1. 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.

2. 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: Neoptolemos JP, et al. Lancet. 2004;350: Neoptolemos JP, et al. JAMA. 2010;304: Neoptolemos JP, et al. ASCO Abstract LBA4006.
Slide credit: clinicaloptions.com

3. 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 Abstract LBA4006.

4. 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: )
Slide credit: clinicaloptions.com
Neoptolemos JP, et al. ASCO Abstract LBA4006.

5. 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 Abstract LBA4006.

6. Mos From Randomization
ESPAC-4: Survival
100
Gemcitabine Gemcitabine-Capecitabine 90 80 70
HR: 0.82 (95% CI: ) χ2 (1): 4.61; P = .032 60
OS (%) 50 40 30 20
Median S(t): 25.5 mos (95%CI: )
Median S(t): 28.0 mos (95% CI: ) 10
GEMCAP, gemcitabine/capecitabine; GEM, gemcitabine; 10 20 30 40 50 60
Mos From Randomization
Pts at Risk, n GEM GEMCAP
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 Abstract LBA4006. Reproduced with permission.
Slide credit: clinicaloptions.com

7. 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 Abstract LBA4006. Reproduced with permission.

8. 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
( )
7.03
.030*
No chemotherapy
143
8.0 ( )
CRT (5-FU/RT)
145
10.8 ( )
ESPAC-3
GEM
539
17.5 ( )
0.74
.390*
5-FU/ leucovorin
551
15.9 ( )
ESPAC-4
366
16.3 ( )
4.61
.032†
GEMCAP
364
28.8 ( )
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 Abstract LBA4006.

9. 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 mos, and superior to previous ESPAC trial arms, including 5- FU/leucovorin, CRT, and no chemotherapy
Higher toxicity in GEMCAP arm manageable, not significant: 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 Abstract LBA4006.

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