Pancreatic Cancer Ali Shamseddine MD Proessor of Medicine AUBMC

Adjuvant Therapy: Historical Lack of Consensus GITSG1 Survival advantage for chemoradiation followed by 5-FU for 1 year, but Early termination, and Slow accrual (43 patients in 8 years) EORTC2 No survival benefit for chemoradiation, but no maintenance chemotherapy 5-FU, 5-fluorouracil; EORTC, European Organisation for the Research and Treatment of Cancer; GITSG, Gastro-Intestinal Study Group. 1. Kaiser MH, et al. Arch Surg. 1985;120:899-903. 2. Klinkenbijl JH. Ann Surg. 1999;230:776-782.

Adjuvant Chemotherapy Two recent randomized clinical trials demonstrated benefit ESPAC-11 N = 289 (4-arm study also evaluating chemoradiation) Observation vs 5-FU/LV (Mayo) 5-year survival: 8% vs 21% (P = .009) CONKO-0012 N = 368 Observation vs gemcitabine (Days 1, 8, and 15 of 4-week cycle x 6 months) Disease-free survival: 6.9 vs 13.4 months 5-year disease-free survival: 5.5% vs 16.5% 5-FU/LV, 5-fluorouracil/leucovorin; CONKO, Charite Onkologie; ESPAC, European Study Group for Pancreatic Cancer. 1. Neoptolemos JP, et al. NEJM. 2004;350:1200-1210. 2. Oettle H, et al. J Am Med Assoc. 2007;297:267-277.

Adjuvant Chemotherapy: Outcomes CONKO-001: Disease-Free Survival ESPAC-1: Survival 100% 75% 100% 75% Cumulative Disease Free Survival 50% Survival (%) 50% gemcitabine 25% Chemotherapy 25% observation No chemotherapy 0% 0% 12 24 36 48 60 72 84 12 24 36 48 60 72 Months Months Neoptolemos JP, et al. NEJM. 2004;350:1200-1210. Oettle H, et al. J Am Med Assoc. 2007;297:267-277. Oettle H, et al. J Am Med Assoc. 2007;297:267-277.

CONKO-001: Previous Analysis Previously reported data indicated that the median DFS was 13.4 and 6.9 mos in the gemcitabine and control groups, respectively Estimated DFS at 3 and 5 yrs was 23.5% and 16.5% in the gemcitabine group and 7.5% and 5.5% in the control group, respectively Subgroup analyses showed the effect of gemcitabine on DFS was significant in patients with either R0 and R1 resection No difference in OS between the gemcitabine and control groups Oettle H, et al. JAMA. 2007;297:267-277.

*CHARITÉ ONKOLOGIE:Clinical studies in GI cancers CONKO*-001: Final results of the randomized, prospective, multicenter phase III trial of adjuvant chemotherapy with gemcitabine versus observation in patients with resected pancreatic cancer (PC) U.P. Neumann P. Neuhaus, H.Riess, S. Post, K. Gellert, K. Ridwelski, H. Schramm, C. Zülke, G. Fahlke, J. Langrehr, H. Oettle Charitè - Universitätsmedizin Berlin - Campus Virchow Klinikum; Ruprecht-Karls-Universität, Mannheim; Oskar-Ziethen-Krankenhaus, Berlin; Otto-von-Guericke-Universität, Magdeburg; Wald-Klinikum, Gera; Universität Regensburg, Regensburg; AIO; CAO; Deutsche Krebsgesellschaft e.V. *CHARITÉ ONKOLOGIE:Clinical studies in GI cancers

Disclosure I have Consultant or Advisory Role to disclose: Lilly Oncology Roche Sanofi-Aventis

CONKO-001 Study Design and Patient Disposition Resected pancreatic cancer 368 patients enrolled 7/98 - 12/04 Stratification R; T; N 182 pts. for Observation 179 eligible* pts. (96%) for Intent-to-Treat Analysis 175 eligible* pts. (96%) for Intent-to-Treat Analysis 186 pts. for Gemcitabine * 7 excluded Patients: 4 pts. withdrew consent 1 pt. no histologic verification 1 pt. persistent disease after resection 1 pt. another malignant disease * 7 excluded Patients: 4 pts. withdrew consent 3 pts. another malignant disease Date of Analysis: March 2008

CONKO-001 Endpoints Primary Endpoint Secondary Endpoint Disease free survival (DFS) Secondary Endpoint Overall survival (OS) Toxicity

CONKO-001 Inclusion Criteria Histologically proven resected pancreatic carcinoma Standard operation No measurable disease No prior chemo- or radiotherapy No active infection Karnofsky performance status  50% Adequate hematologic, renal and hepatic function CA 19-9, CEA < 2.5 ULN Start with adjuvant therapy within 6 weeks after resection Written informed consent

CONKO-001 Treatment Schedule Ran domi sa t i on Ultrasound after week 8 Ultrasound after week 16 CT Scan after week 32 Gem Gem Gem Gem Gem Gem Follow up every 8 weeks Obs Obs Obs Obs Obs Obs 4 weeks 4 weeks 4 weeks 4 weeks 4 weeks 4 weeks Gem Gemcitabine 1000 mg/m²: d1, 8, 15; q 4 weeks Obs Observation: d1; q 4 weeks

CONKO-001 Patient Characteristics

CONKO-001 Tumor Characteristics

CONKO-001 Disease Free Survival (DFS) We already demonstrated safety data and superior DFS for adjuvant treatment with gemcitabine as compared to observation in patients with resected pancreatic cancer. P. Neuhaus et al., ASCO 2005 H. Oettle et al., JAMA 2007

Date of Analysis: March 2008 CONKO-001 DFS Date of Analysis: March 2008 Gemcitabine Median: 13.4 months (95% CI. 11.3-15.4) (21.2% censored) Observation Median: 6.9 months (95% CI. 6.2-7.5) (7.4% censored) Log Rank P<0.001 (14.4% censored)

CONKO-001 DFS Hazard Ratios 0.59 [0.46, 0.76] 0.33 [0.18, 0.58] Test for heterogeneity: Chi² = 3.54, df = 1 (P = 0.06), I² = 71.7% 0.53 [0.34, 0.84] 0.53 [0.41, 0.69] Test for heterogeneity: Chi² = 0.00, df = 1 (P = 0.96), I² = 0% 0.52 [0.27, 1.00] 0.55 [0.43, 0.70] Total (95% CI) 0.55 [0.44, 0.69] Test for heterogeneity: Chi² = 0.02, df = 1 (P = 0.87), I² = 0% 0.2 0.5 1 2 5 Favours gemcitabine Favours control R Status R0 R1 N stage N- N+ T stage T1-2 T3-4 DFS (fixed) 95% CI Hazard ratio 95% CI Sub-category

CONKO-001 Overall Survival (OS) Gemcitabine Median: 22.8 months (95% CI. 18.5-27.2) (23.5% censored) Observation Median: 20.2 months (95% CI. 17.7-22.8) (10.9% censored) Log Rank P=0.005 (17.2% censored)

CONKO-001 Longterm Survival

CONKO-001 OS Resection Margin R0 n=293 Gemcitabine Median: 22.8 months (95% CI. 18.0-27.6) (24.8% censored) Observation Median: 20.3 months (95% CI. 17.9-22.7) (11.5% censored) Log Rank P=0.018 (18.1% censored) R1 n=61 Gemcitabine Median: 22.1 months (95% CI. 9.4-34.9) (17.6% censored) Observation Median: 14.1 months (95% CI. 12.2-16.0) (7.4% censored) Log Rank P=0.088 n.s. (13.1% censored)

CONKO-001 OS Primary Tumor T1+T2 n=49 Gemcitabine Median: 40.6 months (95% CI. 26.6-54.5) (44.0% censored) Observation Median: 27.0 months (95% CI. 21.4-32.7) (20.8% censored) Log Rank P= 0.12 n.s. (32.7% censored) T3+T4 n=305 Gemcitabine Median: 21.0 months (95% CI. 16.2-25.8) (20.1% censored) Observation Median: 19.0 months (95% CI. 16.3-21.7) (9.3% censored) Log Rank P= 0.018 (14.8% censored)

CONKO-001 OS Hazard Ratios OS (fixed) 95% CI Hazard ratio 95% CI Sub-category R Status R0 R1 0.74 [0.57, 0.95] 0.62 [0.36, 1.08] Test for heterogeneity: Chi² = 0.30, df = 1 (P = 0.59), I² = 0% N stage N- N+ 0.57 [0.36, 0.91] 0.80 [0.61, 1.04] Test for heterogeneity: Chi² = 1.50, df = 1 (P = 0.22), I² = 33.5% T stage T1-2 T3-4 0.58 [0.29, 1.16] 0.74 [0.58, 0.95] Total (95% CI) 0.72 [0.57, 0.91] Test for heterogeneity: Chi² = 0.44, df = 1 (P = 0.50), I² = 0% Test for overall effect: Z = 2.74 (P = 0.005) 0.2 0.5 1 2 5 Favours gemcitabine Favours control

CONKO-001 Conclusions Treatment with gemcitabine as compared to observation in patients with resected pancreatic cancer results in improved disease free survival and overall survival Adjuvant treatment with gemcitabine doubles the longterm survival rate after 5 years compared to observation Gemcitabine should be the standard of care for adjuvant treatment of pancreatic cancer