Study JMDB - A Randomised Phase III Trial of Cisplatin + Pemetrexed vs

Slides:

Advertisements

Similar presentations

FOLFOXIRI plus bevacizumab (bev) vs FOLFIRI plus bev

Advertisements

I I. B.- T R E A T M E N T P L A N: DOCETAXEL 75 mg/m2 40 mg/m2 THORACIC RT (66 Gys: 180 cGy/d) CISPLATIN 40 mg/m2 Days E V A L U A.

Treatment in Advanced Non-Small Cell Lung Cancer.

C.P. Belani 1, T. Brodowicz 2, P. Peterson 3, W. John 3, G. Scagliotti 4 1 Penn State Cancer Institute, Hershey, PA USA; 2 Medical University, Vienna,

PARAMOUNT: phase III study of pemetrexed continuation maintenance therapy in advanced non-squamous NSCLC.

Non-small Cell Lung Cancer

Paz-Ares LG et al. Proc ASCO 2011;Abstract CRA7510.

Questions and answers about PARAMOUNT: phase III study of pemetrexed continuation maintenance therapy in advanced non-squamous NSCLC.

Randomized Phase II Trial of Erlotinib (E) Alone or in Combination with Carboplatin/Paclitaxel (CP) in Never or Light Former Smokers with Advanced Lung.

Fabio Puglisi Dipartimento di Oncologia Azienda Ospedaliero Universitaria di Udine Antiangiogenic Treatment Mediterranean School of Oncology.

Presented by Martin H. Cohen, M.D. at the 27 July 2004 meeting of the Oncologic Drugs Advisory Committee.

Phase III Study Comparing Gemcitabine plus Cetuximab versus Gemcitabine in Patients with Locally Advanced or Metastatic Pancreatic Adenocarcinoma Southwest.

First-Line TKI Use in EGFR Mutation-Positive NSCLC

A single-arm phase II trial in p treated with C, D and B (15 mg/kg) every 3 weeks followed by B showed a promising efficacy, in terms of progression free.

Bevacizumab Update.

1 Phase II trial of sequential gemcitabine and carboplatin followed by paclitaxel as first-line treatment of advanced urothelial carcinoma Presented by.

Taxane-pretreated metastatic breast cancer (MBC): investigational agents TTP = median time to disease progression OS = median overall survival.

1-line Treatment of Advanced-NSCLC WT Cesare Gridelli Division of Medical Oncology “S.G. Moscati” Hospital – Avellino (Italy)

Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content.

Capecitabine versus Bolus 5-FU/Leucovorin as Adjuvant Therapy for Colon Cancer: X-ACT Trial Results James Cassidy, MD Colorectal Cancer Update Think Tank.

Lung cancer perspectives. Targeted therapy : one for all or a few for one ? Miklos Pless, Winterthur

1 SNDA Gemzar plus Carboplatin Treatment of Late Relapsing Ovarian Cancer.

This house believes that FOLFIRINOX is the best treatment for patients with metastatic pancreatic adenocarcinoma Pro Marc YCHOU Montpellier.

Randomized Phase III Trial Comparing FOLFIRINOX (F: 5FU/Leucovorin [LV], Irinotecan [I], and Oxaliplatin [O]) versus Gemcitabine (G) as First-Line Treatment.

Gemcitabine + Cisplatin +/- Bevacizumab as 1st-line Treatment of Advanced NSCLC: AVAiL Study Manegold PASCO 25:#7514, 2007/Ann.

A paradigm shift in the treatment of advanced lung cancer: survival and symptom benefits with Tarceva Tudor-Eliade Ciuleanu Cancer Institute Ion Chiricuta.

Final Efficacy Results from OAM4558g, a Randomized Phase II Study Evaluating MetMAb or Placebo in Combination with Erlotinib in Advanced NSCLC Spigel DR.

AVADO TRIAL David Miles Mount Vernon Cancer Centre, Middlesex, United Kingdom A randomized, double-blind study of bevacizumab in combination with docetaxel.

Rituximab plus Lenalidomide Improves the Complete Remission Rate in Comparison with Rituximab Monotherapy in Untreated Follicular Lymphoma Patients in.

Overall survival in NSCLC

. Background Paclitaxel and Irinotecan in Platinum Refractory or Resistant Small Cell Lung Cancer: a Galician Lung Cancer.

Il Paziente senza target

C.P. Belani 1, D.M. Waterhouse 2, H.H. Ghazal 3, S. Ramalingam 4, J.M. Waples 5, R.E. Bordoni 6, G.A. Reznikoff 7, C.P. Curran 8, R. H. Greenberg 9 1 Penn.

1 Albumin-Bound Paclitaxel for the Treatment of Non-small Cell Lung Cancer Monotherapy Studies.

CV-1 Trial 709 The ISEL Study (IRESSA ® Survival Evaluation in Lung Cancer) Summary of Data as of December 16, 2004 Kevin Carroll, MSc Summary of Data.

12 th Annual CTOS Meeting 2006 AP23573 Induced Long-term Stability in 2 Patients with Desmoplastic Small Round Cell Tumor (#561) Scott Schuetze, Warren.

until tumour progression until tumour progression

Low Dose Decitabine Versus Best Supportive Care in Elderly Patients with Intermediate or High Risk MDS Not Eligible for Intensive Chemotherapy: Final Results.

EORTC OSN/CTOS11 Safety of Caelyx combined with ifosfamide in previously untreated adult patients with advanced or metastatic soft tissue sarcomas. Final.

1 A Randomized, Multi-Center Phase III Trial of Irinotecan in Combination with Three Different Methods of Administration of Fluoropyrimidine with Celecoxib.

Journal Club Dr. Eyad Al-Saeed Radiation Oncology 12 January, 2008.

A Phase III, Open-Label, Randomized, Multicenter Study of Eribulin Mesylate versus Capecitabine in Patients with Locally Advanced or Metastatic Breast.

Personalized medicine in lung cancer R4 김승민. Personalized Medicine in Lung Cancer patients with specific types and stages of cancer should be treated.

Mok TS, Wu SL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361: Gefitinib Superior.

Erlotinib plus Gemcitabine Compared with Gemcitabine Alone in Patients with Advanced Pancreatic Cancer: A Phase III Trial of the National Cancer Institute.

CCO Independent Conference Coverage* of the 2016 ASCO Annual Meeting, June 3-7, 2016 GOG0213: Bevacizumab Retreatment of Recurrent Platinum-Sensitive Ovarian.

Esophageal Cancer: A Critical Evaluation of Systemic Second-Line Therapy Christiane Maria Rosina Thallinger, Markus Raderer, and Michael Hejna J Clin Oncol.

POPLAR: Atezolizumab Improved Survival vs Docetaxel in Patients With Advanced NSCLC and Increasing Levels of PD-L1 Expression CCO Independent Conference.

Weekly Paclitaxel Combined with Monthly Carboplatin versus Single-Agent Therapy in Patients Age 70 to 89: IFCT-0501 Randomized Phase III Study in Advanced.

Outcomes for Elderly, Advanced-Stage Non–Small-Cell Lung Cancer Patients Treated With Bevacizumab in Combination With Carboplatin and Paclitaxel: Analysis.

RANDOMIZED PHASE II STUDY OF NABPACLITAXEL, IN RECURRENT ADVANCED OR METASTATIC CERVICAL CANCER MITO CER-NAB Enrica Mazzoni, MD Medical Oncology & Breast.

1 LUX-Lung 3 clinical trial ECOG=Eastern Cooperative Oncology Group. Sequist LV et al. J Clin Oncol. 2013;31(27): Treatment-naïve Advanced NSCLC.

CCO Independent Conference Coverage

Randomized phase III trial of gemcitabine and cisplatin vs. gemcitabine alone inpatients with advanced non-small cell lung cancer and a performance status.

CCO Independent Conference Highlights

Belani CP et al. ASCO 2009; Abstract CRA8000. (Oral Presentation)

A cura di Filippo de Marinis

Alessandra Gennari, MD PhD

LUX-Lung 6 clinical trial

LUX-Lung 3 clinical trial

Phase II Study of Docetaxel (D) and Oxaliplatin (O) in Recurrent Metastatic Transitional Cell Carcinoma of the Bladder Davar D1, Appleman LA1, Friedland.

Farletuzumab in platinum sensitive ovarian cancer with low CA125

Outcomes of patients in the North Trent region with advanced non-small-cell lung cancer treated with maintenance pemetrexed following induction with platinum.

Ruolo di carboplatino + nab-paclitaxel nel trattamento di I linea nel carcinoma polmonare non a piccole cellule P.Bidoli S.C. Oncologia Medica.

Intervista a Lucio Crinò

until tumour progression until tumour progression

Barrios C et al. SABCS 2009;Abstract 46.

Cost-Effectiveness of Pemetrexed Plus Cisplatin as First-Line Therapy for Advanced Nonsquamous Non-small Cell Lung Cancer Robert Klein, MS, Catherine.

Maintenance paradigm in non-squamous NSCLC

LV5FU2-cisplatin followed by gemcitabine or the reverse sequence in metastatic pancreatic cancer: Preliminary results of a randomized phase III trial (FFCD.

Presentation transcript:

Study JMDB - A Randomised Phase III Trial of Cisplatin + Pemetrexed vs Study JMDB - A Randomised Phase III Trial of Cisplatin + Pemetrexed vs. Cisplatin + Gemcitabine in Locally Advanced or Metastatic Non-small Cell Lung Cancer (Scagliotti et al, 2007) Prescribing information can be found on the last slide IEALM00180 November 2012

Current indications for ALIMTA (EU)1 Regimen First-line Non-squamous NSCLC Alimta in combination with cisplatin is indicated for the first line treatment of patients with locally advanced or metastatic NSCLC other than predominantly squamous cell histology The recommended dose of ALIMTA is 500mg/m2 of body surface area (BSA) administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle. The recommended dose of cisplatin is 75mg/m2 BSA infused over two hours approximately 30 minutes after completion of the pemetrexed infusion on the first day of each 21-day cycle. Second-line Non-squamous NSCLC ALIMTA is indicated as monotherapy for the second-line treatment of patients with locally advanced or metastatic non‑small cell lung cancer other than predominantly squamous cell histology In patients treated for non‑small cell lung cancer after prior chemotherapy, the recommended dose of ALIMTA is 500mg/m2 BSA administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle. Malignant pleural mesothelioma (MPM) ALIMTA in combination with cisplatin is indicated for the treatment of chemotherapy naive patients with unresectable malignant pleural mesothelioma. Maintenance Therapy in Non-squamous NSCLC ALIMTA is indicated as monotherapy for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology in patients whose disease has not progressed immediately following platinum-based chemotherapy. First-line treatment should be a platinum doublet with gemcitabine, paclitaxel or docetaxel 1. Refer to Summary of Product Characteristics for full Prescribing Information

ALIMTA® (Pemetrexed) Mechanism of Action*1 ALIMTA is a folate analog metabolic inhibitor that exerts its action by disrupting folate‑dependent metabolic processes essential for cell replication by inhibiting folate‑dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. In-vitro studies have shown that pemetrexed inhibits: Glycinamide ribonucleotide formyltransferase (GARFT) Dihydrofolate reductase (DHFR) Thymidylate synthase (TS) ALIMTA is taken into cells by membrane carriers such as the reduced folate carrier, membrane folate binding protein transport systems. Once in the cell, Pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. Polyglutamation is a time‑ and concentration‑dependent process that occurs in tumor cells and, is thought to occur to a lesser extent, in normal tissues. Polyglutamated metabolites are thought to have an increased intracellular half‑life resulting in prolonged drug action in malignant cells. *As determined through in-vitro studies 1. ALIMTA Summary of Product Characteristics. Eli Lilly and Co; February 2010.

ALIMTA® (Pemetrexed): Mechanism of Action1 1. Robinson DM, et al.American Journal of Cancer. 2004 2 (6):387-399.

JMDB Background (Scagliotti et al, 2007) Cisplatin/Gemcitabine is an effective, widely-used reference regimen for the first-line treatment of advanced NSCLC1 Pemetrexed is one of the standards of care for second-line treatment of NSCLC2 Cisplatin/Pemetrexed is the standard of care for the management of malignant pleural mesothelioma Phase II studies of Pemetrexed plus platinum compounds have shown activity in advanced NSCLC3,4 1. Le Chevalier T, et al. Lung Cancer. 2005 47(1):69-80. 2. Hanna N, et al. J Clin Oncol. 2004 22(9):1589-97. 3. Scagliotti GV et al. Clin Cancer Res. 2005 11(2 Pt 1):690-6. 4. Zinner RG, et al. Cancer. 2005 104(11):2449-56.

JMDB Background (Scagliotti et al, 2007) Pemetrexed is a multitargeted antifolate which inhibits TS, DHFR and GARFT1 TS expression is lower in non-squamous tumours2 Lower intratumoural TS levels increase chemosensitivity to pemetrexed3,4 1.ALIMTA Summary of Product Characteristics. Eli Lilly and Company Limited. January 2009 2.Ceppi P et al, Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase. Cancer 107:1589-1596. 2006 3.Eismann U et al, Pemetrexed: mRNA expression of the target genes TS, GARFT and DHFR correlates with the in-vitro chemosensitivity of human solid tumours. Int J Clin Pharmacol Ther 43:567-569, 2005 4.Hanauske AR et al, In vitro chemosensitivity of freshly explanted tumor cells to pemetrexed is correlated with target gene expression. Invest New Drugs 25(5):417-423, 2007

JMDB (Scagliotti et al, 2007) – Study Design1 Cisplatin 75 mg/m2 day 1 plus Pemetrexed 500 mg/m2 day 1 Randomization Factors Stage Performance status Gender Histologic vs cytologic diagnosis History of brain metastases R Each cycle repeated q3 weeks up to 6 cycles Cisplatin 75 mg/m2 day 1 plus Gemcitabine 1250 mg/m2 days 1 & 8 Vitamin B12, folate, and dexamethasone given in both arms 1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

JMDB (Scagliotti et al, 2007) – Main Inclusion Criteria1 Histologic or cytologic diagnosis of NSCLC stage IIIB/IV At least 1 measurable lesion per RECIST ECOG PS 0-1 At least 18 years of age Adequate organ function Prior radiation allowed to <25% of bone marrow if completed at least 4 weeks before enrollment Estimated life expectancy of 12 weeks 1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

JMDB (Scagliotti et al, 2007) – Main Exclusion Criteria1 Symptomatic brain metastases Peripheral neuropathy grade 1 Weight loss 10% over previous 6 weeks Uncontrolled pleural effusions Prior systemic chemotherapy 1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

JMDB (Scagliotti et al, 2007) – Endpoints1 Primary Endpoint Overall survival Secondary Endpoints Response rate Duration of response Progression-free survival Time to progressive disease Time to treatment failure Toxicity 1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

JMDB (Scagliotti et al, 2007) – Study Statistics1 Non-inferiority study design - Fixed Margin Method 80% power to reject H0. H0 is that Cisplatin plus Gemcitabine would provide a 15% reduction in the risk of death over Cisplatin plus Pemetrexed H0 = HR (upper 95% CI) 1.176 vs HA < 1.176 Assuming HR = 1.0, 1190 deaths needed Randomize 850 patients per arm, 30% censored Pre-specified subset analyses: randomization factors plus age, ethnicity, smoking & histology 1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

JMDB (Scagliotti et al, 2007) – Main Patient Characteristics1 Pemetrexed/Cisplatin (N=862) Gemcitabine/Cisplatin (N=863) Median age (range) 61.1 (29–83) 61.0 (26–79) Age < 65 years 541 (62.8%) 577 (66.9%) Males 605 (70.2%) 605 (70.1%) ECOG PS 1 556 (64.5%) 554 (64.2%) Never-smokers 128 (14.8%) 122 (14.1%) Caucasians 669(77.6%) 680(78.8%) 1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

JMDB (Scagliotti et al, 2007) – Main Disease Characteristics1 Cis/Pem N=862 Cis/Gem N=863 Adenocarcinoma Squamous cell Large cell NSCLC, NOS 436 (50.6%) 244 (28.3%) 76 (8.8%) 106 (12.3%) 411 (47.6%) 229 (26.5%) 77 (8.9%) 146 (16.9%) Stage IV Stage IIIB (all) Stage IIIB (wet only) 657 (76.2%) 205 (23.8%) 67 (7.8%) 653 (75.7%) 210 (24.3%) 51 (6.0%) Brain metastases 17 (2.0%) 1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

JMDB (Scagliotti et al, 2007) – CTC Grade 3 & 4 Drug-related Toxicities*1 Cis/Pem N=839 Cis/Gem N=830 P-value Neutropenia 127 (15.1%) 222 (26.7%) < 0.001 Anaemia 47(5.6%) 82 (9.9%) 0.001 Thrombocytopenia 34 (4.1%) 105 (12.7%) Leukocytes 40 (4.8%) 63 (7.6%) 0.019 Febrile neutropenia 11 (1.3%) 31 (3.7%) 0.002 Alopecia (any grade) 100 (11.9%) 178 (21.4%) Nausea 60 (7.2%) 32 (3.9%) 0.004 Vomiting 51 (6.1%) 1.000 Fatigue 56 (6.7%) 41 (4.9%) 0.143 Dehydration (any grade) 30 (3.6%) 17 (2.0%) 0.075 *Includes toxicities reported in at least 3% of patients in at least one arm. 1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

JMDB (Scagliotti et al, 2007) – Transfusions and Supportive Care1 % of Patients Treatment Cis/Pem N=839 Cis/Gem N=830 P-value Any transfusion Platelet Red Blood Cell 138 (16.4%) 15 (1.8%) 135 (16.1%) 240 (28.9%) 37 (4.5%) 227 (27.3%) < 0.001 0.002 Erythropoiesis Stimulating Agents* 90 (10.4%) 156 (18.1%) G-CSF/GM-CSF* 27 (3.1%) 53 (6.1%) 0.004 *Based on intent–to-treat population 1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea. Version: Modified by: ; Date:

JMDB (Scagliotti et al, 2007) – Drug Delivery1 Cis/Pem N=839 Cis/Gem N=830 Median no. cycles 5.0 Cycles delayed* 315 (8.6%) 408 (11.3 %) Doses reduced* Cis 64 (1.8%) Pem 54 (1.5%) Cis 154 (4.2%) Gem 362 (10.0%) Gem day-8 omission* Not Applicable 339 (9.3%) Relative dose intensity Cis 95.0% Pem 94.8% Cis 93.5% Gem 85.8% * % of total cycles 1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

JMDB (Scagliotti et al, 2007) – Response Rates1 Cis/Pem N=762 Cis/Gem N=755 P-value CR 2 (0.3%) 3 (0.4%) 0.647 PR 231 (30.3%) 210 (27.8%) 0.284 SD 314 (41.2%) 346 (45.8%) 0.070 PD 174 (22.8%) 155 (20.5%) 0.276 ORR (95% CI) 233 (30.6%) (27.3, 33.9%) 213 (28.2%) (25.0, 31.4%) 0.312 Duration of response 4.5 months (4.27, 5.32) 5.1 months (4.57, 5.52) 0.198 1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

JMDB (Scagliotti et al, 2007) – Overall Survival (Total population)1 ALIMTA + Cisplatin (N=862) GEMZAR + Cisplatin (N=863) Median OS (95% CI) 10.3 mos (9.8, 11.2) (9.6, 10.9) Adjusted HR (95% CI) 0.94 (0.84, 1.05) p<0.001* 1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

JMDB (Scagliotti et al, 2007) – Progression-free Survival (PFS) in Overall Population1 ALIMTA + Cisplatin (N=862) GEMZAR + Cisplatin (N=863) Median PFS (95% CI) 4.8 mos (4.6, 5.3) 5.1 mos (4.6, 5.5) Adjusted HR (95% CI) 1.04 (0.94, 1.15) p=0.008* 1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

JMDB (Scagliotti et al, 2007) – Overall Survival: Adenocarcinoma or Large Cell1 ALIMTA + Cisplatin (N=512) GEMZAR + Cisplatin (N=488) Median (95% CI) 11.8 mos (10.4, 13.2) 10.4 mos (9.6, 11.2) Adjusted HR (95% CI) 0.81 (0.70, 0.94) p=0.005* *Superiority p-value. 1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

JMDB (Scagliotti et al, 2007) – Progression Free Survival (PFS): Adenocarcinoma or Large Cell1 ALIMTA + Cisplatin (N=512) GEMZAR + Cisplatin (N=488) Median PFS (95% CI) 5.3 mos (4.8, 5.7) 4.7 mos (4.4, 5.4) Adjusted HR (95% CI) 0.90 (0.79,1.02) p=0.096* *Superiority p-value; Data on file. Eli Lilly and Company. 1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

JMDB (Manegold et al, 2007) – Efficacy by Histology1 MST*, mos Adjusted P-value HR (95% CI) PFS#, mos RR**, % C/P C/G Adeno (n=847) 12.6 10.9 P=0.033 0.84 (0.71, 0.99) 5.5 5.0 P=0.125 0.90 (0.78, 1.03) 31.9 24.5 0.024 Large Cell (n=153) 10.4 6.7 P=0.027 0.67 (0.48, 0.96) 4.5 4.2 P=0.499 0.89 (0.65, 1.24) 31.3 30.9 0.954 Squamous (n=473) 9.4 10.8 P=0.050 1.23 (1.00, 1.51) 4.4 P=0.002 1.36 (1.12, 1.65) 26.9 36.7 0.033 NSCLC, NOS (n=252) 8.6 9.2 P=0.586 1.08 (0.81, 1.45) 5.6 P=0.064 1.28 (0.99, 1.67) 33.0 24.2 0.156 *MST=Median Survival Time #PFS=Progression Free Survival **RR=Response Rate Manegold C et al, Presented at 14th European Congress of Clinical Oncology: Sept 27, 2007; Barcelona, Spain.

JMDB (Scagliotti et al, 2007) – Systemic Post-study Therapy1 Drug name Cis/Pem N=862 Cis/Gem N=863 P-value Any post-study treatment 453 (52.6%) 484 (56.1%) 0.147 Gemcitabine 144 (16.7%) 74 (8.6%) < 0.001 Pemetrexed 30 (3.5%) 116 (13.4%) Cisplatin 53 (6.1%) 34 (3.9%) 0.037 Carboplatin 73 (8.5%) 84 (9.7%) 0.403 Docetaxel 219 (25.4%) 238 (27.6%) 0.326 Paclitaxel 42 (4.9%) 37 (4.3%) 0.567 Vinorelbine 63 (7.3%) 64 (7.4%) 1.000 Bevacizumab 9 (1.0%) 6 (0.7%) 0.452 Cetuximab 1 (0.1%) 2 (0.2%) TKI (Erlotinib or Gefitinib) 215 (24.9%) 194 (22.5%) 0.235 1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

JMDB (Scagliotti et al, 2007) – Subgroup Analyses Forest Plot1 1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

JMDB (Scagliotti et al, 2007) – Prognostic Variables*1 Subgroups HR (95% CI) Superiority P-value Females vs males 0.76 (0.67, 0.86) < 0.001 Ever/Former- vs never-smoker 1.74 (1.44, 2.09) Age (continuous) 1.00 (0.99, 1.00) 0.656 Caucasian vs others 1.36 (1.18, 1.57) E/SE Asian vs others 0.65 (0.54, 0.78) ECOG PS 0 vs 1 0.65 (0.58, 0.73) Stage IIIB vs IV 0.82 (0.71, 0.93) 0.003 Histo vs Cyto Dx 1.02 (0.91, 1.15) 0.693 Adeno vs others 0.75 (0.67, 0.84) Squamous cell vs others 1.12 (0.98, 1.27) 0.088 Large cell vs others 1.29 (1.07, 1.54) 0.007 *From separate Cox models, controlling for treatment, disease stage, ECOG PS, gender, and basis of diagnosis 1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

JMDB (Scagliotti et al, 2008) Dosing and administration: 1st-line treatment of NSCLC1 Physician Cycle 1 Cycle 2 Vitamin B12 1000 μg IM (once during pre-treatment, then once after every 3rd cycle) ALIMTA 500 mg/m2 IV over 10 minutes (every 21 days) Cisplatin 75 mg/m2 over 2 hours (every 21 days) Day -7 -6 -5 -4 -3 -2 -1 DD +1 +2 +3 +4 +5 +6 +7 +8 +9 +10 +11 +12 +13 +14 +15 +16 +17 +18 +19 +20 Patient Cycle 1 Cycle 2 Folic Acid 350-1000 μg PO daily from Day-7 until 20 days after last ALIMTA infusion Dexamethasone (or equivalent) 4 mg PO BID for 3 days Day -7 -6 -5 -4 -3 -2 -1 DD +1 +2 +3 +4 +5 +6 +7 +8 +9 +10 +11 +12 +13 +14 +15 +16 +17 +18 +19 +20 ALIMTA Summary of Product Characteristics (Eli Lilly, 2010).

Dosing modifications for ALIMTA® (Pemetrexed) injection as a single agent or in combination with cisplatin1 1. ALIMTA Summary of Product Characteristics. Eli Lilly and Company Limited. July 2009 UKALM00065 October 2009

Summary In this large randomized phase III trial concluded in first-line advanced NSCLC, Pemetrexed/cisplatin demonstrated similar overall survival compared to Gemcitabine/cisplatin (HR=0.94) in the ITT population and met its primary endpoint. Pemetrexed/cisplatin demonstrates improved efficacy in non squamous population compared to Gemcitabine/cisplatin. Pemetrexed/cisplatin provided tolerability advantages over Gemcitabine/cisplatin by demonstrating fewer Grades 3/4 events for select hematologic toxicities (anaemia, neutropenia, thrombocytopenia, febrile neutropenia). Patients receiving Pemetrexed/cisplatin required fewer transfusions (RBC and platelet) and were less dependent on haematopoietic growth factors compared with Gemcitabine/cisplatin. This is the first phase III NSCLC trial to report survival differences for a platinum doublet based on histology. A prespecified analysis of the impact of NSCLC histology on overall survival was examined. Clinically relevant differences in survival according to histology were observed. This difference in treatment effect for Pemetrexed based on histology was also observed in a post-hoc analysis of the single-agent, second-line study.

Backup UKALM00065 October 2009

ALIMTA/Cisplatin (N=839) GEMZAR/Cisplatin (N=830) Dose Intensity: ALIMTA (Pemetrexed for injection)/cisplatin vs GEMZAR (Gemcitabine HCl for injection)/cisplatin1 ALIMTA/Cisplatin (N=839) GEMZAR/Cisplatin (N=830) Median cycles/patient (range) 5.0 (1–7a) 5.0 (1–8b) Total cycles administered 3648c 3626c % of total cycles delayed 8.6% 11.3% Dose adjustments Doses reduced on day 1 (%) ALIMTA: 1.5% Cisplatin: 1.8% GEMZAR: 10% Cisplatin: 4.2% Doses omitted on day 8 (%) Not applicable GEMZAR: 9.3% Relative dose intensity ALIMTA: 94.8% Cisplatin: 95.0% GEMZAR: 85.8% Cisplatin: 93.5% aOne patient on ALIMTA/cisplatin arm received more than 6 cycles. bFour patients on GEMZAR/cisplatin arm received more than 6 cycles. cClinical Trials Registry available at www.clinicalstudyresults.org (accessed April 27, 2008). 1. Scagliotti GV, et al. J Clin Oncol. 2008.

1st line NSCLC: Recent plateau of efficacy 1. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 311:899-909 2. Cardenal F et al: Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 12:12-18, 1999 3. Sandler AB et al: Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 18:122-130, 2000 4. Scagliotti et al: Phase III Randomized Trial Comparing Three Platinum-Based Doublets in Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 20:4285-4291, 2002 5. Schiller JH et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92-98, 2002 6.Sandler A et al: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542-2550, 2006 7. Scagliotti GV et al: Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naïve patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 26:3543-3551, 2008

JMDB (Scagliotti et al, 2008) – Patients Enrolled by Geographic Region1 1. Manegold C et al, Presented at 14th European Congress of Clinical Oncology: Sept 27, 2007; Barcelona, Spain.