1. Attending Physician, Member Memorial Sloan-Kettering Cancer Center
Management of Metastatic Esophagogastric Cancer: Novel Biologic + / - Chemo
David H. Ilson, M.D., Ph.D.
Attending Physician, Member
Memorial Sloan-Kettering Cancer Center
New York, NY

2. Advanced Esophagogastric Cancer Chemotherapy: What Regimen to Use?
Oxali:
EOX or EOF
Cape:
ECX or EOX XP
FLO
FOLFIRI
FUFIRI
S-1 Cis
DCF
ECF
Pts
489
513
160
109
209
170
305
221
126
%RR
44%
45%
41%
34%
39%
32%
54%
36%
TTP, months
6.7
6.5
5.6
5.5
5.3
5.0
6.0
7.4
OS, months
10.9
10.4
10.5
10.7
9.5
9.0
13.0
9.2
8.9
Cunningham NEJM 358:36;2008, Kang Annals Oncol 20:666;2009, Al-Batran JCO 26:1435;2008, Dank Annals Oncol 19:450;2008 Koizumi Lancet Oncol 9:215;2008, Van Cutsem JCO 24:4991;2006, Webb JCO 15:61;1997

3. Second Line Chemo Gastric Cancer Phase III Trials  Improved Survival
Docetaxel vs
BSC
Docetaxel or Irinotecan vs
Paclitaxel vs
Irinotecan
Patients 84
133 69
111
112
RR % 7% --
11% 8%
21%
14%
PFS
12.2 wks NS
3.6 mo
2.3 mo OS
5.2 mo
5.3 mo
( )
3.8 mo
9.5 mo
8.4 mo
Significance
HR 0.67
P = 0.01
HR P = 0.007
Ford H Lancet Oncol 15:78; 2014; Kang JH J Clin Oncol 30:1513; Hironaka JCO 31: 4438; 2013

4. Second Line Chemo Gastric Cancer Phase III Trials  Improved Survival
Docetaxel/Irinotecan vs BSC
Docetaxel vs BSC
Ford H Lancet Oncol 15:78; 2014; Kang JH J Clin Oncol 30:1513; 2012

5. FIRST LINE
SECOND LINE
THIRD LINE

6. VEGFr2: Ramucirumab in Gastric Cancer: REGARD Trial
Gastric/GEJ Cancer with POD on FU or Platinum Based Chemo
RANDOMIZATION, 355 patients
BSC + Placebo
BSC + Ramucirumab 8 mg/kg q 2 weeks
Fuchs CS, et al. Lancet. 2014;383(9911):31-39

7. Time Since Randomization, Months Time Since Randomization, Months
REGARD Trial: Results OS
PFS 20
HR (95% CI) = ( )
Log-rank P value (stratified) <.0001 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 40 60 80
100
PFS, %
238
117
Number at risk
Ramucirumab
Placebo
213 92
113 27 65 61 45 30 18
Time Since Randomization, Months
Ramucirumab (n = 238)
Placebo (n = 117)
Censored 27
HR (95% CI) = ( )
Log-rank P value (stratified) =.047 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 26 28 40 60 80
100
OS, %
238
117
Number at risk
Ramucirumab
Placebo
154 66 92 34 49
Ramucirumab (n = 238)
Placebo (n = 117)
Censored
Time Since Randomization, Months
Fuchs CS, et al. Lancet. 2014;383(9911):31-39.

8. Median OS in Randomized Second-Line Gastric Cancer Studies Presented/Published in 2009-2013
Ramucirumab vs PBO (BSC)
(N = 355)
5.2
3.8
Docetaxel vs ASC
(N = 131)
5.2
3.6
Docetaxel or Irinotecan vs BSC
(N = 202)
5.3
Irinotecan vs BSC
(N = 40)
Ford HER, et al. The Lancet Oncology. 2014;15(1):78-86.
Kang JH, et al. J Clin Oncol. 2012;30(13):
Thuss-Patience PC, et al. Eur J Cancer. 2011;47(15):

9. VEGFr2: RAINBOW: Second Line
1:1
Ramucirumab 8 mg/kg day 1&15
+ Paclitaxel 80 mg/m2 day 1,8 &15
of a 28-day cycle
N = 330 R A N D O M I Z E
Treat until disease progression or intolerable toxicity
Survival and safety follow-up S C R E EN
Placebo day 1&15
+ Paclitaxel 80 mg/m2 day 1,8 &15
N = 335
Important inclusion criteria:
- Metastatic or loc. adv. unresectable gastric or GEJ* adenocarcinoma
- Progression after 1st line platinum/fluoropyrimidine based chemotherapy
Stratification factors:
- Geographic region,
- Measurable vs non-measurable disease,
- Time to progression on 1st line therapy (< 6 mos vs. ≥ 6 mos)
Wilke GI Symposium 2014 LBA 7

12. Comprehensive Molecular Characterization
The Cancer Genome Atlas Research Network, Nature. 2014;513(7517):

13. (cytokines, lysis, proliferation, migration to tumor)
Blocking CTLA-4 and PD-1
Tumor Microenvironment
Activation
(cytokines, lysis, proliferation, migration to tumor)
TCR
TCR
MHC
MHC + + + + + +
Dendritic cell B7
CD28
Tumor cell + + +
T cell
T cell B7 - - -
PD-1
PD-L1
CTLA-4 - - -
anti-PD-1
anti-CTLA-4
PD-1
PD-L2 - - -
anti-PD-1
CTLA-4 Blockade (ipilimumab)
PD-1 Blockade (nivolumab)
Highly Confidential

14. Trials of Targeted Agents Second Line
Regimen
Number
Status
mTOR
Everolimus
AIOST00111
Pac + / - Evero
665
Ongoing
HER2
TDM-1
GATSBY
Pac vs TDM-1
412
Completed
MM-111
NCT
Pac + Tras + MM
120
Afatinib
NCT
Trastuz + Afat 40
NCT
Pac + Afat 36
MET
AMG337
NCT
AMB337
140
EGFr
Nimotuzumab
NCT
Irino + / - Nimo
400
PARP
Olaparib
NCT
Pac + / - Olap
FGFr
Nindetanib
NCT
PDL-1
Pembrolizumab
KEYNOTE 59
Pembro monotherapy
270
FRFr2
Dovitinib
NCT
Dovit (FGFR2 amplified) 31
FGFr2
NCT
Doce + Dovit 59

15. Esophagogastric Cancer: Novel Biologic Second Line + / - Chemo
Modest improvements with doce/paclitaxel or irinotecan vs BSC
Expected toxicities of chemotherapy
Targeted therapies
VEGFR2 now a validated target
Ramucirumab achieves similar PFS and OS benefits as chemo
Less toxicity
Targeted agent + Chemo
Ramucirumb plus paclitaxel enhances RR, PFS, and OS
New care standard for second line therapy
Minimal increase in toxicity (HTN, neutropenia)
Future directions
Ongoing trials in HER2 +
Evaluation of immunotherapy