ESPAC-4: Adjuvant Gemcitabine/ Capecitabine Improves 5-Yr Survival vs Gemcitabine Alone in Resected Pancreatic Ductal Carcinoma CCO Independent Conference Coverage* of the 2016 ASCO Annual Meeting, June 3-7, 2016 *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. This activity is supported by educational grants from Amgen, Ariad, Bayer Healthcare Pharmaceuticals, Celgene Corporation, Genentech, Incyte, Merck, and Taiho Pharmaceuticals.

Adjuvant Gemcitabine/Capecitabine in Pancreatic Cancer: Background ESPAC-1 (N = 289): CRT not superior to no CRT (HR: 1.28; P = .053) for resected pancreatic ductal adenocarcinoma but chemotherapy superior to no chemotherapy (HR: 0.71; P = .009)[1,2] ESPAC-3 (N = 1088): gemcitabine not superior to 5-FU/ leucovorin Median OS: nearly 24 mos in both arms[3] Current multicenter, international, open-label, randomized, controlled phase III trial, ESPAC-4, evaluated adjuvant gemcitabine + capecitabine vs gemcitabine in pts pancreatic ductal adenocarcinoma undergoing intended curative resection[4] 5-FU, 5-fluorouracil; CRT, chemoradiotherapy. 1. Neoptolemos JP, et al. Lancet. 2001;358:1576-1585. 2. Neoptolemos JP, et al. Lancet. 2004;350:1200-1210. 3. Neoptolemos JP, et al. JAMA. 2010;304: 1073-1081. 4. Neoptolemos JP, et al. ASCO 2016. Abstract LBA4006. Slide credit: clinicaloptions.com

Phase III ESPAC-4: Adjuvant GEMCAP vs GEM in Resected Pancreatic Cancer Gemcitabine 1000 mg/m2 Days 1, 8, 15 for 6 cycles + Capecitabine 1660 mg/m2/day 21/28 days (n = 364) Pts with pancreatic ductal adenocarcinoma undergoing macroscopic R0 or R1 (≤ 1 mm any surface) resection, WHO PS ≤ 2, no prior or concurrent malignancies, life-expectancy > 3 mos (N = 730) Follow-up every 3 mos from randomization until death Gemcitabine 1000 mg/m2 Days 1, 8, 15 for 6 cycles (n = 366) GEMCAP, gemcitabine/capecitabine; PS, performance status; QoL, quality of life; RFS, relapse-free survival; WHO, World Health Organization. Primary endpoint: OS Secondary endpoint: toxicity, RFS, 2- and 5-yr survival, and QoL Slide credit: clinicaloptions.com Neoptolemos JP, et al. ASCO 2016. Abstract LBA4006.

ESPAC-4: Baseline Characteristics GEMCAP (n = 364) GEM (n = 366) Total (N = 730) Median age, yrs (range) 65 (39-81) 65 (37-80) 65 (37-81) Male, % 55 58 57 Baseline PS, % 1 2 41 56 3 43 54 42 Smoking status, % Never Past Present Unknown 40 17 37 5 39 Surgery to randomization, median days (range) 64 (21-111) 65 (23-111) GEMCAP, gemcitabine/capecitabine; GEM, gemcitabine; PS, performance status. Trial was stopped early by Independent Trial Steering Committee due to efficacy Median follow-up of alive patients: 43.2 mos (95% CI: 39.7-45.5) Slide credit: clinicaloptions.com Neoptolemos JP, et al. ASCO 2016. Abstract LBA4006.

ESPAC-4: Toxicity Grade 3/4 AE (NCI CTC v4), % GEMCAP (n = 359) GEM (n = 366) P Value* Anemia 2 4 .279 Diarrhea 5 .008 Fatigue 6 .870 Fever 1.000 Infection and infestations, other 3 7 .012 Lymphocytes .821 Neutrophils 38 24 < .001 Hand-foot syndrome Platelets .800 Thromboembolic event WBC 10 8 .242 AE, adverse event; GEMCAP, gemcitabine/capecitabine; GEM, gemcitabine; NCI CTC, National Cancer Institute Common Terminology Criteria; WBC, white blood cell count. *Exploratory analysis: Fisher’s exact test No difference in treatment-related serious AEs between treatment arms 24% with GEMCAP vs 26% with gemcitabine; Χ2df1 test P >.05 Slide credit: clinicaloptions.com Neoptolemos JP, et al. ASCO 2016. Abstract LBA4006.

Mos From Randomization ESPAC-4: Survival 100 Gemcitabine Gemcitabine-Capecitabine 90 80 70 HR: 0.82 (95% CI: 0.68-0.98) χ2 (1): 4.61; P = .032 60 OS (%) 50 40 30 20 Median S(t): 25.5 mos (95%CI: 22.7-27.9) Median S(t): 28.0 mos (95% CI: 23.5-31.5) 10 GEMCAP, gemcitabine/capecitabine; GEM, gemcitabine; 10 20 30 40 50 60 Mos From Randomization Pts at Risk, n GEM GEMCAP 366 364 302 328 207 219 109 139 61 83 27 50 9 19 Greatest benefit with GEMCAP and R0, but treatment benefit evident even with R1 resection Neoptolemos JP, et al. ASCO 2016. Abstract LBA4006. Reproduced with permission. Slide credit: clinicaloptions.com

ESPAC-4: Factors Affecting OS Survival by Grade of Disease Survival by Stage of Disease 100 100 χ2(2): 38.21; P < .001 χ2(3): 12.71; P = .005 90 Well Moderate Poor 90 I II III IV 80 80 70 70 60 60 OS (%) 50 OS (%) 50 40 40 Median S(t): N/A Median S(t): 39.3 Median S(t): 26.0 Median S(t): 15.7 30 Median S(t): 41.1 Median S(t): 30.7 Median S(t): 19.0 30 20 20 10 10 10 20 30 40 50 60 10 20 30 40 50 60 Mos From Randomization Mos From Randomization Survival by Lymph Nodes Survival by Resection Margins 100 χ2(1): 38.66; P < .001 100 χ2(1): 17.65; P < .001 90 Negative Positive 90 R0 R1 80 80 70 70 60 60 OS (%) 50 OS (%) 50 40 40 30 30 20 Median S(t): 58.0 Median S(t): 23.5 20 Median S(t): 34.6 Median S(t): 23.3 10 10 10 20 30 40 50 60 10 20 30 40 50 60 Mos From Randomization Mos From Randomization Slide credit: clinicaloptions.com Neoptolemos JP, et al. ASCO 2016. Abstract LBA4006. Reproduced with permission.

Adjuvant GEMCAP vs GEM in Pancreatic Cancer: 5-Year OS in ESPAC Studies Trial Treatment Pts, n (N = 2092) 5-Yr OS, % (95% CI) Stratified Log-Rank Χ2 P Value ESPAC-1 5-FU/ leucovorin 149 21 (14.6-28.5) 7.03 .030* No chemotherapy 143 8.0 (3.8-14.1) CRT (5-FU/RT) 145 10.8 (6.1-17.0) ESPAC-3 GEM 539 17.5 (14.0-21.2) 0.74 .390* 5-FU/ leucovorin 551 15.9 (12.7-19.4) ESPAC-4 366 16.3 (10.2-23.7) 4.61 .032† GEMCAP 364 28.8 (22.9-35.2) 5-FU, 5-fluorouracil; CRT, chemoradiotherapy; GEMCAP, gemcitabine/capecitabine; GEM, gemcitabine. *Stratification factor: resection margin status. †Stratification factors: resection margin status and country. Slide credit: clinicaloptions.com Neoptolemos JP, et al. ASCO 2016. Abstract LBA4006.

ESPAC-4: Conclusions Median survival for pts with resected pancreatic cancer who received GEMCAP was significantly longer than with GEM 28.0 vs 25.5 mos, respectively Estimated 5-yr survival with GEMCAP superior vs GEM: 28.8 vs 16.3 mos, and superior to previous ESPAC trial arms, including 5- FU/leucovorin, CRT, and no chemotherapy Higher toxicity in GEMCAP arm manageable, not significant: 154 serious AEs in 86 pts treated with GEMCAP (24%) vs 151 serious AEs in 94 pts with GEM (26%) Investigators recommend offering all pts with pancreatic cancer the opportunity to participate in trials Evaluation of relevant biomarkers needed Investigators suggest that GEMCAP is the new standard of care for resected pancreatic cancer 5-FU, 5-fluorouracil; AE, adverse event; CRT, chemoradiotherapy; GEMCAP, gemcitabine/capecitabine; GEM, gemcitabine. Slide credit: clinicaloptions.com Neoptolemos JP, et al. ASCO 2016. Abstract LBA4006.

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