1. 1 Presentation to the Oncologic Drugs Advisory Committee Paolo Paoletti, MD Vice President Clinical Research Oncology 27 July 2004 Eli Lilly and Company Alimta ® (Pemetrexed) as a Second- Line Treatment for Patients with Non-Small Cell Lung Cancer ID : 001Content Owner:InformationalSubCat:SubSubCatPaolettiStatus: CoreStudyID

2. 2 Agenda ID : 002Content Owner:InformationalAgendaSubSubCatPaolettiStatus: CoreStudyID  IntroductionPaolo Paoletti, MD – Objectives of Presentation Vice President, Clinical Research Oncology, Eli Lilly and Company  Background Frances A. Shepherd, MD – 2nd-Line Treatment of NSCLC Professor of Medicine, University of Toronto Scott Taylor Chair in Lung Cancer Research, President IASLC  Alimta DevelopmentRoy Herbst, MD, PhD Chief, Thoracic Oncology, University of Texas M.D. Anderson Cancer Center  Clinical EfficacyPaul A. Bunn, Jr., MD – Pivotal Study JMEI Director, University of Colorado Cancer Center  Safety ProfileRichard J. Gralla, MD – Pivotal Study JMEI President, Multinational Association of Supportive Care in Cancer, Director IASLC  ConclusionsPaul A. Bunn, Jr., MD

3. 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 : 141Content Owner:InformationalList of ExpertsSubSubCatPaolettiStatus: CoreStudyID

4. 4 Lilly Team ID : 152Content Owner:InformationalList of ExpertsSubSubCatPaolettiStatus: CoreStudyID 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

5. 5 Provide evidence that Alimta is effective and safe. Lilly intends to show that given its superior safety, Alimta has a better risk-benefit profile than docetaxel (Taxotere®) and provides clinical benefit to patients with non-small cell lung cancer (NSCLC).  Alimta is a novel, effective agent in the treatment of NSCLC – Demonstrates similar efficacy to docetaxel – Shows consistent results across all assessed endpoints and subgroups – Estimated to retain 102% of docetaxel's benefit over BSC – Is superior to historical BSC  Alimta has an excellent safety profile – Has a superior safety profile to docetaxel Alimta offers an effective and safer option in the treatment of second-line NSCLC Objective of Presentation ID : 003Content Owner:InformationalObjectivesSubSubCatPaolettiStatus: CoreStudyID

6. 6 Proposed Indication and Dosage Schedule  Alimta as a single ‑ agent is indicated for the treatment of patients with locally advanced or metastatic non ‑ small cell lung cancer (NSCLC) after prior chemotherapy  Dose: 500 mg/m 2 iv, 10 minutes, Day 1 of each 21-day cycle  Folic Acid: 350-1000 µg orally daily; Vitamin B 12 1000 µg im, q 3 cycles  Dexamethasone: 4 mg bid on d-1, d0, d+1 ID : 450Content Owner:Dosage and DelaysObjectivesSubSubCatPaolettiStatus: CoreStudyID

7. 7 Development of Alimta in Second-Line Treatment of NSCLC  Consistent evidence of activity in seven Phase II studies – Single agent (3 studies) – In combination with platinum agents (4 studies) – Both in 1st and 2nd-line  Supplementation with Folic Acid/B 12 improved safety profile of Alimta – Degree of toxicity reduction was not fully characterized  Decision to proceed with a Phase III study (JMEI) in 2nd- line treatment of NSCLC ID : 176Content Owner:BackgroundSubCat:SubSubCatPaolettiStatus: CoreStudyID

8. 8 Design of Global, Pivotal Study JMEI  Decision to run “Head to Head” trial of Alimta vs docetaxel – Global study to support global registration – BSC in 2nd-line NSCLC considered not feasible in US – Combination chemotherapy not appropriate in 2nd-line setting – Docetaxel only approved agent for treatment of 2nd-line NSCLC  Survival as a primary endpoint – Limited historical data on the effect of docetaxel – “Pure equivalency” study would require >4000 pts ID : 177Content Owner:Statistical DesignSubCat:SubSubCatPaolettiStatus: CoreStudyID

9. 9 Design of Global, Pivotal Study JMEI  Sample size of 520 patients allows for testing both superiority and non inferiority  Compare treatment arms by HR for survival  Protocol Specified: – Superiority – 10% fixed margin NI (EU regulatory)  Statistical Analysis Plan Specified (prior to unblinding): – Percent Retention of the effect of docetaxel over BSC – 50% retention – basis of approval for capecitabine (colorectal) and docetaxel (breast cancer) – Percent Retention methodology published January 2003 ID : 157Content Owner:Statistical DesignSubCat:SubSubCatPaolettiStatus: CoreStudyID

10. 10  JMEI first patient enrolled 20 March 2001  JMEI last patient enrolled 06 February 2002  Final Statistical Analysis Plan for 24 January 2003 JMEI approved  Unblinding of JMEI analysis data sets30 January 2003  US fast track designation for 2nd-23 July 2003 line treatment of NSCLC  US NSCLC submission04 November 2003  NSCLC 2nd Line and Mesothelioma22 June 2004 EU-CHMP positive opinion Alimta Second-Line Treatment of NSCLC Global Development Timeline ID : 004Content Owner:TimelineSubmission TimelineSubSubCatPaolettiStatus: CoreStudyID

11. 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 051015202530 100 Months 75 50 25 0 Method: Kaplan-Meier % Alive Alimta+Cis (n=226) Cis (n=222) ID : 011Content Owner:BackgroundApproval in MesoSubSubCatPaolettiStatus: CoreStudyID

12. 12  Seven Alimta Phase II studies show consistent evidence of activity  From this large Phase III randomized study in 2nd-line NSCLC, consistently similar efficacy results compared to docetaxel: –All primary and secondary efficacy endpoints –All subgroup analyses  Significantly better efficacy than historical BSC  Alimta has a significantly better safety profile when compared with docetaxel for clinically relevant events Alimta is safe and effective and offers a superior benefit-to-risk profile compared to docetaxel Why Alimta Merits FDA Approval as Second-Line Treatment for NSCLC ID : 007Content Owner:Risk-Benefit Conclusions SubCat:SubSubCatPaolettiStatus: CoreStudyID

13. 13 Points for Consideration  Docetaxel is effective in the 2nd-line treatment of NSCLC, but its use is limited by toxicity – Results in the 288 patients receiving docetaxel in the JMEI trial confirms docetaxel’s survival effect and safety profile  The small size of the docetaxel vs BSC pivotal trial made non-inferiority designs and analyses very challenging.  Inevitable post study treatment may confound a survival endpoint; analysis of JMEI data suggest such a confounding effect is unlikely  Interpretation of the results we present must consider the whole body of evidence ID : 451Content Owner:InformationalObjectivesSubSubCatPaolettiStatus: CoreStudyID

14. 14 Non-Small Cell Lung Cancer Second-Line Treatment 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 : 013Content Owner:NSCLCSubCat:SubSubCatShepherdStatus: CoreStudyID

15. 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 : 138Content Owner:TAX 317/320SubCat:SubSubCatShepherdStatus: CoreStudyID

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

17. 17 Study Design - TAX 317 NSCLC Stratified by: ECOG PS (0,1 vs 2) Best response to prior platinum (PD vs. non-PD) 1 0 Objective: survival No prior paclitaxel RANDOMIZERANDOMIZE 317A Docetaxel 100 mg/m 2, one-hour iv infusion on Day 1 q 21d Premedication: Dexamethasone 8 mg x 10 doses, beginning 12 hours before docetaxel By Protocol Amendment: Docetaxel 75 mg/m 2, one-hour IV infusion on Day 1 q 21d Premedication: Dexamethasone 8 mg x 5 doses, beginning 12 hours before docetaxel 317B Best Supportive Care without chemotherapy ID : 014Shepherd, FrancesTAX 317/320Study DesignSubSubCatShepherdStatus: CoreStudyID

18. 18 Summary of Efficacy Results – TAX 317 Doc100 (n=49) Doc75 (n=55) BSC (n=49) Partial Response6% — TTPD—2.8 mo1.6 mo Median Survival5.9 mo7.5 mo4.6 mo Log-rank p-value0.7800.010*— One-Year Survival19%37%12% ID : 018Shepherd, FrancesTAX 317/320EfficacySubSubCatShepherdStatus: CoreStudyID * 44% reduction in risk of death compared to BSC

19. 19 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 Survival – TAX 317B Docetaxel 75mg/m 2 vs BSC ID : 016Shepherd, FrancesTAX 317/320EfficacySubSubCatShepherdStatus: CoreStudyID

20. 20 TAX 317B Updated Survival (Number of Prior Regimens) ID : 138Content Owner:TAX 317/320SubCat:SubSubCatShepherdStatus: CoreStudyID

21. 21 Study Design – TAX 320 RANDOMIZERANDOMIZE NSCLC Stratified by:  Best response to last platinum (PD vs. non-PD)  ECOG PS (0,1 vs. 2)  1 0 Objective: survival  Prior Paclitaxel allowed Docetaxel 100 mg/m² iv q 3wks Premedication: Dexamethasone 8 mg x 5 doses, beginning 12 hours before docetaxel Docetaxel 75 mg/m² iv q 3wks Premedication: Dexamethasone 8 mg x 5 doses, beginning 12 hours before docetaxel Vinorelbine 30 mg/m² iv Days 1, 8, 15 q 3wks - or - Ifosfamide 2 gm/m² iv (+ Mesna) Days 1, 2, 3 q 3wks Response assessment every 2 cycles ID : 017Shepherd, FrancesTAX 317/320Study DesignSubSubCatShepherdStatus: CoreStudyID

22. 22 Summary of Efficacy Results – TAX 320 Doc100 (n=124) Doc75 (n=124) V/I (n=122) Partial Response11%7%1% TTPD1.9 mo2.0 mo1.8 mo Median Survival5.5 mo5.7 mo*5.6 mo One-Year Survival21%32%**19% ID : 015Shepherd, FrancesTAX 317/320EfficacySubSubCatShepherdStatus: CoreStudyID * Log-rank p=0.13 ** Chi square p=0.05

23. 23 Cumulative Probability 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Survival Time (Mo) 03 6 912 151821 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% Overall Survival – TAX 320 ID : 019Shepherd, FrancesTAX 317/320EfficacySubSubCatShepherdStatus: CoreStudyID

24. 24 Docetaxel Toxicities (75 mg/m 2 ) Regardless of Causality (per Label)* ToxicityAnyGrade 3/4 Neutropenia84.165.3 Febrile Neutropenian/a6.3** Infection33.510.2 Diarrhea22.72.8 Neurosensory23.31.7 Alopecia56.3n/a * 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 : 452Content Owner:TAX 317/320ObjectivesSubSubCatShepherdStatus: CoreStudyID

25. 25 Opioid Analgesic Use – TAX 317B Change from Baseline p=nsp<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 : 840Shepherd, FrancesTAX 317/320LCSSSubSubCatShepherdStatus: CoreStudyID

26. 26 Weight Loss During Treatment Percent of Patients with Weight Loss > 10% 5 % 8 % 0% 5% 10% 15% 20% 25% T75V/I TAX 317BTAX 320 2 % 25 % 0% 5% 10% 15% 20% 25% T75BSC75 p<0.001p=ns ID : 138Content Owner:TAX 317/320SubCat:SubSubCatShepherdStatus: CoreStudyID

27. 27 Performance Status Evaluation Performance Status (ECOG) Cycle 1 Cycle 2 Cycle 3 Mean Across Cycles 1- 3 Last Assessment TAX 317BTAX 320 Better for BSC75 Better for Doc75 Better for V/I Better for Doc75 -0.8-0.6-0.4-0.20.00.20.40.60.81.0 -0.6-0.5-0.4-0.3-0.2-0.10.00.10.20.30.40.5 0.6 ID : 841Shepherd, FrancesTAX 317/320LCSSSubSubCatShepherdStatus: CoreStudyID

28. 28  Showed that 2nd-line chemotherapy could prolong survival in NSCLC  Showed that 2nd-line chemotherapy could improve performance status and symptom control in NSCLC  Showed that 2nd-line chemotherapy did not have a negative impact on QoL in NSCLC  Led to the approval of docetaxel 75 mg/m 2 for the 2nd-line treatment of NSCLC in 1999 These Landmark Trials … ID : 092Content Owner:TAX 317/320SubCat:SubSubCatShepherdStatus: CoreStudyID

29. 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 : 089Content Owner:TAX 317/320SubCat:SubSubCatShepherdStatus: CoreStudyID

30. 30 Current Second-Line Treatment of NSCLC ID : 160Content Owner:TAX 317/320SubCat:SubSubCatShepherdStatus: CoreStudyID  Patients benefit from treatment with docetaxel  Safer or more effective alternatives to docetaxel are needed  Unmet medical need – Performance status and toxicity of 1st-line therapy may preclude docetaxel use – Increased use of 1st-line docetaxel  No other approved options There is a need for additional options in second-line treatment of NSCLC

31. 31 Roy Herbst, MD, PhD Chief and Associate Professor, Thoracic Oncology, University of Texas M. D. Anderson Cancer Center Alimta Development ID : 009Content Owner:InformationalSubCat:SubSubCatHerbstStatus: CoreStudyID

32. 32 Alimta (Pemetrexed) Chemical Structure ID : 203 Chen, Victor 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. 33 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 Alimta Mechanism of Action ID : 010Content Owner:Chemical Structure, MOAMechanism of ActionSubSubCatHerbstStatus: CoreStudyID

34. 34 Alimta Preclinical Results in Non Small Cell Lung Cancer Tumor GraftDose In vivo % Tumor Inhibition LX-1 Lung300 100 75 62 ID : 142Content Owner:BackgroundIn VivoSubSubCatHerbstStatus: CoreStudyID Tumor Cell LinesIn vitro IC 50 (nM) NSCLC LX-14 NSCLC H46060 NSCLC H2350 NSCLC A549156

35. 35 First-Line NSCLC Monotherapy – Alimta and Docetaxel Efficacy N EvaluableRegimen Dose (mg/m 2 ) Response Rate (%) Median Survival Fossella41Docetaxel1003310.8 mo Gandara80Docetaxel100167.0 mo Alexopoulos60Docetaxel100257.4 mo Miller20Docetaxel7525NR Roszkowski*137Docetaxel100136.0 mo Clarke 1 57Alimta600167.2 mo Rusthoven 1 **30Alimta500239.2 mo * Phase III study** Dosage amended from 600 mg/m 2 due to toxicity 1 No Vitamin Supplementation ID : 161Content Owner:Phase 1 and 2Approval in MesoSubSubCatHerbstStatus: CoreStudyID

36. 36 First-Line NSCLC Combination – Alimta Phase II Studies ID : 276 Kayitalire, Louis Phase 1 and 2 Combination Efficacy Herbst Status: Core StudyID Manegold et al. (2000)* Shepherd et al. (2001)* Scagliotti et al. (2003) Koshy et al. (2003) N36293950 Alimta (mg/m 2 ) Combination (d1 q21d) 500 Cisplatin 75 mg/m 2 500 Cisplatin 75 mg/m 2 500 Carboplatin AUC 6 500 Carboplatin AUC 6 Response Rate Median Survival 1-Year Survival Median TTPD 39% 10.9 mo 50% 6.3 mo 45% 8.9 mo 49% NR 31.6% 10.5 mo NR 5.7 mo 29% 13.5 mo 55.8% 4.8 mo * Before vitamin supplementation

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

38. 38 Alimta Safety Profile Content Owner:Story-HcySubCat:SubSubCatHerbstStatus: CoreStudyID ID : 101  As with most antifolates, the primary toxicity is hematologic  Early data showed that high serum homocysteine levels – a surrogate for functional folate and/or B 12 deficiency – correlated with higher levels of toxicity  A decision was made to supplement all patients with folic acid and vitamin B 12  This resulted in decreased toxicity with no detrimental effect on efficacy

39. 39 Or G3/4 Nonhem Tox Toxicity in Patients With and Without FA/ Vitamin B 12 Supplementation P=<0.0001 P =0.0053 P =0.026 * No toxic death reported * ID : 842Shepherd, FrancesStory-HcyLCSSSubSubCatHerbstStatus: CoreStudyID

40. 40 Summary of the Development of Alimta Content Owner:Phase 1 and 2SubCat:SubSubCatHerbstStatus: CoreStudyID ID : 101  Alimta has shown activity in NSCLC – Single agent 1st and 2nd-line – Combination with platinum agents in 1st-line  Safety of Alimta has been well characterized – Toxicity significantly reduced after Folic Acid / B 12 – Very low incidence of neutropenia, febrile neutropenia, and other non-hematologic toxicities  A pivotal Phase III study in the treatment of 2nd-line NSCLC was indicated

41. 41 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:InformationalSubCat:SubSubCatBunnStatus: CoreStudyID ID : 100

42. 42  Study Design  Patient Characteristics  Survival  Survival Analysis – Alimta vs docetaxel – Alimta vs historical BSC  Other Secondary Endpoints  Toxicity  Conclusion Outline of Presentation ID : 453Content Owner:InformationalObjectivesSubSubCatBunnStatus: CoreStudyID

43. 43 Alimta (N=283) 500 mg/m 2 iv q3wks (folic acid 350-1000 µg daily + vitamin B 12 1000 µg q 9wks; dexamethasone 4 mg bid on d-1, d0, d+1) Balanced for:  ECOG PS 0/1 vs 2  Stage III vs IV  No. of prior regimens (1 or 2)  Best response to prior chemo  Time since last chemo ( 3 mo)  Prior platinum  Prior taxane  Homocysteine level ( 12 µm)  Center Phase III Study of Alimta vs Docetaxel in 2nd-Line NSCLC Content Owner: Statistical Design SubCat: SubSubCatBunn Status: CoreStudyID ID : 101 RANDOMIZERANDOMIZE Docetaxel (N=288) 75 mg/m 2 iv q3wks (dexamethasone 8 mg bid on d-1, d0, d+1)

44. 44  Primary Endpoint: – Overall Survival HR  Major Secondary Endpoints: – Progression-Free Survival – Time to Progressive Disease – Tumor Response Rate – Toxicity – Lung Cancer Symptom Scale JMEI: Endpoints Content Owner:Statistical DesignSubCat:SubSubCatBunnStatus: CoreStudyID ID : 102

45. 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 : 454Content Owner:Statistical DesignObjectivesSubSubCatBunnStatus: CoreStudyID

46. 46  Inclusion Criteria – Histologic/cytologic Stage III or IV NSCLC – Only 1 regimen for metastatic disease – ECOG PS 0-2 – Adequate end organ function  Exclusion Criteria – Symptomatic brain metastasis – Grade 3 or 4 peripheral neuropathy – Weight loss > 10% over previous 6 weeks – Uncontrolled pleural effusions – Prior docetaxel therapy JMEI: Inclusion/Exclusion Criteria ID : 105Content Owner:Statistical DesignSubCat:SubSubCatBunnStatus: CoreStudyID

47. 47 JMEI: Baseline Characteristics (ITT) Percent of Patients Alimta (N=283) Docetaxel (N=288) ECOG PS 211.4%12.4% Stage IV74.9%74.7% Median Age, years (range) Male 59 (22-81) 68.6% 57 (28-87) 75.3% Histology Adenocarcinoma Squamous 54.4% 27.6% 49.3% 32.3% Homocysteine levels <12 μm71.4%68.9% ID : 106Content Owner:Baseline CharactSubCat:SubSubCatBunnStatus: CoreStudyID

48. 48 JMEI: Baseline Characteristics (ITT) Percent of Patients Alimta (N=283) Docetaxel (N=288) Best Response to Prior Chemo CR/PR35.6%36.5% < 3 mo since Last Chemo50.4%48.1% Prior Taxane25.8%27.8% Prior Platinum92.6%89.9% ID : 455Content Owner:Baseline CharactSubCat:SubSubCatBunnStatus: CoreStudyID

49. 49 JMEI: Treatment Delivered (RT) Alimta (N=265) Docetaxel (N=276) No Treatment Delivered (ITT-RT)1812 Patients Received > 4 Cycles136139 No. Cycles, Median (range)4 (1-20)4 (1-14) Planned Dose Intensity96.6%94.4% Dose Delays19.8%17.8% Dose Reductions*1.2%5.6% ID : 107Content Owner:Dosage and DelaysSubCat:SubSubCatBunnStatus: CoreStudyID * p<0.001

50. 50 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 JMEI: Survival (ITT) 018151296321 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 : 108Content Owner:Overall SurvivalSubCat:SubSubCatBunnStatus: CoreStudyID

51. 51 Interpreting the Efficacy of Alimta Relative to BSC  Retention method was used to estimate the percent of docetaxel benefit over BSC retained by Alimta – 95% CI for %-retention pre-specified in the Analysis Plan – Based on TAX 317B (75 mg/m 2 docetaxel randomized vs BSC) – Accounts for variability (sample size) in TAX 317B and JMEI – Allows for a survival comparison of Alimta to historical BSC – Assumes a reasonable comparability of TAX 317B and JMEI ID : 165Content Owner:Overall SurvivalAnalysis PlanSubSubCatBunnStatus: CoreStudyID

52. 52 Patient Demographics for TAX 317 and JMEI TAX 317 Data (N=204) JMEI (N=571) Performance status (2)15%12% Stage IV79%75% Median Age, years6158 Male67%72% Best response to prior chemo (other than CR/PR) 65%64% Prior taxane0%27% Prior platinum100%91% Number of prior chemo (2)25%6% ID : 487 Paul, Sofia Baseline Charact. SubCat: SubSubCat Bunn Status: Core StudyID

53. 53 JMEI: Survival with TAX 317 (ITT) ID : 108Content Owner:Overall SurvivalSubCat:SubSubCatBunnStatus: CoreStudyID HR (Alimta vs BSC) 0.55 95% CI: 0.33, 0.90 p-value= 0.019 JMEI Alimta (N=276) TAX 317B BSC (N=49)

54. 54 JMEI: Overall Survival ID : 164Content Owner:Overall SurvivalAnalysis PlanSubSubCatBunnStatus: CoreStudyID * Percent retention based on TAX 317 (B) results JMEI 95% CI 0% 0.701.40 0.82 157% 52% Alimta superior to BSC* 1.33 1.20 102% Percent Retention* Hazard Ratio Alimta vs docetaxel 78% 1.11 Alimta within 10% margin of docetaxel Alimta retains >50% of docetaxel benefit* 1.21 1.00 Alimta superior to docetaxel 0.99

55. 55 JMEI: Overall Survival ITT PopulationRT Population Alimta (N=283) Docetaxel (N=288) Alimta (N=265) Docetaxel (N=276) Events206203192198 NI p-value for testing 50% retention 0.0470.036 95% CI of estimated percent of efficacy retained by Alimta (52%, 157%)(58%, 168%) 50% retention non-inferiority test based on point estimate of control effect (HR docetaxel/BSC = 0.555) ID : 808Content Owner:Overall SurvivalSubCat:SubSubCatBunnStatus: CoreStudyID

56. 56  Stage of disease (III vs IV)  Performances status (0 or 1 vs 2)  Time since last chemotherapy (  3 vs  3 mo)  Best response to prior chemotherapy (CR/PR vs SD vs PD/unknown)  Prior taxane use (Yes vs No)  Prior platinum use (Yes vs No)  Prior chemotherapies (1 vs 2) JMEI: Stepwise Cox Multiple Regression Survival Model ID : 120Content Owner:Statistical DesignSubCat:SubSubCatBunnStatus: CoreStudyID

57. 57 Variable p-value HR (95% CI for HR) Performance Status (0 – 1 over 2)< 0.0010.25 (0.19, 0.34) Time since last chemotherapy (  3 mo over  3 mo) 0.0040.74 (0.60, 0.90) Stage of Disease (III over IV)0.0260.77 (0.60, 0.97) Cox Multiple Regression Model JMEI: Factors Predictive of Survival ID : 121Content Owner:Survival Other SubsSubCat:SubSubCatBunnStatus: CoreStudyID

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

59. 59 JMEI: Survival Analyses for Key Subgroups N EvaluableHR Adjusted HR Prior Platinum5211.030.95 No Prior Platinum500. 740.91 No Prior Taxane Prior Taxane 418 153 1.03 0.97 0.97 0.84 Performance Status 0 or 14741.000.99 Performance Status 2640.750.73 Stage III1441.011.11 Stage IV4270.990.89 < 3 mo since last chemo2771.060.97 > 3 mo since last chemo2860.920.90 ID : 075Peterson, PatrickStatistical ResultsSubgroup SurvivalSubSubCatBunnStatus: CoreStudyID No treatment differences within subgroups

60. 60  Primary Endpoint: – Overall Survival HR  Major Secondary Endpoints: – Progression-Free Survival (PFS) – Time to Progressive Disease (TTPD) – Tumor Response Rate – Toxicity – Lung Cancer Symptom Scale JMEI: Endpoints ID : 114Content Owner:JMEI Stats and DesignSubCat:SubSubCatBunnStatus: CoreStudyID

61. 61 MPFS = median progression-free survival JMEI: Progression-Free Survival (ITT) HR 0.97 95% CI of HR (0.82, 1.16) MPFS = 2.9 mo 018151296321 1.00 0.75 0.50 0.25 0.00 Survival Distribution Months Alimta (N=283) Docetaxel (N=288) ID : 113Content Owner:Secondary EfficacySubCat:SubSubCatBunnStatus: CoreStudyID

62. 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 0181512963 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. 63 Type No. of Patients in Each Arm (%) Alimta (N=265) Docetaxel (N=276)  1 Chemotherapy 126 (47.5)107 (38.8) Platinum 9 (3.4)15 (5.4) Docetaxel85 (32.1) 11 (4.0) Paclitaxel4 (1.5) 3 (1.1) Vinorelbine6 (2.3) 25 (9.1) Gemcitabine17 (6.4) 32 (11.6) Other chemo22 (8.4) 34 (12.3) Gefitinib5 (1.9) 21 (7.6) JMEI: Post Study Chemotherapy Received (RT) ID : 047Content Owner:Survival by Post StudyPost Study ChemoSubSubCatBunnStatus: CoreStudyID

64. 64 JMEI: Survival by Post Study Chemotherapy Group (RT) Patient Population Alimta (N=265)MS Docetaxel (N=276)MS No post-study chemo 1396.2 mo1695.0 mo Any post-study chemo1269.8 mo10710.8 mo Post-study docetaxel therapy 859.6 mo1110.1 mo Other chemotherapy 4110.6 mo9611.2 mo ID : 048Content Owner:Survival by Post StudyPost Study ChemoSubSubCatBunnStatus: CoreStudyID

65. 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 1.00 0.75 0.50 0.25 0.00 Survival Distribution Factor 01512.5107.552.5 17.520 Post Progression Survival

66. 66 JMEI: Response Rates 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 : 111Content Owner:Secondary EfficacySubCat:SubSubCatBunnStatus: CoreStudyID

67. 67 Statistically Significant Grade 3/4 CTC Toxicities Regardless of Causality (RT) Percent of Patients Toxicity Alimta (N=265) Docetaxel (N=276)p-value Febrile Neutropenia1.912.7<0.001 Neutropenia5.340.2<0.001 Infect w Gr 3/4 Neutropenia 05.8<0.001 Diarrhea0.44.00.006 Alopecia (all grades)11.342.4<0.001 ALT2.60.40.034 ID : 701Content Owner:Lab Tox and Feb Neut.ObjectivesSubSubCatBunnStatus: CoreStudyID

68. 68 Benefit of Alimta in Second-Line NSCLC  Survival of Alimta compared to docetaxel: – Overall survival is similar – Retains 102% of docetaxel benefit (over BSC) – Internal consistency within subgroups – No cross-over or other post-study chemotherapy effect  Superior survival to historical BSC  Similar response rate to docetaxel  Similar PFS and TTPD to docetaxel  Superior safety profile to docetaxel ID : 169Content Owner:Risk-Benefit ConclusionAnalysis PlanSubSubCatBunnStatus: CoreStudyID

69. 69 ID : 088Content Owner:NSCLCSubCat:SubSubCatZhangStatus: CoreStudyID Safety Results and Patient Reported Outcomes Richard J. Gralla, MD President, Multinational Association of Supportive Care in Cancer JMEI Randomized Trial: Alimta vs Docetaxel in Second-Line NSCLC

70. 70  Primary Endpoint: – Survival  Major Secondary Endpoints: – Progression-Free Survival – Time to Progressive Disease – Tumor Response Rate – Toxicity – Lung Cancer Symptom Scale JMEI: Endpoints ID : 114Content Owner:JMEI Stats and DesignSubCat:SubSubCatZhangStatus: CoreStudyID

71. 71 Patient Reported Outcomes: Evaluation Methods in the JMEI Trial  Lung Cancer Symptom Scale (LCSS) – Well validated with published psychometrics * – Patient (9 items) & Observer (6 items) forms – Developed for clinical trials and patient management – Used in many randomized, multicenter trials in lung cancer  Evaluation – Patients completed the instrument weekly while on trial – 85% of patients adequately completed the PRO evaluation * Reference: Hollen et al Cancer, 1994. ID : 081Content Owner:JMEI SafetyQoLSubSubCatGrallaStatus: CoreStudyID

72. 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 : 175Content Owner:QoLSymptom ImprovementSubSubCatGrallaStatus: CoreStudyID

73. 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 : 173Content Owner:QoLSymptom ImprovementSubSubCatGrallaStatus: CoreStudyID

74. 74  Primary Endpoint: – Survival  Major Secondary Endpoints: – Progression-Free Survival – Time to Progressive Disease – Tumor Response Rate – Toxicity – Lung Cancer Symptom Scale JMEI: Endpoints ID : 114Content Owner:JMEI Stats and DesignSubCat:SubSubCatZhangStatus: CoreStudyID

75. 75 Docetaxel Toxicities (75 mg/m 2 ) Regardless of Causality (per Label)* ToxicityAnyGrade 3/4 Neutropenia84.165.3 Febrile Neutropenia-6.3** Infection33.510.2 Asthenia52.818.2 Nausea33.55.1 Vomiting21.62.8 Stomatitis26.11.7 Diarrhea22.72.8 Neurosensory23.31.7 Hypersensitivity5.72.8 Fluid Retention35.52.8 Rash19.90.6 Alopecia56.3- * Data combined from TAX 317 and TAX 320 ** ANC Grade 4 with fever >38°C with iv antibiotics and/or hospitalization ID : 702Content Owner:Lab Tox, CTC, HospObjectivesSubSubCatGrallaStatus: CoreStudyID

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

77. 77 JMEI: Summary of Deaths On-Study* DeathsAlimtaDocetaxelp-value Study drug related350.725 Study disease related18260.276 Other1090.818 Total31400.374 Number of patients ID : 640Content Owner:Non LabSubCat:SubSubCatGrallaStatus: CoreStudyID * On-study or within 30 days of discontinuation

78. 78 JMEI: Adverse Events (RT) NCI Common Toxicity Criteria v2 – Example: Neutropenia Neutrophils/mm3Risk / Impact Grade 1> 1500 < 2000None Grade 2> 1000 < 1500Very Low Grade 3> 500 – 1000Moderate Grade 4< 500Very High ID : 138Content Owner:Lab Tox and Feb NeutSubCat:SubSubCatGrallaStatus: CoreStudyID

79. 79 Percent of Patients Toxicity Alimta (N=265) Docetaxel (N=276)p-value Neutropenia5.340.2<0.001 Febrile Neutropenia1.912.7<0.001 Infection with Gr 3/4 Neutropenia 05.8<0.001 Anemia Thrombocytopenia Creatinine ALT AST 7.5 1.9 0.0 2.6 1.1 6.2 0.7 0.0 0.4 0.4 0.610 0.277 1.0 0.034 0.364 Bilirubin0.80.0— JMEI: Grade 3/4 Lab Toxicities (NCI-CTC) Regardless of Drug Causality (RT) ID : 060Content Owner:Lab Tox and Feb. Neut.Lab ToxSubSubCatGrallaStatus: CoreStudyID

80. 80 Percent of Patients Toxicity Alimta (N=265) Docetaxel (N=276) p-value Fatigue15.816.70.817 Nausea3.82.50.466 Vomiting1.51.41.0 Stomatitis1.1 1.0 Diarrhea0.44.00.006 Neurosensory7.59.80.365 Hypersensitivity0.01.80.062 Fluid Retention0.4 1.0 Rash0.0 1.0 Alopecia (all grades)11.342.4<0.001 JMEI: Gr 3/4 Non-Lab Toxicities (NCI- CTC) Regardless of Drug Causality (RT) ID : 062Content Owner:Non-Lab ToxicitiesNon-Lab ToxSubSubCatGrallaStatus: CoreStudyID

81. 81 Percent of Patients Toxicity Alimta (N=265) Docetaxel (N=276)p-value All Grade 1 2623.9 0.620 All Grade 2 29.425.0 0.288 All Grade 3 18.130.4<0.001 All Grade 45.334.1<0.001 JMEI: Lab Toxicities (NCI-CTC) Regardless of Drug Causality (RT) ID : 059Content Owner:Lab Tox and Feb. Neut.Lab ToxSubSubCatZhangStatus: CoreStudyID

82. 82 JMEI: Transfusions and Growth Factors (RT) Percent of Patients Alimta (N=265) Docetaxel (N=276)p-value Red Blood Cell Transfusions 16.611.60.108 Erythropoietin6.810.10.169 G-CSF/GM-CSF2.619.2<0.001 ID : 066Content Owner:Lab Tox and Feb. Neut.TransfusionsSubSubCatGrallaStatus: CoreStudyID

83. 83 Percent of Patients Toxicity Alimta (N=265) Docetaxel (N=276)p-value All Grade 195.192.0 0.165 All Grade 293.693.8>0.999 All Grade 360.068.1 0.060 All Grade 414.322.5 0.020 JMEI: Non-Lab Toxicities Regardless of Drug Causality (RT) ID : 061Content Owner:Non-Lab ToxicitiesNon-Lab ToxSubSubCatGrallaStatus: CoreStudyID

84. 84 JMEI: Hospitalizations (RT) Percent of Patients Alimta (N=265) Docetaxel (N=276)p-value Any Hospitalizations48.752.90.345 >1 Hospitalization due to AE31.740.60.032 All drug-related hospitalization Any drug-related hospitalization Due to febrile neutropenia 7.2 1.5 21.7 13.4<0.001 Due to other drug-related AEs6.410.50.092 ID : 063Content Owner:Non-Lab ToxicitiesHospitalizationsSubSubCatGrallaStatus: CoreStudyID

85. 85 Toxicity-Free (Any Grade 4) Survival Curve ID : 177Content Owner:Risk Benefit Conclusions Clinical BenefitSubSubCatGrallaStatus: CoreStudyID

86. 86 JMEI: Safety Conclusions  From a safety standpoint, Alimta represents a superior treatment option in the second line treatment of NSCLC — Significantly less neutropenia and febrile neutropenia* — Significantly less alopecia and diarrhea* — Significantly fewer drug-related serious adverse events* — Fewer on-study deaths — Significantly fewer hospitalizations due to adverse events — Less use of supportive care * p < 0.006 ID : 086Content Owner:Lab Tox and Feb NeutNon-Lab ToxSubSubCatGrallaStatus: CoreStudyID

87. 87 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 : 131Content Owner:InformationalSubCat:SubSubCatBunnStatus: CoreStudyID

88. 88 Treatment Options in Second-Line NSCLC Alimta provides a safe and effective 2nd-line option for NSCLC patients and this is especially important because:  Advanced stage NSCLC patients are living longer and better lives, therefore more receive 2nd-line therapy  Docetaxel is the only approved compound for 2nd-line NSCLC  Docetaxel safety profile limits its use in 2nd-line ID : 133 Content Owner:Risk-Benefit Conclusions SubCat:SubSubCatBunnStatus: CoreStudyID

89. 89 Evidence for Clinical Benefit of Alimta in 2nd-Line NSCLC (RT): Safety ID : 180Content Owner:Lab Tox and Feb. Neut.SubCat:SubSubCatBunnStatus: CoreStudyID Alimta (N=265) Docetaxel (N=276) Febrile Neutropenia1.9%12.7% G-CSF/GM-CSF2.6%19.2% Grade 3/4 Diarrhea0.4%4.0% Alopecia (all grades)11.3%42.4% Drug-induced AE hospitalization 7.2%21.7% Alimta is safer with respect to clinically important toxicities

90. 90 Toxicity Comparison of Safety Database for Single Agent Alimta* Regardless of Drug Causality Other Alimta SA** (N=207) JMEI (N=265) Gr. 3/4 Neutropenia14.05.3 Febrile Neutropenia1.81.9 Gr. 3/4 Platelets3.71.9 Gr. 3/4 Anemia2.47.5 Alopecia (any grade)11.611.3 Gr. 3/4 Diarrhea3.00.4 Toxic Deaths01.1 * With vitamin supplementation ** Single Agent ID : 846Content Owner:Single AgentSubCat:SubSubCatBunnStatus: CoreStudyID

91. 91 Direct Comparison to Docetaxel – HR=0.99 (0.93 adjusted) – Median Survival (8.3 mo vs 7.9 mo) – One-Year Survival (29.7% vs 29.7%) – Internal consistency of subgroups Indirect Comparison to BSC – Preserves at least 50% of docetaxel’s benefit over BSC – Superior to historical BSC – Consistent Alimta survival results across 1st and 2nd line trials Evidence for Clinical Benefit of Alimta in 2 nd Line NSCLC: Survival ID : 178 Content Owner:Overall SurvivalSubCat:SubSubCatBunnStatus: CoreStudyID

92. 92 Evidence for Clinical Benefit of Alimta in 2 nd Line NSCLC: Response, TTP Direct Comparison vs. docetaxel  Time to Tumor Progression (3.4 mo vs 3.5 mo)  Progression-Free Survival (2.9 mo vs 2.9 mo)  Response Rate (9.1% vs 8.8%)  Over 50% of Alimta and docetaxel patients had improved or stable symptoms Indirect Comparison to BSC  Comparable Overall response rates and median time to progression between Alimta trials  Superior response rates and TTPD ID : 705Content Owner:Secondary EfficacyObjectivesSubSubCatBunnStatus: CoreStudyID

93. 93 Consistency of Survival Results in Randomized Studies in 2nd-Line NSCLC 0 8 Median Survival (mo) 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 TAX 317B N=104 TAX 320 N=248 Gridelli N=220 Camps N=254 JMEI N=571 ID : 132Content Owner:Overall SurvivalSubCat:SubSubCatBunnStatus: CoreStudyID JBR21 N=364 BSC Erlotinib 150 mg q d Placebo and BSC Alimta produces survival equivalent to the best docetaxel results and superior to BSC 4 2 6

94. 94 Alimta Clinical Benefit Alimta merits full approval as a single agent for the treatment of patients with locally advanced or metastatic NSCLC after prior chemotherapy based on: – Superior PFS and survival compared to BSC – Similar OR, PFS and survival compared to docetaxel – Superior safety profile as compared with docetaxel. Making available a safer effective treatment will improve the physicians’ ability to make treatment decisions for patients with this devastating disease. ID : 706Content Owner:Risk-Benefit Conclusion ObjectivesSubSubCatBunnStatus: CoreStudyID