1. Rome, 11 april 2008 Progress in treatment of pancreatic cancer Mariacristina Di Marco S.S.D. Oncologia Medica Prof.G.Biasco Istituto di Ematologia ed Oncologia Medica L. & A. Seragnoli Alma Mater Studiorum, Università di Bologna

2. Ten Leading Cancer Types for the Estimated New Cancer Cases and Deaths, by Sex, United States, 2008

3. 15-20% of patients present resectable disease at the time of diagnosis; median life expectancy is 3 to 6 months for metastatic disease and 6 to 10 months for non metastatic disease; 1-4% will be alive at 5 years. Pancreatic cancer Sultana A et al.: J Clin Oncol. 2007 Jun 20;25(18):2607-15

5. Pancreatic cancer: a major therapeutic challenge  Most patients are not able to have surgery  Gemcitabine has been the standard of care for patients with advanced disease 1  Little progress in improving clinical outcomes over the last decade  Treatment options remain limited 1 Burris H, et al. J Clin Oncol 1997;15:2403–13

6. Gemcitabine: standard of care for advanced pancreatic cancer since 1996 Study Design  126 chemotherapy-naïve patients  Primary endpoint: survival and clinical benefit Results  Surv: G>5Fu (p=.0025)  TTP: G>5Fu (p=.0002)  CB: G>5Fu (p=.0022) Treatment Schedule  GEM 1000mg/m 2 IV weekly x7/8 then x3/4  5Fu600mg/m 2 weekly Burris HA III, et al. J Clin Oncol. 1997 Jun;15(6): 2403-13.

10. Head-to-head studies Phase III trials

11. GEM vs. Marimastat: Bramhall SR, et al. – JCO 2001 Study Design  414 chemotherapy-naïve patients  Primary endpoint: survival Results  Surv: G>5Fu (p=.0025)  TTP: G>5Fu (p=.0002)  CB: G>5Fu (p=.0022) Treatment Schedule  GEM 1000mg/m 2 IV weekly x7/8 then x3/4  MAR5 mg, 10 mg, or 25 mg bid orally J Clin Oncol. 2001 Aug 1;19(15):3447-55 GMar 5 Mar 10 Mar 25 # Pts.103104105102 RR (%) 263 PFS (wk) 16,488,48,1 MS (mo) 5,53,63,54,1 1YrS (%) 1914 20

12. GEM combinations vs. GEM alone Phase III trials

13. GEM vs. GEM/5-Fu: Berlin JD, et al. – JCO 2002 Study Design  327 chemotherapy-naïve patients  Primary endpoint: survival Results  The addition of 5Fu to Gem did not improve the median survival of patients with advanced pancreatic carcinoma J Clin Oncol. 2002 Aug 1;20(15):3270-5. Treatment Schedule  GEM 1000mg/m 2 IV weekly x3/4  GEM1000mg/m 2 IV weekly x3/4 5Fu600mg/m 2 after G GG5Fu # Pts.163164 RR (%) 5,66,9 PFS (mo) 2,23,4 MS (mo) 5,46,7 1YrS (%) n.a.

14. GEM vs. GEM/Cis: Colucci G, et al. – Cancer 2002 Study Design  107 chemotherapy-naïve patients  Primary endpoint: TTP, clinical benefitResults  Surv: GP=G (p=n.s.)  TTP: GP>G (p=.048)  CBR: GP=G (p=n.s.) Cancer. 2002 Feb 15;94(4):902-10. Treatment Schedule  GEM 1000mg/m 2 IV weekly x7/8 then x3/4  GEM1000mg/m 2 IV weekly x7/8 then x3/4 CIS25mg/m 2 1h before G GGP # Pts.5453 RR (%) 9,226,4 TTP (mo) 1,84,6 MS (mo) 4,66,9 1YrS (%) 11 CBR (%) 4953

15. GEM vs. GEM/Irinotecan: Rocha-Lima CMS, et al. – ASCO 2003 Study Design  360 chemotherapy-naïve patients  Primary endpoint: overall survival Results  RR: GIrino>G (p<.001)  Based on this study, single agent GEM remains the standard of care for 1 st line therapy. Treatment Schedule  GEM 1000mg/m 2 IV weekly x7/8 then x3/4  GEM1000mg/m 2 IV Irino100mg/m 2 after G D1,8 Q21 GGIrino # Pts.180 RR (%) 4,416,1 TTP (mo) 3,03,5 MS (mo) 6,66,3 1YrS (%) 2221 Proc Am Soc Clin Oncol. 2003:abstr 1005.

16. GEM vs. GEM/Cisplatin: Heinemann, et al. – ASCO 2003 Study Design  198 chemotherapy-naïve patients  Primary endpoint: survival Results  PFS: GP>G (p<.01)  RR+SD: GP>G (p<.001) Treatment Schedule  GEM 1000mg/m 2 weekly x3/4  GEM1000mg/m 2 IV CIS50mg/m 2 after G once every 2 weeks GGP # Pts.10098 RR (%) 810.2 PFS (mo) 2,85,4 MS (mo) 67.6 1YrS (%) n.a. Proc Am Soc Clin Oncol. 2003:abstr 1003.

17. GEM vs. GEM/Oxaliplatin: Louvet C, JCO 2005 Study Design  313 chemotherapy-naïve patients  Primary endpoint: survival Results  RR: GOxa>G (p=.03)  PFS: GOxa>G (p=.048) Treatment Schedule  GEM 1000mg/m 2 IV weekly x7/8 then x3/4  GEM1000mg/m 2 D1 OXA100mg/m 2 D2 every two weeks GGOxa # Pts.156157 RR (%) 17,326,8 PFS (mo) 3,75,8 MS (mo) 6.98.8 1YrS (%) 27.834.7 CBR (%) 26.938.2

21. 21 Xeloda: a new treatment option for pancreatic cancer Ian Chau Royal Marsden Hospital, London and Surrey, UK

22. Xeloda active in advanced pancreatic cancer  Single agent Xeloda 1  objective response rate: 7.3%  clinical benefit: 24%  median survival: 6 months  Two phase I studies evaluated the combination of gemcitabine and Xeloda 2,3  DLTs myelosuppression and mucositis 1 Cartwright TH et al. J Clin Oncol 2002;20:160–4 2 Hess V et al. J Clin Oncol 2003;21:66–8 3 Schilsky RL et al. J Clin Oncol 2002;20:582–7

23. UK NCRI GEMCAP versus gemcitabine phase III study in advanced pancreatic cancer Cunningham D et al. Eur J Cancer Suppl 2005;3:4 (Abst PS11) Gemcitabine 1 000mg/m 2 weekly x7 q8w, thereafter weekly x3 q4w GEMCAP Gemcitabine 1 000mg/m 2 weekly x3 q4w Xeloda 830mg/m 2 twice daily days 1–21 q4w n=266 n=267 RANDOMIZATIONRANDOMIZATION  1º endpoint: overall survival

25. Superior response rate with GEMCAP p=0.008 Cunningham D et al. Eur J Cancer Suppl 2005;3:4 (Abst PS11)

26. Significantly improved overall survival with GEMCAP Hazard ratio: 0.80 95% CI: 0.65–0.98 Log-rank p=0.026 0369121518212427 100 75 50 25 0 Patients surviving (%) Months 12-month survival GEMCAP (n=267)26% Gemcitabine (n=266) 19% 7.46.0 Cunningham D et al. Eur J Cancer Suppl 2005;3:4 (Abst PS11)

28. Of the 113 potentially relevant studies, 51 trials involving 9,970 patients met the inclusion criteria, and 33 of these trials involving 6,026 patients were included in the meta-analyses.

32. Targeted agents  Erlotinib  Cetuximab  Bevacizumab  Sorafenib

33. Targeted agents  Erlotinib  Cetuximab  Bevacizumab  Sorafenib

34. Erlotinib Plus Gemcitabine Compared to Gemcitabine Alone in Patients With Advanced Pancreatic Cancer. A Phase III Trial of the National Cancer Institute of Canada Clinical Trials Group [NCIC-CTG] MJ Moore

36. Rationale for targeting HER1/EGFR in pancreatic cancer  HER1/EGFR overexpression is common 1,2  Elevated HER1/EGFR and EGF is associated with 3–5  more aggressive disease  increased tumour size  late clinical stage  poor prognosis  reduced sensitivity to chemotherapy 1 Tobita K, et al. Int J Mol Med 2003;11:305–9 2 Srivastava A, et al. Hum Pathol 2001;32:1184–89 3 Ueda S, et al. Pancreas 2004;29:1–8 4 Nicholson R, et al. Eur J Cancer 2001;37:S9–S15 5 Xiong H, et al. Semin Oncol 2002;29:31–7 HER1/EGFR = human epidermal growth factor receptor

37. Rationale for Tarceva (erlotinib) in pancreatic cancer  In a preclinical study, Tarceva significantly inhibited cell growth and proliferation in pancreatic cancer cell lines in vitro 1  Tarceva has been shown to enhance gemcitabine-induced apoptosis in pancreatic tumour cells 2 1 Durkin A, et al. Am J Surg 2003;186:431–6 2 Ng SS, et al. Mol Cancer Ther 2002;1:777–83

38. *1:1 randomisation ECOG = Eastern Cooperative Oncology Group PS = performance status PA.3: study schema Stratified by: Centre ECOG PS (0/1 vs 2) Stage of disease (locally advanced vs distant metastases) (n=569) RANDOMISERANDOMISE Gemcitabine 1,000mg/m 2 i.v. + Tarceva 100/150mg/day p.o. (n=285) Gemcitabine 1,000mg/m 2 i.v. + placebo 100/150mg/day p.o. (n=284) * Moore M, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):1s (Abs. 1) Genentech: Tarceva ® full prescribing information

40. PA.3: overall survival (100mg cohort) 1723 1-year survival (%) 5.95 6.37 Median survival (months) Placebo + gemcitabine Tarceva + gemcitabine *HR=0.82 (0.67–0.98), p=0.03 1.00 0.75 0.50 0.25 0 Survival probability 06121824 Time (months) Erlotinib (n=261) Placebo (n=260) *Hazard ratio (HR) adjusted for PS and extent of disease at baseline Moore M, et al. J Clin Oncol 15: 1960-1966, 2007

41. PA.3: survival by HER1/EGFR status (100mg cohort) HER1/EGFR positive (n=70)HER1/EGFR negative (n=66) 1.00 0.75 0.50 0.25 0 06121824 Survival time (months) Survival probability 1.00 0.75 0.50 0.25 0 06121824 Survival time (months) Survival probability Tarceva (n=34) Placebo (n=32) HR=0.75 95% CI: 0.46–1.23 (p=NS) Tarceva (n=41) Placebo (n=29) HR=0.82 95% CI: 0.50–1.32 (p=NS) NS = not significant Moore M, et al. J Clin Oncol 2005;23(Suppl.16 Pt I):1s (Abs. 1)

43. PA.3: overall survival according to grade of rash HR (rash)=0.71, p<0.0001 Grade 0 Grade 1 Grade 2 1.0 0.8 0.6 0.4 0.2 0 Survival probability 05101520 Time (months) 439161-year survival (%) 10.55.85.3 Median survival (months) Grade 2 (n=102) Grade 1 (n=101) Grade 0 (n=79) Moore M, et al. J Clin Oncol 15: 1960-1966, 2007

44. Summary  Gemcitabine has long been regarded as the standard of care  PA.3 is the first randomised trial to show any drug to prolong survival in advanced pancreatic cancer versus single-agent gemcitabine  Provides ‘proof of principle’ for targeted cancer therapies  first demonstration of overall survival benefit with a HER1/EGFR inhibitor combined with chemotherapy  Tarceva was recently approved in the USA for treatment of advanced pancreatic cancer

45.  molecular characterization of a subgroup of patients enrolled onto the Erlotinib trial showed mutations of K-ras in 79% (92 of 117) of the patients;  in non–small-cell lung cancer and in colorectal cancer patients have demonstrated that patients carrying K-ras mutations are resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors;  the anti-EGFR agent produced a similar advantage in EGFR-positive and EGFR-negative patients;  no significant correlation were found between K-ras mutations and outcome in the patients enrolled on to Erlotinib trial. J Clin Oncol. 2007 Dec 20;25(36):5836-7

46.  endothelial cells express the EGFR and its expression is correlated with the expression of EGFR ligands within the tumor;  treatment with anti-EGFR agents can induce apoptosis in endothelial cells of experimental tumors due to the ability of anti-EGFR agents to reduce the levels of secretion of VEGF in pancreatic cancer cells and directly to block the proliferation and the motility of endothelial cells, as evaluated in vitro;  these agents were found to produce significant levels of apoptosis only in tumor-associated endothelial cells that express activated EGFR; Erlotinib in Pancreatic Cancer: Are Tumor Cells the (only) Target? J Clin Oncol. 2007 Dec 20;25(36):5836-7

47.  an antiangiogenic effect of erlotinib in pancreatic cancer is apparently in contrast with the negative findings of the phase III trial comparing the anti-VEGF antibody bevacizumab plus gemcitabine versus gemcitabine in pancreatic cancer patients;  EGF plays an important role in endothelial cell proliferation, survival, and sprouting in conditions of limiting VEGF. In the presence of high levels of VEGF, EGF did not induce cell proliferation of endothelial cells, and anti-EGFR agents had no effect on endothelial cell sprouting;  selected patients, with low intratumoral levels of VEGF, blockade of EGFR in endothelial cells might result in a significant antiangiogenic effect and, therefore, in an antitumor activity even in tumors that do not express the EGFR; Erlotinib in Pancreatic Cancer: Are Tumor Cells the (only) Target? J Clin Oncol. 2007 Dec 20;25(36):5836-7

48.  Conclusion: EGFR is expressed in different nontransformed cell types of the neoplastic environment that are involved in tumor growth and progression, including endothelial cells. Studying the effects of anti-EGFR agents in the different components of the tumor microenvironment might improve our knowledge of the mechanism of action of these drugs. Erlotinib in Pancreatic Cancer: Are Tumor Cells the (only) Target? J Clin Oncol. 2007 Dec 20;25(36):5836-7

49. Targeted agents  Erlotinib  Cetuximab  Bevacizumab  Sorafenib

51. 41 patients with advanced pancreatic - Cetuximab 250 mg/m2 for 7 weeks, after a loading dose of 400 mg/m2; - Gemcitabine 1000 mg/m2 for 7 weeks, followed by 1 week of rest. In subsequent cycles, cetuximab was administered weekly, and gemcitabine was administered weekly for 3 weeks every 4 weeks. Cetuximab and Gemcitabine for Advanced Pancreatic Cancer: A Multicenter Phase II Trial The objectives of the trial were to determine the objective tumor response rate, time to disease progression, survival, and safety profile. Xiong HQ et al.: J Clin Oncol. 2004 Jul 1;22(13):2610-6.

59. SWOG S0205 study Conclusions: This study failed to demonstrate a clinically significant advantage of the addition of cetuximab to gemcitabine for overall survival, PFS and response in advanced pancreatic cancer.

60. 84 patients with advanced pancreatic - Cetuximab 250 mg/m2 weekly, after a loading dose of 400 mg/m2; - Gemcitabine 1000 mg/m2 on days 1 and 8 of a 21-day cycle; - Cisplatin 35 mg/m2 on days 1 and 8 of a 21-day cycle. - Gemcitabine 1000 mg/m2 on days 1 and 8 of a 21-day cycle; - Cisplatin 35 mg/m2 on days 1 and 8 of a 21-day cycle. Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial  The primary endpoint was objective response (OR), defined as the proportion of patients whose best response was either partial response (PR) or complete response (CR);  Secondary endpoints included disease control (defined as the proportion of patients whose best response was PR, CR, or stable disease [SD]), progression-free survival (PFS), and overall survival (OS).

61. Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial

62. Targeted agents  Erlotinib  Cetuximab  Bevacizumab  Sorafenib

63. VEGF in pancreatic cancer  VEGF promotes pancreatic cancer growth via a paracrine angiogenic pathway and an autocrine mitogenic pathway 1,2  Both VEGF and its receptors are overexpressed in pancreatic cancer 3  High VEGF expression correlates with advanced stage, postoperative recurrence, lymph node and distant metastases, and decreased survival in patients with pancreatic cancer 4  These observations provide a rationale for anti-VEGF therapy for the treatment of pancreatic cancer 1 von Marschall Z, et al. Gastroenterology 2000;119:1358–72 2 Buchler P, et al. Surgery 2003;134:772–82 3 Seo Y, et al. Cancer 2000;88:2239–45 4 Karayiannakis AJ, et al. Cancer Lett 2003;194:119–24 VEGF = vascular endothelial growth factor

64. Tumour characteristics and environment promote VEGF expression EGF Hypoxia PDGF IL-8 bFGF COX-2 Nitric oxide Oncogenes VEGF release Binding and activation of VEGF receptor IGF-1 ProliferationSurvivalMigration ANGIOGENESIS Permeability Increased expression (MMP, tPA, uPA, uPAr, eNOS, etc.) – P P–

65. Summary: mechanism of action of anti-VEGF therapy  Inhibition of VEGF may act against tumours in three ways  regression of existing microvasculature  normalisation of mature vasculature  inhibition of production of new vasculature EARLY BENEFITCONTINUED BENEFIT Regression of existing microvasculature Normalisation of surviving microvasculature Inhibition of vessel regrowth and neovascularisation

66. Avastin plus gemcitabine in patients with advanced pancreatic cancer: phase II study design  Uncontrolled phase II multicentre trial (NCI sponsored) at seven sites  Two-stage sequential design: trial to be stopped if  2 responses in first 21 patients  Treatment  gemcitabine 1,000mg/m 2 i.v. on days 1, 8 and 15 of a 4-week cycle  Avastin 10mg/kg i.v. every 2 weeks  initially six cycles of Avastin/gemcitabine planned  CT scans obtained every two cycles  Primary endpoint: objective tumour response NCI = National Cancer Institute CT = computed tomography Kindler HL, et al. J Clin Oncol 2005;23:8033-8040

67. Avastin plus gemcitabine in patients with advanced pancreatic cancer: efficacy results 13 (25)Tumour progression 10 (19)Partial response 25 (48)Stable disease 0Complete response Patients* n (%)Response *52 patients available for evaluation Median duration of stable disease was 5.4 months Criteria for concluding Avastin plus gemcitabine is an active regimen (≥9 responses in 50 patients) met Kindler HL, et al. J Clin Oncol 2005;23:8033-8040

68. Avastin plus gemcitabine in patients with advanced pancreatic cancer: efficacy results (cont’d) 75 (95% CI: 60–85)6-month survival (%) 8.7 (95% CI: 7.3–9.7)Median survival (months) 29 (95% CI: 16–44)1-year survival (%) 5.8 (95% CI: 4.8–7.1)Time to progression (months) OutcomeResponse 52 patients available for evaluation CI = confidence interval Kindler HL, et al. J Clin Oncol 2005;23:8033-8040

69. Avastin plus gemcitabine in patients with advanced pancreatic cancer: Avastin- related non-haematological safety profile 4‡4‡ 0 4 0 0 1†1† 4 0 1 3 2 1 0 3 0 7 3 1 2 0 2 10Headache 12 * Bleeding 0Phlebitis/DVT/PE 4Hypertension 0Other GI 10Proteinuria 1Adverse event (n=52) Grade *Epistaxis (11); gum bleeding (1) † Fatal GI bleed ‡ Three bowel perforations (one fatal); one oesophageal tear GI = gastrointestinal Kindler HL, et al. J Clin Oncol 2005;23:8033-8040

70. Avastin plus gemcitabine in patients with advanced pancreatic cancer: conclusions  Addition of Avastin to gemcitabine resulted in improved response rate, time to progression and survival compared with that expected with gemcitabine alone in patients with advanced pancreatic cancer  The combination is well tolerated. Rates of thrombosis and significant bleeding are not higher than expected in this patient population  No correlation between pretreatment VEGF levels and response, progression-free or overall survival  Further study is warranted Kindler HL, et al. J Clin Oncol 2005;23:8033-8040

71. Locally advanced (stage III) and metastatic (stage IV) first-line pancreatic cancer (n=530) Gemcitabine + placebo Gemcitabine + Avastin (10mg/kg) every 2 weeks PD Phase III trial of first-line Avastin with gemcitabine in pancreatic cancer (CALGB 80303)  Primary endpoint: overall survival (90% power to detect a 35% increase in survival from 6 to 8.1 months)  Treatment administration  gemcitabine 1,000mg/m 2 weekly for 3 weeks of each 4-week cycle  Avastin 10mg/kg every 2 weeks CALGB = Cancer and Leukemia Group B

79. Rationale for combining bevacizumab and erlotinib  Both HER1/EGFR and VEGF are overexpressed in many tumours 1  VEGF has been implicated in resistance to anti-HER1/EGFR therapy  Treatment with two agents targeted against critical pathways may be more effective than a single pathway 2  Preclinical studies have shown that anti-VEGF and anti- HER1/EGFR therapies have at least additive effects 3  Clinical trials in various indications (renal cell cancer, 4 non-small cell lung cancer, 5 head and neck squamous cell carcinoma 6 ) have shown that the combination of bevacizumab and erlotinib is active 1 Viloria-Petit A, et al. Cancer Res 2001;61:5090–101; 2 Herbst RS, et al. Eur J Cancer Suppl 2003;1:S293; 3 Ciardiello F, et al. Clin Cancer Res 2000;6:3739–47; 4 Spigel DR, et al. J Clin Oncol 2005;23(June 1 Suppl.): Abstract 4540; 5 Sandler AB, et al. J Clin Oncol 2004;22(July 15 Suppl.): Abstract 2000; 6 Vokes EE, et al. J Clin Oncol 2005;23(June 1 Suppl.): Abstract 5504

80.  Primary endpoint: overall survival (increase from 6.9 to 9.0 months)  Secondary endpoints include progression-free survival and response rate  Avastin 5mg/kg every 2 weeks until disease progression Previously untreated metastatic pancreatic cancer (n=600) Gemcitabine + Tarceva + placebo Gemcitabine + Tarceva + Avastin 5mg/kg every 2 weeks PD* PD PD = progression of disease *No cross over will be permitted Phase III trial of first-line gemcitabine plus Tarceva with or without Avastin in pancreatic cancer (AVITA)

81. Targeted agents  Erlotinib  Cetuximab  Bevacizumab  Sorafenib

82. Sorafenib  Sorafenib targets the Ras/Raf/MEK/ERK signaling pathway at the level of Raf kinase, and, through its inhibitory effects on this mitogenic kinase cascade, interferes with cellular proliferation, differentiation, and survival;  Moreover, inhibits the phosphorylation and consequent activation of several receptor tyrosine kinases involved in angiogenesis and tumor progression, including those for vascular endothelial (VEGFR-2 and VEGFR-3) and platelet- derived (PDGFR-ß) growth factors.

83. Sorafenib and Gemcitabine A phase II study

84. 17 patients enrolled

85.  Gemcitabine is commonly used in patients with pancreatic cancer with the purpose of symptom palliation, there is no clear evidence of efficacy in terms of survival increase or progression control;  EGFR inhibitor (erlotinib) showed a small survival advantage when combined with gemcitabine;  A meta-analysis of randomised trials comparing gemcitabine versus gemcitabine and platinum analogues showed a statistical significant survival advantage for the combination;  RAS and RAF mutations are quite common in pancreatic cancer;  Sorafenib is an inhibitor of the RAS/RAF signalling pathway. Furthermore, sorafenib is able to inhibit both VEGFR and PDGFR. A RANDOMIZED PHASE II STUDY OF GEMCITABINE/CISPLATIN WITH OR WITHOUT SORAFENIB TO EVALUATE THE EFFICACY AND SAFETY IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC PANCREATIC CANCER

86. 114 patients with pancreatic cancer - Sorafenib 400 mg po bid, continuously; - Gemcitabine 1000 mg/m2 on days 1 and 8 of a 21-day cycle; - Cisplatin 25 mg/m2 on days 1 and 8 of a 21-day cycle. - Gemcitabine 1000 mg/m2 on days 1 and 8 of a 21-day cycle; - Cisplatin 25 mg/m2 on days 1 and 8 of a 21-day cycle. A RANDOMIZED PHASE II STUDY OF GEMCITABINE/CISPLATIN WITH OR WITHOUT SORAFENIB TO EVALUATE THE EFFICACY AND SAFETY IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC PANCREATIC CANCER  Proposed number of countries and centers ► 21  Primary endpoint: efficacy, in term of Progression Free Survival (PFS)  Secondary endpoints include Overall Response Rate (RECIST Criteria), Duration of response, Time to treatment failure, Overall survival time and Safety of the combination.

87. Novel agent TS-1 (S-1)

88. Novel agent TS-1 (S-1) Efficacy Toxicity Conclusions: gemcitabine and S-1 therapy produced a high response rate and good survival associated with an acceptable toxicity profile in patients with metastatic pancreatic cancer. 55 patients enrolled Ueno H et al.: ASCO 2007 abstract 148

89. S-1 + gemcitabine (a) No. of patients38 SchemaGemcitabine 1,000 mg/m 2 over 30 min on days 1 and 8; S-1 40 mg/m 2 orally twice daily from day 1 to day 14, repeated every 3 weeks Response rate23.5% PFS or TTPProgression free survival: 5.4 months Median survival9.3 months Grade 3-4 toxicities Neutropenia: 10.0% Leucopenia: 2.8% Thrombocytopenia: 0.9% Anemia: 1.4% Anorexia: 4% Rash: 2% Fatigue: 2% Hyperglycemia: 2% a. Oh D et al.: A multicenter phase II study of gemcitabine and S-1 combination chemotherapy in patients with unresectable pancreatic cancer. TS-1 (S-1) Oh D et al.: Asco – 2008 Gastrointestinal Cancers Symposium Abstract 212

90. Can We Use a Non-Gemcitabine Chemotherapy Regimens in Advanced Pancreatic Cancer ? After the approval of gemcitabine (compared against bolus 5-FU), many cytotoxic and targeted agents were compared against gemcitabine in randomized phase III trials. No such single agent was shown to be superior to single-agent gemcitabine. DrugMedian survivalP value Single-agentGemcitabine Exatecan [22]4.95 months6.46 months0.993 SCH 66336 [23]3.3 months4.4 months- Marimastat [24]3.5-4.1 months5.6 months- BAY 12-9566 [25]3.2 months6.4 months0.0001 It is time to investigate gemcitabine-free regimens. Two such studies tested in the first-line treatment for advanced pancreatic cancer were presented at ASCO: irinotecan/docetaxel (ECOG) or FOLFIRINOX (5-FU/leucovorin, irinotecan and oxaliplatin). FOLFIRINOX induces a response rate greater than 30% with manageable toxicity in ECOG 0-1 patients with advanced pancreatic cancer. ECOG study of weekly irinotecan/docetaxel plus/minus cetuximab also showed median survival of 6.5 months for irinotecan/docetaxel and 7.4 months for irinotecan/docetaxel plus cetuximab. These two studies indicate that non-gemcitabine containing therapy is active in advanced pancreatic cancer. JOP. J Pancreas (Online) 2007; 8(4):365-373.

93. Progress made but more needed in pancreatic cancer  Gemcitabine monotherapy reference treatment until 2005  Unprecedented survival benefits in 2005  GEM-Tarceva  GEMCAP  Future  combine Tarceva and Xeloda  build in new agents  Avastin  oxaliplatin?  optimal patient selection

94. What Actions Need to Be Taken to Change? Study design Locally advanced pancreatic cancer and advanced pancreatic cancer patients need to be studied separately Appropriate trial size Study of gemcitabine plus cisplatin may have been underpowered? Study of gemcitabine plus erlotinib may have been overpowered? Advocacy input needs to be sought early How much benefit is enough to a patient? How much toxicity is too much for a patient? Regulatory environment Gemcitabine vs. drugs "X" plus "Y" wins no FDA approval and may never be able to happen Focus on 2 nd line replace treatment as most 1 st line negative in the last decade JOP. J Pancreas (Online) 2007; 8(4):365-373.