1. Discussion Pancreatic Cancer Abstracts 145, LBA146, 147, & LBA148
Philip Agop Philip, MD, PhD, FRCP
Karmanos Cancer Center
Wayne State University
Detroit, Michigan

2. Japan Adjuvant Study Group of Pancreatic Cancer (JASPAC)
Randomized phase III trial of adjuvant chemotherapy with gemcitabine vs. S-1 for resected pancreatic cancer patients (JASPAC 01 study)
K. Uesaka, et al.
Japan Adjuvant Study Group of Pancreatic Cancer (JASPAC)
Abstract #145

3. JASPAC 01 Surgery Randomization GEM 1000 mg/m2 Q 4 weeks X 6 cycles
Stratification
Center
R0/R1
N0/N1
Randomization
No radiaiton therapy
GEM 1000 mg/m2
Q 4 weeks
X 6 cycles
S mg, BID, PO
4 wks on/2 wks off
X 4 cycles
# ASCO GI

4. JASPAC 01 No Radiotherapy! Surgery Randomization S-1 40-60mg, BID, PO
Stratification
Center
R0/R1
N0/N1
Randomization
No radiaiton therapy
S mg, BID, PO
4 wks on/2 wks off
X 4 cycles
GEM 1000 mg/m2
X 6 cycles
# ASCO GI

5. JASPAC 01 Overall Survival Primary Endpoint50
100 1 2 3 4 5
years
(%)
P< for non-inferiority
P< for superiority
70%
53%
S-1
GEM

6. Gemcitabine vs. Fluoropyrimidine (FP): Phase III Adjuvant Studies
CONKO-001
RTOG 97-04
ESPAC-3
JASPAC 01
GEM v Obs
GEM v inf-FU
+ C-RT
GEM v b-FU
GEM v S-1
mDFS mon
GEM
13.4
11.4
14.3
11.2 FP -
10.1
14.1
23.2
mOS mon
22.8
20.5
23.6
25.5
16.9 23
46.3
From the oettle study the improvement in DFS does not translate well to improvement in survival. What is also lacking in the Japanese study is the pattern of therapy post-recurrence
Number of questions; site of disease, maturity of data, post-relapse therapy
The other thing is that the RTOG study was the only one with radiation included it is noteworthy
In a disease with such a short survival it is possible that small changes can be amplified!
Superiority of s-1 may not be that surprising given the efficacy data of the drug in advanced disease, however the magnitude of the benefit over gemcitabine in this adjuvant setting is intriguing with worth more depth study at the molecular level.
Oettle et al, JAMA, 297: , 2007; Regine et al, 299: , 2008; Neoptolemus et al, 304: , 2010;

7. Gemcitabine vs. Fluoropyrimidine (FP): Phase III Adjuvant Studies
CONKO-001
RTOG 97-04
ESPAC-3
JASPAC 01
GEM v Obs
GEM v inf-FU
+ C-RT
GEM v b-FU
GEM v S-1
mDFS mon
GEM
13.4
11.4
14.3
11.2 FP -
10.1
14.1
23.2
mOS mon
22.8
20.5
23.6
25.5
16.9 23
46.3
Node positive, % 72 67 63
R0, % 81 66 65 87
From the oettle study the improvement in DFS does not translate well to improvement in survival. What is also lacking in the Japanese study is the pattern of therapy post-recurrence
Number of questions; site of disease, maturity of data, post-relapse therapy
The other thing is that the RTOG study was the only one with radiation included it is noteworthy
In a disease with such a short survival it is possible that small changes can be amplified!
Superiority of s-1 may not be that surprising given the efficacy data of the drug in advanced disease, however the magnitude of the benefit over gemcitabine in this adjuvant setting is intriguing with worth more depth study at the molecular level.

8. JASPAC 01
Superiority of adjuvant S-1 over GEM in Japanese patients with resected panc. ca.
“Non-Japanese” studies must be considered to define the role of S-1 in early and late stage disease in conjunction with biomarkers studies (e.g., S-1 metabolism)
The role of adjuvant radiation therapy in panc. ca will be determined by the ongoing RTOG/SWOG/EORTC study
Superiority in the absence of XRT
S-1 alone or in combination such as with radiation therapy

9. Randomized Phase III Study of Weekly nab-Paclitaxel plus Gemcitabine vs Gemcitabine Alone in Patients with Metastatic Adenocarcinoma of the Pancreas (MPACT)
Daniel D. Von Hoff, et al.
Abstract #148

10. 1000 mg/m2 IV qw for 7 weeks then qw 3/4 weeks
Study Design
nab-Paclitaxel
125 mg/m2 IV qw 3/4 weeks +
Gemcitabine
1000 mg/m2 IV qw 3/4 weeks
Planned N = 842
Stage IV
No prior treatment for metastatic disease
Karnofsky PS ≥70
Measurable disease
Total bilirubin ≤ULN
Gemcitabine
1000 mg/m2 IV qw for 7 weeks then qw 3/4 weeks
Von Hoff

11. IMPACT: Efficacy Med OS, mos 8.5 6.7 0.72/ 0.000015 Med PFS, mos 5.5
nab-Pacli + GEM
GEM
Hazard ratio
p value
Med OS, mos
8.5
6.7
0.72/
Med PFS, mos
5.5
3.7
0.69/
12-mon alive, % 35 22
0.0002
Objective response, % 23 7
1.1x10-10

12. Major Treatment Options for Metastatic Pancreatic Cancer
Gemcitabine +/- erlotinib
FOLFIRINOX
Nab-paclitaxel plus gemcitabine
Others (e.g., GemCape, GTX)
Clinical trial

13. Major Treatment Options for Metastatic Pancreatic Cancer
Gemcitabine +/- erlotinib
FOLFIRINOX
Nab-paclitaxel plus gemcitabine
Others (e.g., GemCape, GTX)
Clinical trials

14. Tolerability: Selected Grade 3+ Toxicities, %
nab-pacli + GEM
FOLFIRINOX
Fatigue 17
23.6
Diahhrea 6
12.7
Neuropathy 9
Neutropenia 38
45.7
Neutropenic fever 3
5.4
Thrombocytopenia 13
9.1
Conroy et al, NEJM, 364: , 2011

15. Efficacy nab-pacli + GEM FOLFIRINOX Median OS, mos 8.7 11.1
Median PFS, mos
5.5
6.4
ORR (%)
23.0
31.6
Conroy et al, NEJM, 364: , 2011

16. Study Populations IMPACT PRODIGE/ACCORD Median age median 63 61
Liver, % 84 88
Head of pancreas, % 43 38
Males, % 58
Good PS, % 60
Median sites of mets 3 2
Number of patients
861
342
Treatment centers
Multiple countries
Comparing full prtocvol doses
Conroy et al, NEJM, 364: , 2011

17. IMPACT
Is an example of pre-clinical to pilot testing to Phase III drug stepwise developmental program
Nab-paclitaxel plus GEM is a new frontline regimen in patients with metastatic panc. ca. and favorable performance status
Nab-paclitaxel +/- GEM (or other drugs) must be investigated in earlier stage disease and in combinations with biologicals
The molecular basis of nab-paclitaxel’s activity and its association with a biomarker(s) must be determined (going back to the lab!)

18. the Final Results of the SCALOP Trial
Induction GEMCAP Chemotherapy followed by Gemcitabine (Gem) or Capecitabine (Cap)-based Chemoradiation (CRT) for Locally Advanced Pancreatic Cancer (LAPC):
the Final Results of the SCALOP Trial
S Mukherjee, et al.
SCALOP Investigators
In an era of limited informaiton on how best to do stduies or trials
Abstract LBA146

19. Gemcitabine 300mg/m2/week
SCALOP
GEMCAP x 3 cycles
Gem 1000mg/m2 D1,8,15 q 4w
Cap 830mg/m2 BD D 1-21 q 4w
Progressive dx
Tumor >6cm diameter
PS 2
>10% wt loss
Not encompassable in radiation volume
RANDOMIZATION
GEMCAP x 1 cycle
GEMCAP x 1 cycle
Gemcitabine 300mg/m2/week
+ RT 50.4Gy
Capecitabine 830mg/m2 bd
+ RT 50.4Gy

20. Gemcitabine 300mg/m2/week
SCALOP
GEMCAP x 3 cycles
Gem 1000mg/m2 D1,8,15 q 4w
Cap 830mg/m2 BD D 1-21 q 4w
Progressive ds
Tumor >6cm diameter
PS 2
>10% wt loss
Not encompassable in radiation volume
35%
RANDOMIZATION
GEMCAP x 1 cycle
GEMCAP x 1 cycle
Gemcitabine 300mg/m2/week
+ RT 50.4Gy
Capecitabine 830mg/m2 bd
+ RT 50.4Gy

21. Gemcitabine 300mg/m2/week
SCALOP
GEMCAP x 3 cycles
Gem 1000mg/m2 D1,8,15 q 4w
Cap 830mg/m2 BD D 1-21 q 4w
Progressive ds
Tumor >6cm diameter
PS 2
>10% wt loss
Not encompassable in radiation volume
RANDOMIZATION
4 cycles/4 months
of systemic therapy
GEMCAP x 1 cycle
GEMCAP x 1 cycle
Gemcitabine 300mg/m2/week
+ RT 50.4Gy
Capecitabine 830mg/m2 bd
+ RT 50.4Gy

22. Summary of Efficacy Data
CAPE-RT
GEM-RT p
PFS at 9 mos, %
62.9
51.4 NS
Median PFS, mos
12.0
10.4
Med OS, mos
15.2
13.4
0.025
All
Randomized
Taken off N
114 74 40
Med OS, mos
12.7
14.6
8.1

23. What do we learn from SCALOP?
Cape-RT is the current preferred standard and will continue as such
Ongoing research questions
The contribution of chemo-RT (GERCOR, Dr P. Hammel; ALLIANCE, Dr A. Ko)
Molecular selection for chemo-RT (RTOG, Dr E. Ben Josef)
More effective systemic therapies
Develop study designs and endpoints that are appropriate to each question
We should continue study them separately

24. A Phase I/II Study of ABT-888, 5-Fluorouracil and Oxaliplatin in Patients with Metastatic Pancreatic Cancer
M. J. Pishvaian, et al.
Abstract #147

25. Phase Ib No patient selection
Pre-treatment biopsies for BRCA-1, -2, PALB-B3, FANC gene expression, others

26. PARPi and Pancreatic Cancer
A platinum +/- PARPi strategy is worth pursuing in patients with BRCA-2 mutations
Explore biologic combinations with PARPi
Need to determine relative contributions of platinum vs. PARPi to anti-tumor activity
National or “preferably” international collaborative effort is necessary for a timely completion of clinical trials (e.g., ARCAD)
Too early!
Still need a lot of pre-clinical evaluations

27. Thank you

28. backup

29. Take Home Messages
Adjuvant S-1 is a new standard for resected pancreas ca. with a potential for its development outside of Japan
nab-Paclitaxel/GEM is a new treatment standard for patients with metastatic pancreas ca. warranting further development in conjunction with a biomarker discovery strategy
The biology of S1 with respect to pancreas cancer will be worth studying
Nab-pacli increases treatment options
Tissue collection in these studies helpful to understand

30. Take Home Messages (2)
Capecitabine 1.66 grams/m2/day will continue to be our radisoenstizer of choice in pancreas ca.
A treatment strategy of a platinum compound +/- PARPi needs pre-clinical/pilot clinical evaluations in BRCA-2 mutated panc. ca.
More tissue-based research and stronger collaborative efforts are necessary for successful studies in pancreatic cancer!

31. Gemcitabine vs. Fluoropyrimidine (FP): Phase III Adjuvant Studies
CONKO-001
RTOG 97-04
ESPAC-3
JASPAC 01
GEM v Obs
GEM v inf-FU
+ C-RT
GEM v b-FU
GEM v S-1
mDFS mon
GEM
13.4
11.4
14.3 12 FP -
10.1
14.1 24
mOS mon
22.8
20.5
23.6 23
16.9 46
Hazard ratio for overall survival
0.80
0.94
0.56
From the oettle study the improvement in DFS does not translate well to improvement in survival. What is also lacking in the Japanese study is the pattern of therapy post-recurrence
Number of questions; site of disease, maturity of data, post-relapse therapy
The other thing is that the RTOG study was the only one with radiation included it is noteworthy
In a disease with such a short survival it is possible that small changes can be amplified!
Superiority of s-1 may not be that surprising given the efficacy data of the drug in advanced disease, however the magnitude of the benefit over gemcitabine in this adjuvant setting is intriguing with worth more depth study at the molecular level.
Oettle et al, JAMA, 297: , 2007; Regine et al, 299: , 2008; Neoptolemus et al, 304: , 2010;