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First-Line Chemotherapy in Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC)

First-Line Chemotherapy in Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC). Thoracic Tumors. Lung Cancer Globally, 1.4 million new cases each year 1 The leading cause of cancer death worldwide 1 Approximately 80% of lung cancer cases are NSCLC 2 NSCLC

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First-Line Chemotherapy in Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC)

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  1. First-Line Chemotherapy in Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC)

  2. Thoracic Tumors Lung Cancer • Globally, 1.4 million new cases each year1 • The leading cause of cancer death worldwide1 • Approximately 80% of lung cancer cases are NSCLC2 NSCLC • Includes adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and bronchoalveolar carcinoma histologies3,4 • Predominant histologic type has shifted from squamous cell to adenocarcinoma in past 2 decades5 • In advanced or metastatic disease, 5-year survival rate is <5%6 1Kamangar et al. J Clin Oncol 2006;24(14):2137-50. 2Felip et al. Ann Oncol 2005;16(Suppl 1):i28-i29. 3Travis et al. IARC Press; 2004: 9-124. 4Travis et al. J Clin Oncol 2005; 23(14):3279-87. 5Gabrielson. Respirology 2006;11:533-8. 6 Breathnach et al. J Clin Oncol 2001;19(6):1734-42.

  3. NSCLC Diagnosis and Staging History and Physical Exam • Diagnostic tests1 • Chest x-ray/CT • Biopsy (bronchoscopy, transthoracic needle biopsy, thoracoscopy, thoracotomy) • Histopathology • Staging tests1 • CT chest/abdomen • PET scan2 • Brain MRI2 • Mediastinoscopy3-6 NSLC, non-small cell lung cancer; CT, computed tomography; PET, positron emission tomography; MRI, magnetic resonance imaging 1Ginsberg et al. Lippincott-Raven;2001:925-81. 2 Pieterman et al. N Engl J Med 2000;343(4):254-61. 3Detterbeck et al. Chest 2007; 2(3Suppl);202S-220S; 4Whiitson et al. Ann Thor Surg 2007;84(3):1059-65; 5De Leyn et al. Eur J Cardiothorac Surg 2007;32(1):1-8; 6Kim and Bosquee. J Thor Oncol 2007;2 Suppl 2;259-67.

  4. Staging of Lung Cancer: Primary Tumor (T) TNM: T, primary tumor; N, regional lymph nodes; M, distant metastasis 1Mountain. Semin Surg Oncol 2000;18(2):106-15.

  5. Staging of Lung Cancer: Regional Lymph Nodes (N) and Distant Metastasis (M) TNM: T, primary tumor; N, regional lymph nodes; M, distant metastasis 1Mountain. Semin Surg Oncol 2000;18(2):106-15.

  6. NSCLC: Treatment • Treatment approach based upon • Diagnosis (histologically or cytologically confirmed) • Prognostic Factors: disease stage, gender, PS, recent weight loss1-5 • Other comorbidities • Treatment options • Surgery, chemotherapy,XRT, other agents, supportive care • Treatment goals to improve PFS, OS, and QoL • Improve PFS and OS • Measurable tumor response, by Response Evaluation Criteria in Solid Tumors (RECIST)6 • Prolong time-to-disease progression • Use therapy with most favorable toxicity profile • Improve QoL7 NSCLC, non-small cell lung cancer; PS, performance status;XRT, radiation therapy; PFS, progression-free survival;OS, overall survival;QoL, quality of life 1Jiroutek et al. 1998. www.asco.org. 2Brudage et al. Chest 2002;122(3);1037-57. 3Mountain. Semin Surg Oncol 2000;18(2):106-15. 4Ginsberg et al. Lippincott-Raven;2001:925-81. 5Oken et al. Am J Clin Oncol 1982;5(6):649-55. 6Therasse et al. J Natl Cancer Inst 2000;92(3):205-16. 7 de Marinis et al. J Thorac Oncol 2008;3(1):30-6.

  7. Prognostic FactorsInfluencing Survival in NSCLC • Stage of disease at diagnosis1-4 • Performance status (PS)1,4,5 • Recent weight loss2,4 • Gender2,4 1Jiroutek et al. 1998. www.asco.org 2Brudage et al. Chest 2002;122(3);1037-57. 3Mountain. Semin Surg Oncol 2000;18(2):106-15. 4Ginsberg et al. Lippincott-Raven;2001:925-81. 5Oken et al. Am J Clin Oncol 1982;5(6):649-55.

  8. Current Treatment for First-Line Advanced and Metastatic NSCLC • Chemotherapy for Stage IIIB-IV • Standard first-line therapy: Platinum doublet combinations using cisplatin or carboplatin1,2 • Agents studied in combination with cisplatin or carboplatin include pemetrexed, gemcitabine, paclitaxel, docetaxel, vinorelbine, irinotecan3-7 • May be administered with radiation for Stage III patients1,2 • Results expected8-10 • Median survival: 7.4 to 9.9 months • 1-year survival: 31% to 43% 1Pfister et al. J Clin Oncol 2004;22:330-53. 2NCCN, 2008. 3Manegold et al. Ann Oncol 2000;11(4):435-40. 4Shepherd et al. Cancer 2001;92(3):595-600. 5Scagliotti et al. Clin Cancer Res 2005;11(2 Pt 1):690-6. 6Zinner et al. Cancer 2005;104(11):2449-56. 7Sandler et al. J Clin Oncol 2000; 18(1):122-30. 8Schiller et al. N Engl J Med 2002;346(2):92-8. 9Scagliotti et al. J Clin Oncol 2002;20:4285-91. 10Le Chevalier et al. Lung Cancer 2005;47(1):69-80.

  9. First-Line Treatment for Advanced and Metastatic NSCLC-Background • In advanced (Stage IIIB or IV) NSCLC, doublet combinations of platinum compounds (cisplatin or carboplatin) with gemcitabine, vinorelbine, or taxanes (paclitaxel or docetaxel) are standard treatment1,2 • When compared, in phase III studies, these doublets had comparable efficacy but showed differences in toxicity profiles3-6 • Cis/Gem is an effective, widely-used reference regimen for the first-line treatment of advanced NSCLC7 Cis/Gem, cisplatin/gemcitabine 1Pfister et al. J Clin Oncol 2004;22:330-53. 2NCCN 2007. 3Schiller et al. N Engl J Med 2002;346:92-8. 4Scagliotti et al. J Clin Oncol 2002;20:4285-91. 5Kelly et al. J Clin Oncol 2001;19:3210-8. 6Fossella et al. J Clin Oncol 2003;21:3016-24. 7Le Chevalier et al. Lung Cancer 2005;47(1):69-80.

  10. Comparison of Four First-Line Doublets: Randomized Phase III Study in NSCLC * All patients were disease stage IIIB or IV and ECOG performance status 0-2, N=1155 †No significant differences found between treatment arms Units = mg/m2; Pac, paclitaxel;Cis, cisplatin;Gem, gemcitabine;Doc, docetaxel;Carb, carboplatin; AUC, area under curve; ORR, overall response rate; ECOG, Eastern Cooperative Oncology Group Schiller et al. N Engl J Med 2002;346:92-8.

  11. Comparison of Three First-Line Doublets: Randomized Phase III Study in NSCLC * All patients were disease stage IIIB or IV and ECOG performance status 0-2, N=607 †No significant differences found between treatment arms units = mg/m2 Vin, vinorelbine; Cis, cisplatin; Gem, gemcitabine;Carb, carboplatin; AUC, area under the curve; Pac, paclitaxel; ORR=overall response rate; ECOG, Eastern Cooperative Oncology Group Scagliotti et al. J Clin Oncol 2002;20:4285-91.

  12. 1 0.9 0.8 0.7 0.6 Survival probability 0.5 0.4 0.3 0.2 0.1 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (months) Survival Meta-Analysis in NSCLC:Gem + Platinum vs. Other Platinum Doublets ▲ Gemcitabine + platinum, N=1861 Non-gemcitabine + platinum, N=2695 HR = 0.90 (0.84–0.96)*p<0.001 4556 patients from 13 randomized trials *95% confidence interval HR, hazard ratio Le Chevalier et al. Lung Cancer 2005;47(1):69-80.

  13. Pemetrexed Mechanism of Action • Compared with other antifolates, pemetrexed has a unique pyrrolopyrimidine nucleus and inhibits multiple folate-dependent enzymes1 • Pemetrexed has a high affinity for binding to folate receptor-,2 and once in the cell, it has very rapid conversion to active polyglutamate derivatives3 • Polyglutamation prolongs its intracellular retention and enhances pemetrexed’s interaction with thymidylate synthase (TS) and other folate-dependent target enzymes1,3-5 • These multiple mechanisms of action may explain how pemetrexed, compared with other antimetabolites such as 5-fluorouracil (5-FU), methotrexate, or raltitrexed, has shown greater potency and a broader spectrum of antitumor activity1,6 1Shih et al. Adv Enzyme Regul 1998;38:135-52. 2Zhao et al. Clin Cancer Res 2000;6(9):3687-95. 3 Chattopadhyay et al. Mol Cancer Ther 2007;6(2):404-17. 4Mendelsohn et al. Semin Oncol 1999;26(2 suppl 6):42-7. 5Taylor et al. J Med Chem 1992;35(23):4450-4. 6Chen et al. Br J Cancer 1998;78(Suppl 3):27-34.

  14. Pemetrexed: Key Intracellular Folate Enzyme Targets TS Pemetrexed 5-FU, raltitrexed dUMP dTMP DNA 5,10-CH2-THF 10-CHO-THF DHF NADPH GARFT DHFR PRPP Methotrexate THF NADP+ GAR fGAR AMP, GMP DNA, RNA TS, thymidylate synthase; 5-FU, 5-fluorouracil; GARFT, glycinamide ribonucleotide formyl transferase;DHFR, dihydrofolate reductase; DNA, deoxyribonucleic acid; RNA, ribonucleic acid Data from Kindler HL. Cancer 2002;95:928-32.

  15. Cis/Pem vs. Cis/Gem in First-Line NSCLC: Rationale • Cis/Pem is the standard of care for the management of MPM and is shown to be a safe efficacious combination1 • Pemetrexed is one of the standards of care for second-line treatment of NSCLCwith a favorable safety profile and a convenient 10-minute administration2 • Phase II studies of pemetrexed+platinum compounds have shown activity in advanced NSCLC and a favorable safety profile3-6 • Cis/Gem, in a 3-week schedule, is an effective, widely used regimen for first-line treatment of NSCLC7,8 Cis/Pem, cisplatin/pemetrexed;MPM, malignant pleural mesothelialoma; Cis/Gem, cisplatin/gemcitabine 1Vogelzang et al. J Clin Oncol 2003;21(14):2636-44. 2Hanna et al. J Clin Oncol 2004;22(9):1589-97. 3Manegold et al. Ann Oncol 2000;11(4):435-40. 4Shepherd et al. Cancer 2001;92(3):595-600. 5Scagliotti et al. Clin Cancer Res 2005;11(2 Pt 1):690-6. 6Zinner et al. Cancer 2005;104(11):2449-56. 7Le Chevalier et al. Lung Cancer 2005;47(1):69-80. 8Scagliotti et al. J Clin Oncol 2002;20:4285-91.

  16. Cisplatin 75 mg/m2 day 1 + Pemetrexed 500 mg/m2 day 1 Each cycle repeated every 3 weeks up to 6 cycles R Cis/Pem vs. Cis/Gem in First-Line NSCLC: Study Design Randomization Factors • Stage • Performance status • (0 vs. 1) • Gender • Histologic vs. cytologic diagnosis • History of brain metastases Cisplatin 75 mg/m2 day 1 + Gemcitabine 1250 mg/m2 days 1 &8 Vitamin B12, folate, and dexamethasone given in both arms Cis/Pem, cisplatin/pemetrexed; Cis/Gem, cisplatin/gemcitabine Scagliotti et al. J Clin Oncoldoi:10.1200/JCO.2007.15.0375

  17. Cis/Pem vs. Cis/Gem in First-Line NSCLC: Study Statistics • Noninferiority study design: 15% fixed margin1 • 80% power to reject null hypothesis (H0). H0 is that Cis/Gem would provide a 15% reduction in the risk of death over Cis/Pem. HA is alternative hypothesis1 • H0=HR (upper 95% CI)  1.17647 vs. HA <1.176472 • Assuming true HR=1.0, 1190 deaths needed • Randomize 850 patients per arm, 30% censored • Pre- specified analyses: randomization factors + age, ethnicity, smoking status, and histology1 Ho, null hypothesis;Cis/Gem, cisplatin/gemcitabine;Cis/Pem, cisplatin/pemetrexed; HA, alterntive hypothesis;HR, hazard ratio; CI, confidence interval 1Scagliotti et al. J Clin Oncoldoi:10.1200/JCO.2007.15.0375 2Scagliotti GV et al, 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea

  18. Cis/Pem vs. Cis/Gem in First-Line NSCLC: Main Patient Characteristics (N=1725) Cis/Pem, cisplatin/pemetrexed;Cis/Gem, cisplatin/gemcitabine; ECOG, Eastern Cooperative Oncology Group; PS, performance status 1Scagliotti et al. J Clin Oncoldoi:10.1200/JCO.2007.15.0375 2Scagliotti GV et al, 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea

  19. Cis/Pem vs. Cis/Gem in First-Line NSCLC: Main Disease Characteristics * Patients whose histologic diagnosis did not clearly qualify as adenocarcinoma, large cell, or squamous cell carcinoma Cis/Pem, cisplatin/pemetrexed; Cis/Gem, cisplatin/gemcitabine 1 Scagliotti et al. J Clin Oncoldoi:10.1200/JCO.2007.15.0375 2Scagliotti GV et al, 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea

  20. Cis/Pem vs. Cis/Gem in First-Line NSCLC: Drug Administration * % of total cycles administered Cis/Pem, cisplatin/pemetrexed;Cis/Gem, cisplatin/gemcitabine; Cis, cisplatin;Pem, pemetrexed; Gem, gemcitabine Scagliotti et al. J Clin Oncoldoi:10.1200/JCO.2007.15.0375

  21. 1.0 OS Median (95% CI) 0.9 Cis/Pem (N=862) 10.3 mos (9.8, 11.2) 0.8 Cis/Gem (N=863) 10.3 mos (9.6, 10.9) 0.7 OS Adjusted HR (95% CI) 0.6 Cis/Pem vs. Cis/Gem 0.94 (0.84–1.05) Cis/Pem statistically noninferior OS vs. Cis/Gem 0.5 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 Cis/Pem vs. Cis/Gem in First-Line NSCLC: Overall Survival (OS) – All Patients Overall Survival Probability Overall Survival Time (months) in All Patients Cis/Pem, cisplatin/pemetrexed;Cis/Gem, cisplatin/gemcitabine;CI, confidence interval; HR, hazard ratio; mos, months Scagliotti et al. J Clin Oncoldoi:10.1200/JCO.2007.15.0375

  22. 1.0 PFS Median (95% CI) 0.9 Cis/Pem (N=862) 4.8 mos (4.6, 5.3) 0.8 Cis/Gem (N=863) 5.1 mos (4.6, 5.5) 0.7 PFS Adjusted HR (95% CI) 0.6 Cis/Pem vs. Cis/Gem 1.04 (0.94–1.15) PFS Probability 0.5 Cis/Pem statistically noninferior PFS vs. Cis/Gem 0.4 0.3 0.2 0.1 0.0 Cis/Pem vs. Cis/Gem in First-Line NSCLC: Progression-Free Survival (PFS) – All Patients 0 6 12 18 24 30 PFS Time (months) in All Patients PFS, progression-free survival; Cis/Pem, cisplatin/pemetrexed;Cis/Gem, cisplatin/gemcitabine; CI, confidence interval; HR, hazard ratio; mos, months Scagliotti et al. J Clin Oncoldoi:10.1200/JCO.2007.15.0375

  23. Cis/Pem vs. Cis/Gem in First-Line NSCLC: Response Rates * N reflects the tumor-qualified population Cis/Pem, cisplatin/pemetrexed;Cis/Gem, cisplatin/gemcitabine; CR, complete response; PR, partial response;SD, stable disease; PD, progressive disease; ORR, objective response rate; CI, confidence interval Scagliotti GV et al, 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

  24. Cis/Pem vs. Cis/Gem in First-Line NSCLC: Toxicities and Supportive Care * Drug-related Grade 3/4 toxicities reported in at least 3% of patients in at least 1 arm are listed † Supportive Care Use Analyses were based on an intent-to-treat population (ITT) and the Ns reflect the ITT groups. G-CSF granulocyte colony-stimulating factor; GM-CSF, granulocyte macrophage colony stimulating factor Scagliotti et al. J Clin Oncoldoi:10.1200/JCO.2007.15.0375

  25. Cis/Pem vs. Cis/Gem in First-Line NSCLC: Nonhematologic Toxicities * Drug-related grade 3/4 toxicitiesreported in at least 3% of patients in at least 1 arm are listed • Deaths attributed to study drug toxicity were low and were similar between arms: • 9 patients (1.0%) for Cis/Pem, 6 patients (0.7%) for Cis/Gem Cis/Pem, cisplatin/pemetrexed; Cis/Gem, cisplatin/gemcitabine; CTC, Common Toxicity criteria Scagliotti et al. J Clin Oncoldoi:10.1200/JCO.2007.15.0375

  26. Cis/Pem vs. Cis/Gem in First-Line NSCLC: Overall Efficacy and Safety Results • In the overall study population, the primary endpoint of overall survival was successfully met: • Cis/Pem is noninferior to Cis/Gem (HR=0.94) • All secondary efficacy endpointscomparable between regimens • Both regimensgenerally well-tolerated;key hematologic and nonhematologic toxicities significantly lower for Cis/Pem • In the Cis/Pem arm, patients required significantly less treatment with red blood cell and platelet transfusions, erythropoiesis-stimulating agents, and colony stimulating factors • Clinically relevant and significant survival differences were observed according to NSCLC histology Cis/Pem, cisplatin/pemetrexed; Cis/Gem, cisplatin/gemcitabine; HR, hazard ratio Scagliotti et al. J Clin Oncoldoi:10.1200/JCO.2007.15.0375

  27. Cis/Pem vs. Cis/Gem in First-Line NSCLC: Rationale for Pre-specified Histology Analyses • Preclinical data indicate that high expression of TS correlates with reduced sensitivity to pemetrexed1,2 • In specimens from chemonaive patients with NSCLC, TS expression was significantly higher in squamous cell carcinoma when compared with adenocarcinoma3 • Retrospective analyses of the large phase III study of pemetrexed vs. docetaxel in advanced NSCLC showed treatment-by-histology interactions for OS and PFS were highly statistically significant4 • These interactions seemed to result from differences in the efficacy of pemetrexed between nonsquamous and squamous histologic groups4 • Since efficacy of pemetrexed may differ by histologic type, analyses were pre-specified for histology and efficacy in the first-line Cis/Pem versus Cis/Gem study5 Cis/Pem, cisplatin/pemetrexed;Cis/Gem, cisplatin/gemcitabine; TS, thymidylate synthase; OS, overall survival; PFS, progression free survival 1Sigmond et al. Biochem Pharmacol 2003;66(3):431-8. 2Giovannetti et al. Mol Pharmacol 2005;68(1):110-8. 3Ceppi et al. Cancer 2006;107(7):1589-96. 4Peterson et al. 12th World Conference on Lung Cancer. 2007; Seoul, Korea. 5Scagliotti et al. J Clin Oncoldoi:10.1200/JCO.2007.15.0375

  28. Cis/Pem vs. Cis/Gem in First-Line NSCLC:Overall Survival in Adenocarcinoma or Large Cell 1.0 OS Median (95% CI) 0.9 Cis/Pem (N=512) 11.8 mos (10.4, 13.2) 0.8 Cis/Gem (N=488) 10.4 mos (9.6, 11.2) 0.7 OS Adjusted HR (95% CI) 0.6 Cis/Pem vs. Cis/Gem 0.81(0.70-0.94) Cis/Pem statistically superior OS vs. Cis/Gem 0.5 Overall Survival Probability 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 Overall Survival Time (months) in Non-Squamous* Patients * non-squamous = patients with adenocarcinoma or large cell carcinoma Cis/Pem, cisplatin/pemetrexed;Cis/Gem, cisplatin/gemcitabine;CI, confidence interval; HR, hazard ratio; mos, months Scagliotti et al. J Clin Oncoldoi:10.1200/JCO.2007.15.0375

  29. Cis/Pem vs. Cis/Gem in First-Line NSCLC: PFS in Adenocarcinoma or Large Cell 1.0 PFS Median (95% CI) 0.9 Cis/Pem (N=512) 5.3 mos (4.8, 5.7) 0.8 Cis/Gem (N=488) 4.7 mos (4.4, 5.4) 0.7 PFS Adjusted HR (95% CI) 0.6 Cis/Pem vs. Cis/Gem 0.90 (0.79-1.02) 0.5 PFS Probability Cis/Pem statistically noninferior PFS vs. Cis/Gem 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 PFS (months) in Non-Squamous* Patients *non-squamous = patients with adenocarcinoma or large cell carcinoma PFS, progression-free survival; Cis/Pem, cisplatin/pemetrexed;Cis/Gem, cisplatin/gemcitabine;CI, confidence interval; HR, hazard ratio; mos,months Scagliotti et al. J Clin Oncoldoi:10.1200/JCO.2007.15.0375

  30. Cis/Pem vs. Cis/Gem in First-line NSCLC: Overall Survival in Squamous Cell Carcinoma 1.0 OS Median (95% CI) 0.9 Cis/Pem (N=244) 9.4 mos (8.4, 10.2) 0.8 Cis/Gem (N=229) 10.8 mos (9.5, 12.1) 0.7 OS Adjusted HR (95% CI) 0.6 Cis/Pem vs. Cis/Gem 1.23 (1.00-1.51) 0.5 Overall Survival Probability OS effect with Cis/Pem less than with Cis/Gem 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 Overall Survival Time (months) in Squamous Patients Cis/Pem, cisplatin/pemetrexed;Cis/Gem, cisplatin/gemcitabine;CI, confidence interval; CP, patients treated with cisplatin+pemetrexed;CG, patients treated with cisplatin+gemcitabine; HR, hazard ratio; mos, months Scagliotti et al. J Clin Oncoldoi:10.1200/JCO.2007.15.0375

  31. PFS Median (95% CI) 0.9 Cis/Pem (N=224) 4.4 mos (4.1, 4.9) 0.8 Cis/Gem (N=229) 5.5 mos (4.6, 5.9) 0.7 PFS Adjusted HR (95% CI) 0.6 Cis/Pem vs. Cis/Gem 1.36 (1.12-1.65) 0.5 PFS Probability OS effect with Cis/Pem less than with Cis/Gem 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 Cis/Pem vs. Cis/Gem in First-Line NSCLC: PFS in Squamous Cell Carcinoma 1.0 PFS (months) in Squamous Patients PFS, progression free survival; Cis/Pem, cisplatin/pemetrexed;Cis/Gem, cisplatin/gemcitabine;CI, confidence interval; HR, hazard ratio; mos, months Scagliotti et al. J Clin Oncoldoi:10.1200/JCO.2007.15.0375

  32. Cis/Pem vs. Cis/Gem in First-Line NSCLC: Efficacy by Histology * Patients whose histologic diagnosis did not clearly qualify as adenocarcinoma, large or squamous cell carcinoma Cis/Pem, cisplatin/pemetrexed;Cis/Gem, cisplatin/gemcitabine; OS, overall survival; PFS, progression free survival; RR, response rate Manegold et al. 14th European Congress of Clinical Oncology: Sept 27, 2007; Barcelona, Spain.

  33. Cis/Pem vs. Cis/Gem in First-Line NSCLC: Systemic Post-Discontinuation Therapy* * Patients could receive multiple post-discontinuation therapies. Cis/Pem, cisplatin/pemetrexed; Cis/Gem, cisplatin/gemcitabine Scagliotti et al. 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

  34. Cis/Pem vs. Cis/Gem in First-Line NSCLC: Impact of Baseline Characteristics on Overall Survival Favors Cis/Pem Favors Cis/Gem 0.94 0.97 0.88 0.84 0.98 0.93 0.88 1.34 0.93 1.00 Hazard Ratio 0.91 0.95 0.92 0.99 0.89 0.95 0.84 0.67 1.23 1.08 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 Overall Survival Hazard Ratio with 95% CI Scagliotti et al. J Clin Oncoldoi:10.1200/JCO.2007.15.0375

  35. Cis/Pem vs. Cis/Gem in First-Line NSCLC: Smoking Status Analysis • On both treatment arms, never-smokers had longer median survival than former/current smokers • Regardless of treatment, former/current smokers had significantly higher risk of death than never-smokers • Cox adjusted analysis (HR=1.74, superiority p<0.001) Cis/Pem, cisplatin/pemetrexed; Cis/Gem, cisplatin/gemcitabine; HR, hazard ratio Scagliotti et al. J Clin Oncoldoi:10.1200/JCO.2007.15.0375

  36. Cis/Pem vs. Cis/Gem in First-Line NSCLC: Conclusions (1 of 2) • Overall Survival with Cis/Pem was noninferior to Cis/Gem (HR=0.94) • All secondary efficacy endpoints comparable between regimens, in the overall study population • Both regimens were generally well-tolerated • Key hematologic and nonhematologic toxicities significantly lower for Cis/Pem • Cis/Pem: patients required significantly fewer red blood cell and platelet transfusions, less use of erythropoietin/darbepoetin and granulocyte colony-stimulating factors Cis/Pem, cisplatin/pemetrexed; Cis/Gem, cisplatin/gemcitabine Scagliotti et al. J Clin Oncoldoi:10.1200/JCO.2007.15.0375

  37. Cis/Pem vs. Cis/Gem in First-Line NSCLC: Conclusions (2 of 2) • Pre-specified histology analyses: • Adenocarcinoma carcinoma: Cis/Pem had statistically superior OS time vs. Cis/Gem (p=0.03) • Large Cell carcinoma: Cis/Pem had statistically superior OS time vs. Cis/Gem (p=0.03) • Squamous carcinoma: OS time with Cis/Pem less than with Cis/Gem (p=0.05) • Overall Survival for patients with nonsquamous* histology significantly improved with Cis/Pem: • Treatment-by-histology interaction analysis (p=0.0011) • These prospective histology analyses confirm retrospective findings in prior pemetrexed vs. docetaxel second-line NSCLC study • This treatment-by-histology interaction for pemetrexed may be related to a differential expression of TS across NSCLC histologic groups * Nonsquamous=adenocarcinoma or large cell Cis/Pem, cisplatin/pemetrexed; Cis/Gem, cisplatin/gemcitabine; TS, thymidylate synthase Scagliotti et al. J Clin Oncoldoi:10.1200/JCO.2007.15.0375

  38. Cis/Pem Therapy in First-line Advanced or Metastatic NSCLC Cis/Pem compared with Cis/Gem: • Largest randomized phase III trial in first-line advanced or metastatic NSCLC, to date • Overall survival and other efficacy endpoints similar between arms • Cis/Pem had statistically and clinically significant safety advantages particularly for grade 3/4 hematologic toxicities • Patients treated with Cis/Pem had fewer transfusions and less use of growth factors • Patients with adenocarcinoma and large cell carcinoma had superior survival with Cis/Pem, while survival time for those with squamous cell carcinoma was less with Cis/Pem than with Cis/Gem • First phase III study in NSCLC to prospectively report survival differences between platinum doublets according to histology • Cis/Pem represents a preferred regimen in the treatment of first-line advanced or metastatic NSCLC1 Cis/Pem, cisplatin/pemetrexed; Cis/Gem, cisplatin/gemcitabine 1Einhorn. In: Scagliotti. 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

  39. Indications Malignant Pleural Mesothelioma: • ALIMTA in combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. Non-small cell lung cancer: • ALIMTA in combination with cisplatin is indicated for the first line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology. • 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. Vials: 500mg. pemetrexed, 100mg pemetrexed יצרן: אלי לילי, צרפת בעל רישום: אלי לילי ישראל בע"מ ת.ד. 2160 הרצליה פיתוח 46120 למידע מלא נא עיין בעלון לרופא כפי שאושר ע"י משרד הבריאות

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