1. Use Irinotecan or a Taxane for 2nd Line GE Cancer Therapy: Don’t Use What Dr. Fuchs Tells You to Use
Jordan D. Berlin, M.D.
Ingram Professor of Cancer Research
Co-director, GI Oncology
Director, Phase I Research
Vanderbilt-Ingram Cancer Center

2. Disclosures Current Research Support
Advisory Boards here and there in last year
Genentech/Roche
Karyopharm
Amgen
Astra Zeneca
BMS
Lilly/Imclone
Symphogen
Celgene
Vertex
Ipsen
Current Research Support
Amgen, Lilly/Imclone, Pfizer, Novartis, Abbvie, Immunomedics, Otsuka, Merrimack, Oncomed, Genentech/Roche, Taiho

3. So what is the data for second-line chemotherapy?

4. AIO: Small trial of irinotecan vs BSC
Fig. 2 Overall survival (intention to treat population) Median survival Irinotecan: 4.0 months, BSC: 2.4 months; one sided logrank test: p = 0.012; HR: 0.48 (95% CI: 0.25–0.92).
Peter C. Thuss-Patience , Albrecht Kretzschmar , Dmitry Bichev , Tillman Deist , Axel Hinke , Kirstin Breithaupt ,...
European Journal of Cancer, Volume 47, Issue 15, 2011,

5. Salvage Chemotherapy for Pretreated Gastric Cancer: A Randomized Phase III Trial Comparing Chemotherapy Plus Best Supportive Care With Best Supportive Care Alone
Jung Hun Kang, Soon Il Lee, Do Hyoung Lim, Keon-Woo Park, Sung Yong Oh, Hyuk-Chan Kwon, In Gyu Hwang, Sang-Cheol Lee, Eunmi Nam, Dong Bok Shin, Jeeyun Lee, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Won Ki Kang and Se Hoon Park⇑
JCO Aug 20, 2012:3035

6. Next 2nd line Chemotherapy (SLC) RCT
Screening & consent for RCT
Refused RCT, but prefer SLC
Willing to participate RCT
Refused RCT, but prefer BSC
2:1 randomization
SLC
SLC
BSC
BSC
Docetaxel
or irinotecan
RCT
N = 202
RCT + PPT
RCT: randomized controlled trial PPT: patient-preference trial
ClinicalTrials.gov, NCT
From Park ASCO 2011

7. Kaplan-Meier estimates for overall survival in randomly assigned patients.
OS 5.3 vs 3.8 months,
HR 0.66, p = 0.007
Kang J H et al. JCO 2012;30:
©2012 by American Society of Clinical Oncology

8. Trial funded by Cancer Research UK grant CRUK/07/013
COUGAR-02: Randomised phase III study of docetaxel versus active symptom control in patients with relapsed esophago-gastric adenocarcinoma
N Cook, A Marshall, JM Blazeby, JA Bridgewater, J Wadsley, FY Coxon, W Mansoor, S Madhusudan, S Falk, GW Middleton, D Swinson, I Chau, J Thompson, D Cunningham, P Kareclas, JA Dunn, HER Ford
On behalf of COUGAR 02 investigators and NCRI Upper GI Clinical Studies Group
Trial funded by Cancer Research UK grant CRUK/07/013
EudraCT Number:
ISRCTN

9. Trial Design Stratified by:
Arm A (n=84):
Docetaxel 75mg/m2 IV every 3 weeks for up to 6 cycles
+ ASC
Assess every 3 weeks for 18 weeks, then every 6 weeks
Adenocarcinoma of esophagus, esophagus-gastric junction or stomach refractory to platinum and fluoropyrimide
RANDOMISE
1:1
n=168
Arm B (n=84):
Active symptom control
May include: Radiotherapy, analgesia, anti-emetics, steroids
Stratified by:
1.Disease status (Locally advanced vs metastatic);
2. Site of disease (Esophagus vs GEJ vs Stomach);
3. Time to progression after previous chemotherapy ( 0 vs 0-3 vs 3-6 months);
4. ECOG PS ( 0/1 vs 2)

10. Overall survival
Median survival: 5.2 months (95% CI ) for Docetaxel
3.6 months (95% CI ) for ASC
Hazard ratio 0.67 (95% CI ), p=0.01

11. This is a difficult population to treat
Docetaxel
BSC
Completed 18 weeks
23%
36%
Reason off
Death
15%
38% PD
40% 2%
Tox
31%
N/A
Treatment
14%
These patients are sick
Most do not complete treatment plan
We still need to learn how best to select patients who will benefit

12. Randomized phase III study of irinotecan (IRI) versus weekly paclitaxel (wPTX) for advanced gastric cancer (AGC) refractory to combination chemotherapy (CT) of fluoropyrimidine plus platinum (FP): WJOG4007 trial
Ueda S, Hironaka S, Yasui H, Nishina T, Tsuda M, Tsumura T, Sugimoto N, Shimodaira H, Tokunaga S, Moriwaki T, Esaki T, Nagase M, Fujitani K, Yamaguchi K, Ura T, Hamamoto Y,
Morita S, Okamoto I, Boku N, Hyodo I,
Gastrointestinal Group of West Japan Oncology Group

13. Institution, PS 0-1/2, target lesion -/+
WJOG4007 Trial – Second line chemotherapy for metastatic gastric cancer
AGC refractory to prior FP confirmed by imaging
Age 20-75, PS 0-2, No history of CPT-11 or Taxane
RANDOMIZATION
Stratified by
Institution, PS 0-1/2, target lesion -/+
weekly Paclitaxel
80 mg/m2 d1, 8, 15 q4w
IRI
150 mg/m2 d1, 15 q4w
Ueda ASCO 2012

14. Progression Free Survival
IRI
wPTX n
111
108
Median
2.3M
3.6M P
0.33
HR (95% CI)
1.14 ( )
3.6
Probability (%)
2.3
Log-rank test
(Months)
Number at risk
wPTX
IRI
108
111 66 46 16 18 9 8 3 6 2 2 1
FAS

15. Overall Survival (Months) IRI wPTX n 111 108 Median 8.4M 9.5M P 0.38
HR (95% CI)
1.13 ( )
Log-rank test
Probability (%)
(Months)
Number at risk
wPTX
IRI
108
111 80 75 36 29 10 2 3 1 1
Udea ASCO 2012

16. Reasons for Treatment Discontinuation
wPTX
(n=106)
IRI
(n=110)
Total
(n=216)
Disease Progression 93
( 88%) 96
( 87%)
189
Adverse Event 6
( 6%) 10
( 9%) 16
Withdraw 5
( 5%) 2
( 2%) 7
Death 1
( 1%)
Other
PPS

17. Post-Study Chemotherapy (3rd line)
wPTX
(n=108)
IRI
(n=111) P
Received 3rd line CT 97
(90%) 80
(72%)
0.001
CPT-11 containing 81
(75%) 5
( 5%)
Taxane containing 8
( 7%) 67
(60%)
Others
Fisher’s exact test
FAS

18. FROM KANG STUDY SHOWN EARLIER
Kaplan-Meier estimates for overall survival in patients treated with best supportive care (BSC), docetaxel, or irinotecan.
Kang J H et al. JCO 2012;30:
©2012 by American Society of Clinical Oncology

19. Chemotherapy Conclusions
Basically, it works
It is not super, but HR of or better fairly consistently
Either irinotecan or taxane—both are reasonable
Don’t give both at the same time. That’s just mean
Probably works best in highly selected patients as in the WJOG study
PS 0-1
Doubtful it benefits PS = 2
But it would be nice to have more selection factors

20. Phase 3 Trial of Everolimus in Previously Treated Patients With Advanced Gastric Cancer: GRANITE-1
Eric Van Cutsem*,
K. H. Yeh, Y. J. Bang, L. Shen, J. A. Ajani, Y. X. Bai, H. C. Chung, H. M. Pan, K. Chin, K. Muro, Y. H. Kim, H. Smith, C. Constantini, S. Rizvi, T. Sahmoud, A. Ohtsu
On behalf of the GRANITE-1 Investigators
* University Hospital Leuven/Belgium
Presented at the 2012 Gastrointestinal Cancers Symposium.

21. Overall Survival (FAS)
Probability of overall survival (%)
100 80 60 40 20 2 4 6 8 10 12
Time (months) 14
Censoring Times
Everolimus + BSC (n/N = 352/439)
Placebo + BSC (n/N = 180/217)
Everolimus + BSC: 5.39 months
Placebo + BSC: 4.34 months
Hazard ratio: 0.90 (95% CI, )
Log-rank P value =
No. of patients still at risk
Everolimus
Placebo 16 18 22 24
217
172 1 17 82 35 28
439
355
253
195
139 87 52 30 13 3

22. Figure 2 Kaplan-Meier estimates of overall survival (A) and progression-free survival (B)
REGARD TRIAL
OS HR = 0.776
The Lancet, Volume 383, Issue 9911, 2014,
Charles S Fuchs , Jiri Tomasek , Cho Jae Yong , Filip Dumitru , Rodolfo Passalacqua , Chanchal Goswami , Howard S...
Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial

23. Let’s Compare: Trials vs BSC
Chemotherapy
Targeted Therapy
AIO (irinotecan)
HR 0.48
Granite-1 (everolimus)
HR 0.90
Kang (irinotecan or docetaxel)
HR 0.66
REGARD (ramucirumab)
HR 0.776
Cougar-02 (docetaxel)
HR 0.67
It all comes down to hazard ratio: For chemotherapy, it is very consistent, but for targeted agents, it is consistently not as good

24. So, if I were Dr. Fuchs, I would concede defeat and
“If you can’t beat ‘em, join ‘em”

25. RAINBOW: A Global, Phase 3, Randomized, Double-Blind Trial of Ramucirumab and Paclitaxel (PTX) Versus Placebo and PTX in the Treatment of Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma Following Disease Progression on First-Line Platinum- and Fluoropyrimidine-Containing Combination Therapy
H. Wilke*
Eric Van Cutsem, Sang Cheul Oh, György Bodoky,
Yasuhiro Shimada, Shuichi Hironaka, Naotoshi Sugimoto,
Oleg Lipatov, Tae You Kim, David Cunningham, Atsushi Ohtsu, Philippe Rougier, Michael Emig, Roberto Carlesi,
Kumari Chandrawansa, Kei Muro
*On behalf of the RAINBOW Investigators

26. Second line metastatic gastric and GEJ adenocarcinoma26
RAINBOW: Randomized Phase III Trial 2nd Line Paclitaxel +/- Ramucirumab
Paclitaxel 80 mg/m2 d1, 8, 15 +
Ramucirumab IV q 2 weeks
Second line metastatic gastric and GEJ adenocarcinoma R
1:1
Paclitaxel 80 mg/m2 d1, 8, 15 +
Placebo q 2 weeks
Primary EP: OS
N = 665 26

27. RAINBOW: Overall Survival
HR (95% CI) = (0.678, 0.962)
Stratified log rank p-value =
RAM + PTX
PBO + PTX
Patients / Events
330 / 256
335 / 260
Median(mos) (95% CI)
9.63 (8.48, 10.81)
7.36 (6.31, 8.38)
6-month OS
72%
57%
12-month OS
40%
30%
Δ mOS = 2.3 months
Censored
No. at risk
RAM + PTX
330
308
267
228
185
148
116 78 60 41 24 13 6 1
PBO + PTX
335
294
241
180
143
109 81 64 47 30 22 5 2

28. Overall conclusion
Thanks to the organizers for giving me the obviously better choice
I can stick with hazard ratio and not even point out the price differentials
And also, thank the organizers for not giving Dr. Fuchs the option of combining targeted and chemo
And also, thank Drs. Van Cutsem, Bendell, Kang, and Cook for the slides of theirs I used.