1 / 33

Prescribing information can be found on the last slide

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.

brandi
Download Presentation

Prescribing information can be found on the last slide

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

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

  2. Current indications for ALIMTA (EU)1 1. Refer to Summary of Product Characteristics for full Prescribing Information

  3. 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.

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

  5. 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.

  6. 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

  7. R 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 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. JMDB (Scagliotti et al, 2007) – Main Patient Characteristics1 1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

  13. JMDB (Scagliotti et al, 2007) – Main Disease Characteristics1 1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

  14. JMDB (Scagliotti et al, 2007) – CTC Grade 3 & 4 Drug-related Toxicities*1 *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.

  15. JMDB (Scagliotti et al, 2007) – Transfusions and Supportive Care1 *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:

  16. JMDB (Scagliotti et al, 2007) – Drug Delivery1 * % of total cycles 1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

  17. JMDB (Scagliotti et al, 2007) – Response Rates1 1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

  18. JMDB (Scagliotti et al, 2007) – Overall Survival (Total population)1 p<0.001* 1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

  19. JMDB (Scagliotti et al, 2007) – Progression-free Survival (PFS) in Overall Population1 p=0.008* 1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

  20. JMDB (Scagliotti et al, 2007) – Overall Survival: Adenocarcinoma or Large Cell1 p=0.005* *Superiority p-value. 1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

  21. JMDB (Scagliotti et al, 2007) – Progression Free Survival (PFS): Adenocarcinoma or Large Cell1 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.

  22. JMDB (Manegold et al, 2007) – Efficacy by Histology1 *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.

  23. JMDB (Scagliotti et al, 2007) – Systemic Post-study Therapy1 1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

  24. 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.

  25. JMDB (Scagliotti et al, 2007) – Prognostic Variables*1 *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.

  26. JMDB (Scagliotti et al, 2008) Dosing and administration: 1st-line treatment of NSCLC1 ALIMTA Summary of Product Characteristics (Eli Lilly, 2010).

  27. 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

  28. 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.

  29. Backup UKALM00065 October 2009

  30. Dose Intensity: ALIMTA (Pemetrexed for injection)/cisplatin vs GEMZAR (Gemcitabine HCl for injection)/cisplatin1 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.

  31. 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

  32. 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.

More Related