PARAMOUNT: Phase III Study of Maintenance Pemetrexed (Pem) Plus Best Supportive Care (BSC) Versus Placebo Plus BSC Immediately Following Induction Treatment with Pem Plus Cisplatin for Advanced Nonsquamous Non-small Cell Lung Cancer L. G. Paz-Ares 1, F. de Marinis 2, M. Dediu 3, M. Thomas 4, J.L. Pujol 5, P. Bidoli 6, O. Molinier 7, T.P. Sahoo 8, E. Laack 9, M. Reck 10, J. Corral 1, S. Melemed 11, W. John 11, N. Chouaki 12, A. H. Zimmermann 11, C. Visseren-Grul 13, C. Gridelli 14 1 University Hospital - Virgen del Rocio, Seville, Spain; 2 San Camillo - Forlanini Hospital, Rome, Italy; 3 Institute of Oncology, Bucharest, Romania; 4 Clinic for Thoracic Diseases at University Hospital Heidelberg, Heidelberg, Germany; 5 Montpellier Academic Hospital, Montpellier, France; 6 Medical Oncology Unit, S. Gerardo Hospital, Monza, Italy; 7 Le Mans Regional Hospital, Le Mans, France; 8 Jawaharlal Nehru Cancer Hospital and Research Center, Bhopal, India; 9 University Hospital Hamburg-Eppendorf, Germany; 10 Hospital Grosshansdorf, Grosshansdorf, Germany; 11 Eli Lilly and Company, Indianapolis, IN, USA; 12 Eli Lilly and Company, Suresnes, Hauts de Seine, France ; 13 Eli Lilly and Company, Houten, The Netherlands; 14 San Giuseppe Moscati Hospital, Avellino, Italy

Disclosure Information  Employment – None  Consultant or Advisory Role – Yes (Eli Lilly and Co.)  Stock Ownership – No  Honoraria – No  Research Funding – No  Testimony – No  Other – No

PARAMOUNT: Background  Most patients with NSCLC have stage IIIB/IV disease at the time of diagnosis 1  Platinum-based combinations are recommended as first-line treatment 2  Pemetrexed has demonstrated efficacy in treating advanced nonsquamous NSCLC: ─ in combination with cisplatin as a first-line doublet 3 ─ as a maintenance agent following a non-pemetrexed platinum doublet 4  Maintenance therapy is used to prolong tumor response or stable disease, with a goal of improving PFS and OS  Pemetrexed maintenance has not been studied following pemetrexed-platinum induction in a phase III setting Azzoli CG et al. J Clin Oncol 2009; 27:6251– Scagliotti GV et al. J Clin Oncol 2008;26: ; 4 Ciuleanu T et al. Lancet 2009;374:

PARAMOUNT: Study Design  Randomized, placebo-controlled, double-blind, phase III study  Folic acid and vitamin B 12 administered to both arms Study Treatment Period Progression Induction Therapy (4 cycles)Maintenance Therapy (Until PD) 21 to 42 Days 500 mg/m 2 Pemetrexed + 75 mg/m 2 Cisplatin, d1, q21d CR, PR, SD PD Placebo + BSC, d1, q21d 500 mg/m 2 Pemetrexed + BSC, d1, q21d 2:1 Randomization Patients enrolled if: Nonsquamous NSCLC No prior systemic treatment for lung cancer ECOG PS 0/1 Stratified for: PS (0 vs 1) Disease stage (IIIB vs IV) prior to induction Response to induction (CR/PR vs SD)

PARAMOUNT: Study Objectives  Primary objective: progression-free survival (PFS)  Secondary objectives: ─ Overall survival (OS) ─ Objective tumor response rate (RR) (RECIST 1.0) ─ Patient-reported outcomes (EQ ‑ 5D) ─ Resource utilization ─ Adverse events (AEs)  All endpoints measured from date of randomization, after completion of induction chemotherapy

PARAMOUNT: Statistical Design  PFS: 90% power, assuming a minimum of 238 events and HR=0.65, α=0.05  900 patients planned to be enrolled in order to randomize an estimated 558 patients to maintenance therapy  Pre-planned full independent radiological review of PFS  Powered for secondary endpoint, OS ─ OS: 93% power, assuming a minimum 390 events and HR=0.70 ─ Alpha was controlled for both a preliminary analysis (α=0.0001) and final analysis of OS (α=0.0499)

400 Patients Not Randomized 217 Progressive Disease 62 Adverse Event 56 Death 29 Study Disease 15 AE 11 Drug-Related AE 1 Procedure-Related AE 65 Other Reasons 1022 Patients Screened 939 Patients Enrolled 539 Patients Randomized (2:1 Randomization) Pemetrexed Arm N=359 Placebo Arm N= Patients Failed Screening Induction Phase Maintenance Phase 136 (38%) Patients on Pemetrexed Maintenance at Data Cut Off 43 (24%) Patients on Placebo at Data Cut Off PARAMOUNT: Patient Disposition 548 Patients Eligible for Maint 8 Discontinued Pt Decision 1 Discontinued Phys Decision

PARAMOUNT: Patient Characteristics (Randomized Patients) *Protocol violations Pemetrexed (N=359) n (%) Placebo (N=180) n (%) Median age, yrs 6162 Age <65 yrs 238 (66)112 (62) Male 201 (56)112 (62) Caucasian 339 (94)171 (95) Smoker Ever smoker 275 (77)144 (80) Never smoker 82 (23)34 (19) ECOG PS (32) 55 (31) (68)123 (68) 2/3* 1 (0.3) 2 (1)

PARAMOUNT: Disease Characteristics (Randomized Patients) Pemetrexed (N=359) n (%) Placebo (N=180) n (%) Disease stage IV* 328 (91)161 (89) Histology Adenocarcinoma 310 (86)160 (89) Large cell 24 (7)12 (7) Other nonsquamous 25 (7) 8 (4) Induction response CR/PR 166 (46) 76 (42) SD 186 (52) 94 (52) PD/Unknown † 7 (2)10 (6) * Lung Cancer Staging System Version V † Protocol violations

PARAMOUNT: Drug Administration (Randomized Patients) Maintenance Phase Pemetrexed (N=359) Placebo (N=180) Patients treated* Number of cycles/patient Median44 Range Mean # of cycles Patients completing >6 cycles84 (23%)25 (14%) Dose intensity95%NA * Due to data cut off, some patients had been randomized but had not yet received maintenance treatment.

PFS Events Overview Progression Free Survival Pemetrexed N=359 Placebo N=180 Investigator Assessed Events184 (51%)118 (66%) Progression Events173 (94%)113 (96%) Deaths11 (6%)5 (4%)

PARAMOUNT: Investigator Assessed PFS (from Maintenance) Pemetrexed: median =4.1 mos ( ) Placebo: median =2.8 mos ( ) Log-rank P= Unadjusted HR: 0.62 ( ) Patients at Risk Pem + BSCN= Placebo + BSCN= Pem + BSC Placebo + BSC

 PFS results were internally consistent; benefit was seen across all subgroups Favors Pemetrexed Favors Placebo Treatment Hazard Ratio (95% CI) ─0.62 ─0.55 ─0.48 ─0.74 ─0.67 ─0.53 ─0.41 ─0.70 ─0.74 ─0.49 ─0.69 ─0.34 ─0.70 ─0.64 ─0.39 ─0.62 All Randomized Patients (N=539) Stage IV (n=489) Stage IIIB (n=50) Induction Response CR/PR (n=242) Induction Response SD (n=280) Pre-randomization PS 1 (n=366) Pre-randomization PS 0 (n=170) Non-smoker (n=116) Smoker (n=419) Male (n=313) Female (n=226) Age <70 (n=447) Age ≥70 (n=92) Age <65 (n=350) Age > 65 (n=189) Other Histologic Diagnosis (n=32) Large Cell Carcinoma (n=36) Adenocarcinoma (n=471) PARAMOUNT: Subgroup PFS Hazard Ratios

PARAMOUNT: Independently Reviewed PFS (from Maintenance) Pemetrexed: median =3.9 mos ( ) Placebo: median =2.6 mos ( ) Log-rank P= Unadjusted HR: 0.64 ( ) Pem + BSC Placebo + BSC  88% of patients were independently reviewed (472/539) Patients at Risk Pem + BSCN= Placebo + BSC N=

PARAMOUNT: Investigator Assessed PFS (from Induction) Pem: median = 6.90 ( ) Placebo: median = 5.59 ( ) Log Rank p< Unadjusted HR : 0.59 ( ) Pem + BSC Placebo + BSC Patients at Risk Pem + BSCN= Placebo + BSC N=

Pemetrexed (N=316) n (%) Placebo (N=156) n (%) P-value CR 00 PR 9 (2.8)1 (0.6) RR: CR+PR 9 (2.8)1 (0.6)0.176 SD 218 (69.0)92 (59.0) DCR: CR+PR+SD 227 (71.8)93 (59.6)0.009 PD 88 (27.8)61 (39.1) Other / ND 1 (0.3)2 (1.3) PARAMOUNT Independently Reviewed Tumor Response* (Maintenance) - All randomized patients * Response represents a further tumor reduction from the baseline response to induction therapy

PARAMOUNT: Health-related Quality of Life Assessment (EQ-5D) ◆ EQ-5D is a health-status questionnaire consisting of two parts: ─ Index score generated from five descriptive questions (relating to mobility, self-care, activities, discomfort, anxiety) ─ Visual analog scale: patients rate their present health ◆ Administered at: ─ Baseline (before induction) ─ Day 1 of each cycle of induction or maintenance therapy (prior to treatment) ─ 30-day post-discontinuation visit ◆ Compliance at all time points during maintenance phase was >80% ◆ No statistical differences in EQ-5D index score or visual analog scale were observed between treatment arms

PARAMOUNT: Drug-related Safety Events (Randomized Patients) Maintenance Phase Pemetrexed (N=359) (%) Placebo (N=180) (%) Drug-related deaths*0.6 Drug-related SAEs † Discontinuation due to AE ≥1 grade 3/4 drug-related CTCAE laboratory toxicities † ≥1 grade 3/4/5* drug-related CTCAE non-laboratory toxicities *On-study deaths: one on pemetrexed (pneumonia); one on placebo (NOS); one death within 30 days (endocarditis on pemetrexed) †Statistically significant between arms (Fisher’s exact test P≤0.05)

PARAMOUNT: CTCAEs Grade 3/4 Drug- related Toxicities (Randomized Patients) Grade 3/4 Event Pemetrexed N=359 (%) Placebo N=180 (%) Fatigue * Anemia * Neutropenia * 3.60 Leukopenia1.70 Anorexia0.30 Nausea0.30 Neuropathy-sensory Mucositis/stomatitis0.30 ALT (SGPT)0.30 *Statistically significant between arms (Fisher’s exact test P≤0.05)

PARAMOUNT: Conclusions  PARAMOUNT met its primary endpoint by showing significantly improved PFS in patients treated with pemetrexed continuation maintenance therapy as compared to placebo  The highly significant PFS results (HR = 0.62) demonstrate that pemetrexed continuation maintenance therapy is an effective treatment for patients with advanced nonsquamous NSCLC following pemetrexed plus cisplatin induction therapy  The independent review was comprehensive (88%) in the percentage of scans and confirmed the robustness of the primary endpoint of investigator-assessed PFS  Pemetrexed had a well-tolerated safety profile, similar to the previous pemetrexed maintenance trial in NSCLC 1  The study was fully powered for OS; this will be reported when data are mature 1 Ciuleanu T, et al. Lancet 2009;374:

Acknowledgements We thank all of the patients and their caregivers for participating in this trial. We thank all of the investigators and their support staff who generously participated in this work.