1. Saint Agnes Medical Center Oncology Symposium October 15, 2011 Neoadjuvant, Adjuvant and Palliative Management Marshall Flam, MD Hematology, Oncology Medical Group

2. Age Specific Incidence Rates of Pancreas Cancer, in California, by Race, 1988-2008 Courtesy of Paul Mills, PhD, MPH

3. Stage at Diagnoses of PAC Stage at DX% of Patients5 Yr. Survival Distant Metastases502% Locally Advanced Un-resectable307% Curative Resection of Operated50 (10)20% Metastases Found at Surgery Un-resectable50 (10)

4. SINGLE AGENT CHEMOTHERAPY

5. Overall Survival: Gemcitabine vs 5-FU

6. Fixed Dose Rate vs. Standard Rate

7. Toxicity Summary Grade 3 and 4 Toxicities (% of Patients) Toxicity per Patient FDRStandard Anemia 23.318.4 Nausea/vomiting 20.914.3 Thrombocytopenia 37.210.2 Neutropenia 48.826.5 Leukopenia 39.522.5 ALT 7.32.2 Diarrhea 4.78.2 Abbreviation: FDR, fixed dose rate.

8. Assessment of Clinical Benefit PAIN Performance Status STABLE In both Parameters WEIGHT Responder Improvement in both Parameters. Stable in one parameter, Improvement in The other parameter Non-responder Worsening in either Parameter Analgesic Consumption Pain Intensity Responder > 7% Increase in body weight Responder Stable or decreased weight

9. COMBINATION CHEMOTHERAPY

10. Phase III Trials of Chemotherapy in Advanced Pancreatic Cancer RegimenOS (mos)5FU OS (mos)P ValueRR (%)5FU RR % Gemcitabine + 5FU6.75.40.099.95.6 Gemcitabine + Irinotecan6.36.60.78916.14.4 Gemcitabine + Cisplatin7.560.1510.28.2 Gemcitabine + Oxaliplatin 9.07.10.1326.817.3 Gemcitabine + Premetrexed 6.26.30.84814.87.1 Capecitabine + Gemcitabine7.460.02614.07.0

11. EGOC Trail: Survival – Gemcitabine vs GEMOX

12. French Trial: Survival Gemcitabine vs GEMOX

13. Objective Responses in the Intention-to-Treat Population

14. Progression-free Survival

15. Overall Survival

16. TARGETED THERAPIES

17. Summary of the CAN-NCIC PA.3 Phase III Trial Gemcitabine +Erlotinib vs Gemcitabine Alone in Advanced Pancreatic Cancer Gemcitabine + Erlotinib Gemcitabine Alone Hazard Ratio P Value No. of Patients 285284 ----- ------- Response Rate 8.6%8.0% ----- ------- Median Survival 6.24 mos 5.91 mos 0.82.038 1 Yr. Survival Rate 23%17% ----- ------- Progression-Free Survival 3.75 mos 3.55 mos 0.77.004 Data from Moore et al. 23,24

18. Phase III Trial of Bevacizumba + Gemcitabine in Patients with Advanced Pancreatic Cancer: Median Overall and Progression-Free Survival Gemcitabine + Bevacizumab Gemcitabine + Placebo P ValueHazard Ratio Median Overall Survival 5.7 mos 6.0 mos 0.401.09 (95% CI) (4.9, 6.5)(5.0, 6.9) ----- ------- Progression-Free Survival 4.8 mos 4.3 mos 0.991.0 (95% CI) (4.3, 5.7)(3.8, 5.6) ----- ------- Data from Kindler et al. 11

19. SECOND LINE THERAPIES

20. Treatment RegimenNo. of patients Metastatic Disease (%) RR (%) a DCR (%) a PFS/TTP (months) OS (months) Oxa/5-FU CI/LV vs. BSC 14 46NA OFF: 5.25 BSC: 2.5 OFF: 10 BSC: 8.5 Oxa/5-FU CI/LV vs. 5-FU CI/LV 36, 27 168 (OFF:77; FF91) OFF: 85.5 FF: 89.2 NA OFF: 3.25 FF: 2.25 OFF: 6.5 FF: 3.25 Oxa/5-FU CI/LV 28 309723535.15.8 FOLFOX-4 29 4283145246.7 Modified FOLFOX(a) vs. modified FOLFIRI.3(b) 30 (a) 30 (b) 30 NA (a) 20 (b) 28 (a) 1.4 (b) 1.9 (a) 4 (b) 4 Oxa/5-FU CI 31 1894.50170.91.3 Oxa + Gem 33 336421584.26.0 Oxa + Cap 34 39NA323NA5.8 Oxa + Cap 36 151007404.110 Oxa + irinotecan 37 3010010334.15.9 Oxa + pemetrexed 38 16NA20603.3NA Oxa + ralitrexed 39 4110024511.85.2 L -Cisplatin + Gem 40 2479867NA4.0 Cisplatin + irinotecan + Gem + 5-FU + LV 41 3410034553.910.3 Cisplatin + S-1 42 175329NA 9.0 Cap + Gem + docetaxel 43 351002960NA11.2 Mitomycin + docetaxel + Irinotecan 44 151000201.76.1 Irinotecan + ralitrexed 18 1910016474.06.5 a Intention-to-treat analysis. b KPS 80-100% Clinical Trials Investigating second-line combination chemotherapy in gemcitabine- pretreated patients with advanced pancreatic cancer

21. CONKO 003

22. Phase II trial of capecitabine + erlotinib in gemcitabine-refractory advanced pancreatic cancer

23. ADJUVANT THERAPY FOLLOWING RESECTION OF PAC

24. Key Trials of Adjuvant Therapy in Resectable Pancreatic Cancer TrialRegimen # of Patients Median Survival (mos) GITSG (1985) 5FU + 40GY XRT2120 Surgery Only2211 GITSG (1987) 5FU + 40GY XRT3018 EORTC (1999) 5FU + 40GY XRT11017.1 Surgery Only10812.6 ESGCP (2004) Chemoradiotherapy14515.9 ESGCP (2004) No Chemoradiotherapy14417.9 Maintenance Chemotherapy14220.1 No Maintenance Chemotherapy14715.5 RTOG (2006) 5FU + 50.4Gy27016.7 Gemcitabine + 5FU + 50.4Gy26818.8* CONKO-001 (2007) Gemcitabine17922.1 Surgery Only17720.2 * Statistically Significant

26. NEO-ADJUVANT (PRE-OPERATIVE) THERAPY

27. Advantages Pre-operative Chemo radiation over Post-operative Chemo radiation More effective chemotherapy delivery with an intact blood supply Avoidance of hypoxia related chemo radiation resistance Avoidance of late radiation toxicity by surgical removal of irradiated duodenum and use of unirradiated jejunum use in reconstruction Immediate use of systemic therapy for a disease that is systemic at diagnosis in the majority of patients Improved patient selection for pancreatic surgery Pancreatic surgery is safer following chemo radiation due to reduced risk of pancreatic anastomotic leak due to pancreatic fibrosis Timely access to therapy. No delays due to post-operative recovery complications Increases R0 (complete) resection rates in patients with borderline resectable tumors

28. Operability Classification of Localized PAC based on high-quality cross-sectional imaging Resectable Borderline Resectable Locally Advanced Metastatic

29. Selected Trials of Neoadjuvant Chemoradiation for Patients with Potentially Resectable Pancreatic Cancer AuthorEvaluable Patients ResectedEBRT Dose (Gy) Chemotherapy Regimen Median Survival All Patients (Mo) Median Survival Resected Patients (Mo) Evans et al. (119)2817 (61%)50.4 + IORTCI 5-FUNA18 Hoffman et al. (121)5324 (45%)50.4Bolus 5-FU9.715.7 Pisters et al. (1203520 (57%)30 + IORTPVI 5-FU725 White et al.53 resectable28 (53%)45PVI 5-FUNR Moutardier et al (261)1915 (79%)30 or 45Bolus 5-FU + CDDP 2030 Arnoletti et al (262)2614 (54%)59.45-FU and/or MMC or Gem NA34 Pisters et al. (123)3520 (57%)30 and 10 IORTPaclitaxel1219 Wolff et al. (125)8664 (75%)30Gem2236 Magnin et al. (263)3219 (59)%30 or 45PVI 5-FU + CDDP1630 Talamonti et al. (126)2017 (85%)36 GyGemNA

31. Kaplan-Meier curves compare overall survival in patients according to timing of systemic therapy. MS indicate medial survival.

32. Kaplan Meier curves compare overall survival in patients with extra pancreatic disease (ie, T3 or T4 Disease) according to timing of sytematic therapy. MS indicates median survival.

34. Add Title

35. Need Title Survival adjusted for age, sex, and comorbidity for patients receiving treatment versus untreated patients.

36. Need Title Kaplan-Meier overall survival curves in patients with good Karnofsky performance score (90 to 100). Gem, gemcitabine; GemCap, Gemcitabine plus capecitabine.