Efficacy Results – TAX 317 ID : 018 Shepherd, Frances TAX 317/320 Efficacy SubSubCat Shepherd Status: Core StudyID * 44% reduction in risk of death compared to BSC — 0.010* 0.780 Log-rank p-value 12% 37% 19% One-Year Survival 4.6 mo 7.5 mo 5.9 mo Median Survival 1.6 mo 2.8 mo — TTPD — 6% 6% Partial Response BSC (n=49) Doc75 (n=55) Doc100 (n=49)

19. Survival – TAX 317B Docetaxel 75mg/m 2 vs BSC Median 7.5 mo vs. 4.6 mo Log-rank p = 0.010 1-year 37% vs. 12% Chi-square p = 0.003 Doc75 (n=55) BSC75 (n=49) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 3 6 9 12 15 18 21 Survival Time (months) Cumulative Probability ID : 016 Shepherd, Frances TAX 317/320 Efficacy SubSubCat Shepherd Status: Core StudyID

20. TAX 317B Updated Survival (Number of Prior Regimens) ID : 138 Content Owner: TAX 317/320 SubCat: SubSubCat Shepherd Status: Core StudyID

22. Summary of Efficacy Results – TAX 320 ID : 015 Shepherd, Frances TAX 317/320 Efficacy SubSubCat Shepherd Status: Core StudyID * Log-rank p=0.13 ** Chi square p=0.05 19% 5.6 mo 1.8 mo 1% V/I (n=122) 32%** 21% One-Year Survival 5.7 mo* 5.5 mo Median Survival 2.0 mo 1.9 mo TTPD 7% 11% Partial Response Doc75 (n=124) Doc100 (n=124)

23. Overall Survival – TAX 320 Cumulative Probability 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Doc100 Doc75 V/I Doc75 vs. V / I Log-rank Test p= 0.12 1-Year 32% vs 19% (p = 0.05, Chi-square) Doc100 vs. V / I Log-rank Test p= 0.13 1-Year 21% vs 19% ID : 019 Shepherd, Frances TAX 317/320 Efficacy SubSubCat Shepherd Status: Core StudyID Survival Time (Mo) 0 3 6 9 12 15 18 21

24. Docetaxel Toxicities (75 mg/m 2 ) Regardless of Causality (per Label)* * Data combined from TAX 317 and TAX 320 ** Grade 4 neutropenia with fever >38 °C with iv antibiotics or hospitalization n/a = Not Applicable ID : 452 Content Owner: TAX 317/320 Objectives SubSubCat Shepherd Status: Core StudyID 6.3** n/a Febrile Neutropenia n/a 56.3 Alopecia 1.7 23.3 Neurosensory 2.8 22.7 Diarrhea 10.2 33.5 Infection 65.3 84.1 Neutropenia Grade 3/4 Any Toxicity

25. Opioid Analgesic Use – TAX 317B Change from Baseline p=ns p<0.001 p<0.001 20% 13% 5% 49% 35% 18% 0% 10% 20% 30% 40% 50% 60% Ongoing at Baseline Additional Opioid Analgesic Newly-started Opioid Analgesic Percentage of Patients Doc75 BSC75 ID : 840 Shepherd, Frances TAX 317/320 LCSS SubSubCat Shepherd Status: Core StudyID

26. Weight Loss During Treatment Percent of Patients with Weight Loss > 10% 5 % 8 % 0% 5% 10% 15% 20% 25% T75 V/I TAX 317B TAX 320 2 % 25 % 0% 5% 10% 15% 20% 25% T75 BSC75 p<0.001 p=ns ID : 138 Content Owner: TAX 317/320 SubCat: SubSubCat Shepherd Status: Core StudyID

27. Performance Status Evaluation Performance Status (ECOG) Cycle 1 Cycle 2 Cycle 3 Mean Across Cycles 1-3 Last Assessment TAX 317B TAX 320 Better for BSC75 Better for Doc75 Better for V/I Better for Doc75 ID : 841 Shepherd, Frances TAX 317/320 LCSS SubSubCat Shepherd Status: Core StudyID -1.0 -0.8 -0.6 -0.4 -0.2 0.0 0.2 0.4 0.6 0.8 1.0 -0.6 -0.5 -0.4 -0.3 -0.2 -0.1 0.0 0.1 0.2 0.3 0.4 0.5 0.6

29. Current ASCO Guidelines for NSCLC “ Docetaxel is recommended as 2nd-line therapy for patients with advanced or metastatic NSCLC with adequate performance status who have progressed on 1st-line platinum-based therapy.”* * ASCO Treatment of Unresectable NSCLC Guideline. JCO 22-: 330-353, 2004 ID : 089 Content Owner: TAX 317/320 SubCat: SubSubCat Shepherd Status: Core StudyID

31. Alimta Development Roy Herbst, MD, PhD Chief and Associate Professor, Thoracic Oncology, University of Texas M. D. Anderson Cancer Center Version: Modified by: Date: 10/13/03 ID : 009 Content Owner: Informational SubCat: SubSubCat Herbst Status: Core StudyID

32. Alimta (Pemetrexed) Chemical Structure ID : 203 Chen, Victor Chemical Structure Chemical Structure SubSubCat Herbst Status: Core StudyID N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H- pyrrolo[2,3-d]pyrimidin -5-yl)ethyl]benzoyl]-L-glutamic acid Alimta (Pemetrexed) Folic Acid

33. Alimta Mechanism of Action GARFT RNA & DNA Synthesis AMP GMP DHFR TS DNA Synthesis IMP PRPP + Gln 10-CHO-FH 4 5, 10-CH 2 -FH 4 FH 4 dUMP FH 2 dTMP Cell Membrane Alimta-Glu n Alimta FPGS Folate Carriers (mainly RFC) Alimta ID : 010 Content Owner: Chemical Structure, MOA Mechanism of Action SubSubCat Herbst Status: Core StudyID

34. Alimta Preclinical Results in Non Small Cell Lung Cancer ID : 142 Content Owner: Background In Vivo SubSubCat Herbst Status: Core StudyID 75 62 300 100 LX-1 Lung In vivo % Tumor Inhibition Dose Tumor Graft 156 NSCLC A549 50 NSCLC H23 60 NSCLC H460 4 NSCLC LX-1 In vitro IC 50 (nM) Tumor Cell Lines

35. First-Line NSCLC Monotherapy – Alimta and Docetaxel Efficacy * Phase III study ** Dosage amended from 600 mg/m 2 due to toxicity 1 No Vitamin Supplementation ID : 161 Content Owner: Phase 1 and 2 Approval in Meso SubSubCat Herbst Status: Core StudyID 9.2 mo 23 500 Alimta 30 Rusthoven 1 ** 16 13 25 25 16 33 Response Rate (%) 7.0 mo 100 Docetaxel 80 Gandara 7.2 mo 600 Alimta 57 Clarke 1 6.0 mo 100 Docetaxel 137 Roszkowski* NR 75 Docetaxel 20 Miller 7.4 mo 100 Docetaxel 60 Alexopoulos 10.8 mo 100 Docetaxel 41 Fossella Median Survival Dose (mg/m 2 ) Regimen N Evaluable

36. First-Line NSCLC Combination – Alimta Phase II Studies ID : 276 Kayitalire, Louis Phase 1 and 2 Combination Efficacy Herbst Status: Core StudyID * Before vitamin supplementation 29% 13.5 mo 55.8% 4.8 mo 31.6% 10.5 mo NR 5.7 mo 45% 8.9 mo 49% NR 39% 10.9 mo 50% 6.3 mo Response Rate Median Survival 1-Year Survival Median TTPD 500 Carboplatin AUC 6 500 Carboplatin AUC 6 500 Cisplatin 75 mg/m 2 500 Cisplatin 75 mg/m 2 Alimta (mg/m 2 ) Combination ( d1 q21d) 50 39 29 36 N Koshy et al. (2003) Scagliotti et al. (2003) Shepherd et al. (2001)* Manegold et al. (2000)*

37. Second-Line NSCLC Monotherapy –Alimta Phase II Study (N=79) ID : 162 Content Owner: Phase 1 and 2 Approval in Meso SubSubCat Herbst Status: Core StudyID * Before vitamin supplementation 8.9% 5.7 mo 23% 2.0 mo Response Rate Median Survival 1-Year Survival Median TTPD Relapsed < 3 mo Relapsed < 1 mo 100% 66% Smit et al. (2003)*

39. Or G3/4 Nonhem Tox Toxicity in Patients With and Without FA/ Vitamin B 12 Supplementation P=<0.0001 P =<0.0001 P =0.0053 P =0.026 * No toxic death reported * ID : 842 Shepherd, Frances Story-Hcy LCSS SubSubCat Herbst Status: Core StudyID

41. Version: Modified by: Date: 10/13/03 Pivotal Study JMEI Randomized Phase III Study of Alimta vs Docetaxel in Patients with Locally Advanced or Metastatic NSCLC Previously Treated with Chemotherapy Paul A. Bunn, Jr., MD Grohne/Stapp Professor & Director, University of Colorado Cancer Center Executive Director, International Association for the Study of Lung Cancer Content Owner: Informational SubCat: SubSubCat Bunn Status: Core StudyID ID : 100

45. Definition of Populations Intent to treat (ITT): All randomized patients, regardless of therapy. Primarily used for efficacy analyses. Randomized and Treated (RT): All randomized patients who received at least one dose of chemotherapy. Primarily used for safety analyses. ID : 454 Content Owner: Statistical Design Objectives SubSubCat Bunn Status: Core StudyID

47. JMEI: Baseline Characteristics (ITT) ID : 106 Content Owner: Baseline Charact SubCat: SubSubCat Bunn Status: Core StudyID 49.3% 32.3% 54.4% 27.6% Histology Adenocarcinoma Squamous 74.7% 74.9% Stage IV 12.4% 11.4% ECOG PS 2 Percent of Patients 68.9% 71.4% Homocysteine levels <12 μm 57 (28-87) 75.3% 59 (22-81) 68.6% Median Age, years (range) Male Docetaxel (N=288) Alimta (N=283)

48. JMEI: Baseline Characteristics (ITT) ID : 455 Content Owner: Baseline Charact SubCat: SubSubCat Bunn Status: Core StudyID Percent of Patients 89.9% 92.6% Prior Platinum 27.8% 25.8% Prior Taxane 48.1% 50.4% < 3 mo since Last Chemo 36.5% 35.6% Best Response to Prior Chemo CR/PR Docetaxel (N=288) Alimta (N=283)

49. JMEI: Treatment Delivered (RT) ID : 107 Content Owner: Dosage and Delays SubCat: SubSubCat Bunn Status: Core StudyID * p<0.001 17.8% 19.8% Dose Delays 5.6% 1.2% Dose Reductions* 139 136 Patients Received > 4 Cycles 12 18 No Treatment Delivered (ITT-RT) 94.4% 96.6% Planned Dose Intensity 4 (1-14) 4 (1-20) No. Cycles, Median (range) Docetaxel (N=276) Alimta (N=265)

50. JMEI: Survival (ITT) MST 8.3 mo 1-yr OS: 29.7% MST 7.9 mo 1-yr OS: 29.7% MST = median survival time * Test of superiority and 10% non-inferiority not statistically significant 0 18 15 12 9 6 3 21 1.00 0.75 0.50 0.25 0.00 Survival Distribution Months HR 0.99 95% CI of HR (0.82, 1.20*) Alimta (N=283) Docetaxel (N=288) ID : 108 Content Owner: Overall Survival SubCat: SubSubCat Bunn Status: Core StudyID

52. Patient Demographics for TAX 317 and JMEI ID : 487 Paul, Sofia Baseline Charact. SubCat: SubSubCat Bunn Status: Core StudyID 12% 15% Performance status (2) 75% 79% Stage IV 6% 25% Number of prior chemo (2) 91% 27% 64% 72% 58 JMEI (N=571) TAX 317 Data (N=204) 100% Prior platinum 0% Prior taxane 65% Best response to prior chemo (other than CR/PR) 67% Male 61 Median Age, years

53. JMEI: Survival with TAX 317 (ITT) ID : 108 Content Owner: Overall Survival SubCat: SubSubCat Bunn Status: Core StudyID HR (Alimta vs BSC) 0.55 95% CI: 0.33, 0.90 p-value= 0.019 JMEI Docetaxel (N=288) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 3 6 9 12 15 18 21 Survival Time (months) Cumulative Probability TAX 317 Docetaxel (N=55) JMEI Alimta (N=276) TAX 317B BSC (N=49)

54. JMEI: Overall Survival ID : 164 Content Owner: Overall Survival Analysis Plan SubSubCat Bunn Status: Core StudyID * Percent retention based on TAX 317 (B) results JMEI 95% CI 0% 0.70 1.40 0.82 157% 52% 1.20 102% Percent Retention* Hazard Ratio Alimta vs docetaxel 0.99 Alimta superior to BSC* 1.33 78% 1.11 Alimta within 10% margin of docetaxel Alimta retains >50% of docetaxel benefit* 1.21 1.00 Alimta superior to docetaxel

55. JMEI: Overall Survival ID : 808 Content Owner: Overall Survival SubCat: SubSubCat Bunn Status: Core StudyID RT Population ITT Population 50% retention non-inferiority test based on point estimate of control effect (HR docetaxel/BSC = 0.555) (52%, 157%) 0.047 206 Alimta (N=283) 95% CI of estimated percent of efficacy retained by Alimta NI p-value for testing 50% retention Events (58%, 168%) 0.036 198 192 203 Docetaxel (N=276) Alimta (N=265) Docetaxel (N=288)

57. JMEI: Factors Predictive of Survival Version: Modified by: ; Date: Cox Multiple Regression Model ID : 121 Content Owner: Survival Other Subs SubCat: SubSubCat Bunn Status: Core StudyID 0.026 0.004 < 0.001 p-value 0.77 (0.60, 0.97) Stage of Disease (III over IV) 0.74 (0.60, 0.90) Time since last chemotherapy (  3 mo over  3 mo) 0.25 (0.19, 0.34) Performance Status (0 – 1 over 2) HR (95% CI for HR) Variable

58. JMEI: Adjusted Overall Survival (ITT) ID : 168 Content Owner: Overall Survival Analysis Plan SubSubCat Bunn Status: Core StudyID 0.70 1.40 0.76 JMEI 95% CI Hazard Ratio 0.93 1.13 HR 0.93 95% CI of HR (0.76, 1.13) p-value vs 1.11 = 0.051 Alimta within 10% margin of docetaxel 3.6 days 1.11

59. JMEI: Survival Analyses for Key Subgroups Version: Modified by: ; Date: ID : 075 Peterson, Patrick Statistical Results Subgroup Survival SubSubCat Bunn Status: Core StudyID No treatment differences within subgroups 0.92 1.06 0.99 1.01 0.75 1.00 1.03 0.97 0. 74 1.03 HR 0.90 0.97 0.89 1.11 0.73 0.99 0.97 0.84 0.91 0.95 Adjusted HR 50 No Prior Platinum 286 > 3 mo since last chemo 277 < 3 mo since last chemo 427 Stage IV 144 Stage III 64 Performance Status 2 474 Performance Status 0 or 1 418 153 No Prior Taxane Prior Taxane 521 Prior Platinum N Evaluable

61. JMEI: Progression-Free Survival (ITT) MPFS = median progression-free survival Alimta (N=283) Docetaxel (N=288) ID : 113 Content Owner: Secondary Efficacy SubCat: SubSubCat Bunn Status: Core StudyID HR 0.97 95% CI of HR (0.82, 1.16) MPFS = 2.9 mo MPFS = 2.9 mo 0 18 15 12 9 6 3 21 1.00 0.75 0.50 0.25 0.00 Survival Distribution Months

62. JMEI: Time to Disease Progression (ITT) ID : 095 Peterson, Patrick Secondary Efficacy TTPD KM Bunn Status: Core StudyID 1.00 0.75 0.50 0.25 0.00 Survival Distribution Factor 0 18 15 12 9 6 3 21 Alimta (N=283) Docetaxel (N=288) Months MTTPD = 3.4 mo MTTPD = 3.5 mo HR 0.97 95% CI of HR (0.80, 1.17) MTTPD = median time to disease progression

63. JMEI: Post Study Chemotherapy Received (RT) Version: Modified by: ; Date: ID : 047 Content Owner: Survival by Post Study Post Study Chemo SubSubCat Bunn Status: Core StudyID 34 (12.3) 22 (8.4) Other chemo 5 (1.9) 17 (6.4) 6 (2.3) 4 (1.5) 85 (32.1) 15 (5.4) 9 (3.4) Platinum 11 (4.0) Docetaxel 3 (1.1) Paclitaxel 25 (9.1) Vinorelbine 32 (11.6) Gemcitabine 21 (7.6) Gefitinib 107 (38.8) 126 (47.5)  1 Chemotherapy No. of Patients in Each Arm (%) Docetaxel (N=276) Alimta (N=265) Type

64. JMEI: Survival by Post Study Chemotherapy Group (RT) Version: Modified by: ; Date: ID : 048 Content Owner: Survival by Post Study Post Study Chemo SubSubCat Bunn Status: Core StudyID 10.8 mo 107 9.8 mo 126 Any post-study chemo 96 11 169 Docetaxel (N=276) 10.6 mo 9.6 mo 6.2 mo MS 11.2 mo 41 Other chemotherapy 10.1 mo 85 Post-study docetaxel therapy 5.0 mo 139 No post-study chemo MS Alimta (N=265) Patient Population

65. JMEI: Post Progression Survival Alimta (N=213) Docetaxel (N=208) HR 1.01 95% CI of HR (0.81, 1.27) MST 4.5 mo MST 4.5 mo 1.00 0.75 0.50 0.25 0.00 Survival Distribution Factor 0 15 12.5 10 7.5 5 2.5 17.5 20 Post Progression Survival

66. JMEI: Response Rates Version: Modified by: ; Date: 0 10 20 30 40 50 9.1% (CI 5.9, 13.2) 8.8% (CI 5.7, 12.8) 45.8% (CI 39.7, 52.1) 46.4% (CI 40.3, 52.5) Complete and partial response Stable Disease Alimta (n=264) Docetaxel (n=274) ID : 111 Content Owner: Secondary Efficacy SubCat: SubSubCat Bunn Status: Core StudyID

67. Statistically Significant Grade 3/4 CTC Toxicities Regardless of Causality (RT) ID : 701 Content Owner: Lab Tox and Feb Neut. Objectives SubSubCat Bunn Status: Core StudyID 0.034 0.4 2.6 ALT <0.001 5.8 0 Infect w Gr 3/4 Neutropenia <0.001 42.4 11.3 Alopecia (all grades) 0.006 4.0 0.4 Diarrhea <0.001 12.7 1.9 Febrile Neutropenia Percent of Patients 40.2 Docetaxel (N=276) 5.3 Alimta (N=265) <0.001 Neutropenia p-value Toxicity

69. JMEI Randomized Trial: Alimta vs Docetaxel in Second-Line NSCLC Version: Modified by: Date: 10/13/03 ID : 088 Content Owner: NSCLC SubCat: SubSubCat Zhang Status: Core StudyID Safety Results and Patient Reported Outcomes Richard J. Gralla, MD President, Multinational Association of Supportive Care in Cancer

72. Maximum Symptom Improvement from Baseline for Patients with CR/PR vs SD vs PD ASBI = Average Symptom Burden Index De Marinis et al, Proc ASCO 2004 ID : 175 Content Owner: QoL Symptom Improvement SubSubCat Gralla Status: Core StudyID

73. Maximum Symptom Improvement from Baseline for Patients with CR/PR + SD All between-arm comparisons were not statistically significant ASBI = Average Symptom Burden Index De Marinis et al, Proc ASCO 2004 ID : 173 Content Owner: QoL Symptom Improvement SubSubCat Gralla Status: Core StudyID

75. Docetaxel Toxicities (75 mg/m 2 ) Regardless of Causality (per Label)* * Data combined from TAX 317 and TAX 320 ** ANC Grade 4 with fever >38 °C with iv antibiotics and/or hospitalization ID : 702 Content Owner: Lab Tox, CTC, Hosp Objectives SubSubCat Gralla Status: Core StudyID 1.7 26.1 Stomatitis 2.8 21.6 Vomiting 5.1 33.5 Nausea 10.2 33.5 Infection - 56.3 Alopecia 0.6 19.9 Rash 2.8 35.5 Fluid Retention 2.8 5.7 Hypersensitivity 1.7 23.3 Neurosensory 2.8 22.7 Diarrhea 18.2 52.8 Asthenia 6.3** - Febrile Neutropenia 65.3 84.1 Neutropenia Grade 3/4 Any Toxicity

76. JMEI: Adverse Events (RT) Version: Modified by: ; Date: ID : 058 Content Owner: Non-Lab Adverse Events SubSubCat Gralla Status: Core StudyID * On-study or within 30 days of discontinuation Percent of Patients On-study deaths*: 98.6 85.9 43.5 23.9 14.5 1.8 Docetaxel (N=276) 97.7 78.1 37.4 10.2 11.7 1.1 Alimta (N=265) NS 0.025 Patients with 1 or more TEAE: Regardless of causality Drug-related NS <0.001 Patients with 1 or more SAE: Regardless of causality Drug-related NS NS Regardless of causality Drug-related p-value Event

77. JMEI: Summary of Deaths Number of patients ID : 640 Content Owner: Non Lab SubCat: SubSubCat Gralla Status: Core StudyID * On-study or within 30 days of discontinuation 40 9 26 5 Docetaxel 31 10 18 3 Alimta On-Study* 0.818 Other 0.374 0.276 0.725 p-value Total Study disease related Study drug related Deaths

78. JMEI: Adverse Events (RT) NCI Common Toxicity Criteria v2 – Example: Neutropenia ID : 138 Content Owner: Lab Tox and Feb Neut SubCat: SubSubCat Gralla Status: Core StudyID Very High < 500 Grade 4 Moderate > 500 – 1000 Grade 3 Very Low > 1000 < 1500 Grade 2 None > 1500 < 2000 Grade 1 Risk / Impact Neutrophils/mm3

79. JMEI: Grade 3/4 Lab Toxicities (NCI-CTC) Regardless of Drug Causality (RT) Version: Modified by: ; Date: ID : 060 Content Owner: Lab Tox and Feb. Neut. Lab Tox SubSubCat Gralla Status: Core StudyID <0.001 40.2 5.3 Neutropenia <0.001 12.7 1.9 Febrile Neutropenia <0.001 5.8 0 Infection with Gr 3/4 Neutropenia Percent of Patients — 0.0 0.8 Bilirubin 6.2 0.7 0.0 0.4 0.4 Docetaxel (N=276) 7.5 1.9 0.0 2.6 1.1 Alimta (N=265) 0.610 0.277 1.0 0.034 0.364 Anemia Thrombocytopenia Creatinine ALT AST p-value Toxicity

80. JMEI: Gr 3/4 Non-Lab Toxicities (NCI-CTC) Regardless of Drug Causality (RT) Version: Modified by: ; Date: ID : 062 Content Owner: Non-Lab Toxicities Non-Lab Tox SubSubCat Gralla Status: Core StudyID 1.0 1.1 1.1 Stomatitis 0.817 16.7 15.8 Fatigue <0.001 42.4 11.3 Alopecia (all grades) 1.0 0.0 0.0 Rash 1.0 1.4 1.5 Vomiting 0.006 4.0 0.4 Diarrhea 0.466 2.5 3.8 Nausea 1.0 0.4 0.4 Fluid Retention Percent of Patients 0.365 9.8 7.5 Neurosensory 0.062 1.8 0.0 Hypersensitivity Docetaxel (N=276) Alimta (N=265) p-value Toxicity

81. JMEI: Lab Toxicities (NCI-CTC) Regardless of Drug Causality (RT) ID : 059 Content Owner: Lab Tox and Feb. Neut. Lab Tox SubSubCat Zhang Status: Core StudyID Percent of Patients 34.1 30.4 25.0 23.9 Docetaxel (N=276) <0.001 <0.001 0.288 0.620 p-value 5.3 All Grade 4 18.1 All Grade 3 29.4 All Grade 2 26 All Grade 1 Alimta (N=265) Toxicity

82. JMEI: Transfusions and Growth Factors (RT) Version: Modified by: ; Date: ID : 066 Content Owner: Lab Tox and Feb. Neut. Transfusions SubSubCat Gralla Status: Core StudyID Percent of Patients <0.001 19.2 2.6 G-CSF/GM-CSF 0.169 10.1 6.8 Erythropoietin 0.108 11.6 16.6 Red Blood Cell Transfusions p-value Docetaxel (N=276) Alimta (N=265)

83. JMEI: Non-Lab Toxicities Regardless of Drug Causality (RT) ID : 061 Content Owner: Non-Lab Toxicities Non-Lab Tox SubSubCat Gralla Status: Core StudyID Percent of Patients 0.020 22.5 14.3 All Grade 4 0.060 68.1 60.0 All Grade 3 >0.999 93.8 93.6 All Grade 2 0.165 92.0 95.1 All Grade 1 p-value Docetaxel (N=276) Alimta (N=265) Toxicity

84. JMEI: Hospitalizations (RT) Version: Modified by: ; Date: ID : 063 Content Owner: Non-Lab Toxicities Hospitalizations SubSubCat Gralla Status: Core StudyID All drug-related hospitalization Percent of Patients 0.092 10.5 6.4 Due to other drug-related AEs <0.001 <0.001 21.7 13.4 7.2 1.5 Any drug-related hospitalization Due to febrile neutropenia 0.032 40.6 31.7 > 1 Hospitalization due to AE 0.345 52.9 48.7 Any Hospitalizations p-value Docetaxel (N=276) Alimta (N=265)

85. Toxicity-Free (Any Grade 4) Survival Curve ID : 177 Content Owner: Risk Benefit Conclusions Clinical Benefit SubSubCat Gralla Status: Core StudyID Survival Distribution Function 0.00 0.25 0.50 0.75 1.00 Toxicity Free Survival Time (Months) 0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5 Alimta (n=265) Docetaxel (n=276) MTFS 7.5 months; 1yr TFS 27.8% MTFS 2.3 months; 1 yr TFS 16.0% HR 0.57 95% CI of HR (0.47, 0.69)

87. Version: Modified by: Date: 10/13/03 Overall Conclusions Paul A. Bunn, Jr., MD Grohne/Stapp Prof. & Director, University of Colorado Cancer Center Exec. Director, International Association for the Study of Lung Cancer ID : 131 Content Owner: Informational SubCat: SubSubCat Bunn Status: Core StudyID

89. Evidence for Clinical Benefit of Alimta in 2nd-Line NSCLC (RT): Safety Version: Modified by: ; Date: ID : 180 Content Owner: Lab Tox and Feb. Neut. SubCat: SubSubCat Bunn Status: Core StudyID Alimta is safer with respect to clinically important toxicities 19.2% 2.6% G-CSF/GM-CSF 21.7% 7.2% Drug-induced AE hospitalization 42.4% 11.3% Alopecia (all grades) 4.0% 0.4% Grade 3/4 Diarrhea 12.7% 1.9% Febrile Neutropenia Docetaxel (N=276) Alimta (N=265)

90. Toxicity Comparison of Safety Database for Single Agent Alimta* Regardless of Drug Causality * With vitamin supplementation ** Single Agent ID : 846 Content Owner: Single Agent SubCat: SubSubCat Bunn Status: Core StudyID 1.1 0 Toxic Deaths 0.4 3.0 Gr. 3/4 Diarrhea 11.3 11.6 Alopecia (any grade) 7.5 2.4 Gr. 3/4 Anemia 1.9 3.7 Gr. 3/4 Platelets 1.9 1.8 Febrile Neutropenia 5.3 14.0 Gr. 3/4 Neutropenia JMEI (N=265) Other Alimta SA** (N=207)

93. Consistency of Survival Results in Randomized Studies in 2nd-Line NSCLC 0 8 Median Survival (mo) TAX 317B N=104 TAX 320 N=248 Gridelli N=220 Camps N=254 JMEI N=571 ID : 132 Content Owner: Overall Survival SubCat: SubSubCat Bunn Status: Core StudyID JBR21 N=364 Alimta produces survival equivalent to the best docetaxel results and superior to BSC 4 2 6 Doc 75 mg/m 2 Doc 75 mg/m 2 Doc 75 m q 21d Doc 75 mg/m 2 Doc 75 m q 21d Doc 33.3m w Doc 36m w Vin/Ifos Alimta 500 mg/m 2 q 21d BSC Erlotinib 150 mg q d Placebo and BSC