1. Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer

2. Acinar secretory cell Ductal epithelial cell Bile Duct Duodenum Main Duct Islets of Langerhans Acinus Duct Anatomy of the pancreas

3. PanIN-1B PanIN-1A Normal PanIN-2 PanIN-3 Pancreatic cancer progression Oncogene activation Loss of tumor suppressor genes Hruban et al

4. Because of early invasion and metastasis, effective systemic therapy will have the most impact following surgery for patients with invasive ductal cancer

5. The best proving ground for new systemic treatment is metastatic disease

6. Efficacy in Pancreatic Cancer Objective response Symptom assessment/QOL survival

7. Objective response can not be adequately measured! Technically difficult to measure dimensions of the primary tumors radiographically Much of the mass effect can result from associated desmoplasia

10. CA19-9 by Quartile GroupPercentage of patients Median survival (mos) Median time to treatment failure (mos) No decline in CA19-942.3%7.603.90 0-25% decline11.5%8.305.95 26-50% decline19.2%12.857.25 51-75% decline11.5%11.056.90  75% decline 15.4%10.355.30 p-value0.0750.37

11. Factors Impacting Survival PS Extent of disease Crossover

12. Does Chemotherapy Improve Survival?

13. Natural History SMS pa LAR vs. Placebo 92 patients (59% with mets) on placebo Median survival 16.9 weeks (3.9 mos.) Pederzoli et al, ASCO 1998

14. Chemotherapy vs. Supportive Care Mallinson, 1980 5FU, CTX, VCN 11 vs. 2.25 mos* MTX, Mito Frey, 19815FU and CCNU 3 vs. 3.9 mos Palmer, 19945FU, Adria, Mito 8.25 vs. 3.75 mos* Glimelius, 19965FU, leucovorin, 6 vs. 2.5mos* ± etoposide RegimenMedian Survival *significant difference noted

15. Overall survival

16. Strategies for Optimizing Therapy Gemcitabine fixed dose rate infusion Selection of synergistic drug combinations with gemcitabine Find more effective drugs

17. Gemcitabine (2’2’-difluorodeoxycytidine, dFdC) Nucleoside analogue with 2 fluorine atoms in deoxyribofuranosyl ring Prodrug metabolized intracellularly Phosphorylated by deoxycytidine kinase Active metabolites: dFdCDP, dFdCTP Rate of dFdCTP formation is dose and dose-rate dependent - exceeding plasma [C] of 20mM can saturate activation process

18. JHFN: A Randomized Phase II Study Comparison of Two Different Infusion Rates of Gemcitabine Therapy in Patients with Locally Advanced or Metastatic Adenocarcinoma of the Pancreas Primary Objective: to determine TTF in patients with measurable metastatic pancreatic adenocarcinoma Secondary Objective: PK, survival Randomized 2200 mg/m 2 over 30’ weekly x3 q 4 wks 1500 mg/m 2 over 150’ weekly x3 q 4wks Tempero et al, JCO, 2003

20. Intracellular Gemcitabine Pharmacokinetics

21. Overall Survival Randomized Phase II Proportion Survival Fixed Dose Rate Standard Survival Time in Months

22. Median survival 8.6 months Estimated 1-year survival 33% UCSF Trial: FDR Gemcitabine + Low Dose Cisplatin Ko et al, ASCO 2004 Phase 2 trial in metastatic pancreatic cancer - early analysis

23. The Lifeline Supportive Care 1996 Std gem 1997 FDR gem 2000 FDR gem/cis 2004 Next? 0 10 months

24. Gemcitabine and Platinum TTP (mos) Heineman, 20032.54.6 Reni, 2004**3.35.3 Louvet, 20043.04.6(M) 5.37.4 (LAD) gem gem/cis or oxali* *all statistically significant **gem/cis plus epirubicin and 5-FU

25. Gemcitabine and Platinum Median Survival (mos) Heineman, 20036.07.6 Reni, 2004*9.09.0 Louvet, 20046.78.5(M) 10.3 10.3 (LAD) gem gem/cis or oxali *gem/cis plus epirubicin and 5-FU

26. Gemcitabine and Platinum 1 year survival Heineman, 2003 ~30 ~30 Reni, 2004** 21.3 38.5 Louvet, 2004 27.8 34.7 **gem/cis plus epirubicin and 5FU gem gem/cis or oxali Previous reports for gem: 17-24%

27. Analysis Options gem/platinum is not superior OR gem/platinum is modestly superior and survival endpoint was affected by crossover (> 50% in Louvet trial)

28. Other Issues interruption of treatment for radiation for LAD could have handicapped the experimental arm we can’t conclude anything about FDR gem or about which platinum LAD and metastatic disease - different natural history?

29. E 6201: Phase III Trial of Gemcitabine and Oxaliplatin in Pancreatic Carcinoma Arm A: Gemcitabine 1000 mg/m 2 /30 minutes qw x 3 every 4 weeks Arm B: Gemcitabine 1500 mg/m 2 /150 minutes qw x 3 every 4 weeks Arm C: Gemcitabine 1000 mg/m 2 /100 minutes Oxaliplatin 100 mg/m 2 /120 minutes q 14 days RANDOMIZERANDOMIZE Accrual Goal: 791

30. Other Gemcitabine Drug Combinations Agentmedian survival (mos) Bolus 5FU (Berlin)*6.7 PVI 5FU (Hidalgo)10.3 Irinotecan (Roche-Lima)*5.7 Docetaxel (Ryan, Lutz)8.9, 7.6 Pemetrexed (Kindler)*6.5 Capecitabine (Scheitauer)9.5 *Phase III

31. Randomized Phase II trial: Germany gemcitabine plus oxaliplatin gemcitabine plus capecitabine capecitabine plus oxaliplatin Heinemann/ASCO, 2004

32. The Future? Phase IBest chemotherapy platform plus targeted therapeutics (bevacizumab, cetuximab, erlotinib, etc) Phase II“Tailored” therapy based on genomic/proteomic profile

33. Managing Locally Advanced and Resectable Pancreatic Cancer

34. Locally Unresectable Pancreatic Cancer chemoRT vs. RT GITSG Study RXMedian Survival 6000 cGy5.5 4000 cGy + 5FU bolus*10 6000 cGy + 5FU bolus10 *recommended for standard of care Moertel et al, Cancer 48:1705, 1981

35. What do we really do? Patterns of care have changed! RT dose closer to 6000 cGy Continuous infusion 5FU Variable use of additional systemic chemotherapy

36. Locally Advanced Disease Is there a better radiation sensitizer than 5FU? Gemcitabine, taxol, cisplatin, a combination? No Phase III trials MDACC retrospective analysis suggests comparable survival with gemcitabine but more toxicity (Crane et al, Int J Radiation Oncology Biol. Phys. 52:1293-1302, 2002)

37. Locally Advanced Disease Do we need “full dose” RT with gemcitabine? “Full dose” gemcitabine can be given with about 3900 cGy delivered over 3 weeks (McGinn et al, JCO Nov 15:4202-4208, 2001)

38. Is radiation really that important? The majority of recent phase II and III chemotherapy trials have included patients with locally advanced disease (LAD). Louvet et algem/oxali 47% 10.5 mos. Reni et alPEF-G 37% 18.5 mos. Colucci et alGem or gem/cis 44% Median survival%LAD Beware: some patients went on to receive chemoRT off study

39. Adjuvant Therapy of Pancreatic Cancer GITSG Study Arch.Surgery 120:899, 1985 Cancer 5:2006, 1987 p = 0.03 + 5FU for 2 years

40. Neoadjuvant Therapy Everyone can be treated Results not inferior “Selects” for more indolent disease Spitz et al, JCO, 1997

41. EORTC Adjuvant Study Adenocarcinoma of pancreas and ampullary carcinoma (apples and oranges) Randomized to observation vs. “standard” split course RT with bolus 5FU - no maintenance 5FU

42. Klinkenbijl, 1999

43. Possible reasons for conflicting results between GITSG and EORTC studies Substantial proportion of patients (20-24%) randomized to treatment arm on both studies never received treatment due to prolonged postoperative course EORTC study included very early stage (T1N0) patients which might skew results in favor of no difference GITSG study included 2 additional years of 5-FU after chemoradiation; EORTC study did not Small sample size/insufficient power

44. RTOG 97-04 Title: A Phase III Study of Pre and Post Chemoradiation 5FU vs. Pre and Post Chemoradiation Gemcitabine for Postoperative Adjuvant Treatment of Resected Pancreatic Adenocarcinoma Surgery STRATIFYSTRATIFY Nodes Size Margins RANDOMIZEDRANDOMIZED c.i. 5FU  5FU chemoRT  c.i. 5FU (1 cycle) (2 cycles, 12 weeks) gemcitabine  5FU chemoRT  gemcitabine (1 cycle) (3 cycles, 12 weeks)

45. RTOG 97-04 Is the systemic treatment component “too little, too late”?

46. ESPAC 1 541 patients randomized: no therapy chemoRT with 5FU 5FU + leucovorin (L) chemoRT followed by 5FU/L chemoRT15.1 moschemo19.7 mos vs. p = 0.24 vs. no chemoRT16.1 mosno chemo14.0 mos P = 0.0005 median survival median survival Neoptolemos et al, Lancet 358: 1576-85, 2001

47. Overall Survival by CT Survival rates2-year5-year No CT:28.7%9.9% CT:43.3%23.3% HR=0.64 (0.52, 0.78), p<0.001 Neoptolemos et al, NEJM, 2004

48. ESPAC I Analysis chemo RT results inconclusive chemotherapy results suggest “chemo component” of adjuvant treatment is important - remember the old GITSG trial mandated 2 years treatment with 5FU hypothesis generating - is chemo RT an essential component of adjuvant therapy?

49. ESPAC 3 Surgery 5FU & leucovorin gemcitabine Without chemoradiation, it’s a simple platform

50. The End We Are Making Progress!