1. Novel Biologic Therapies for Second-Line Gastric Cancer
Charles S. Fuchs, MD
Dana-Farber Cancer Institute
Harvard Medical School
Boston, MA

2. Second-Line Therapy in Gastric Cancer
No approved 2nd-line chemotherapy
20-40% patients receiving 1st-line therapy receive 2nd-line
Taxanes and irinotecan most commonly used 2nd-line therapy

3. Phase II Studies of Taxanes as Second-Line Therapy for Gastric Cancer
Drug
Author
No. of Pts RR
PFS (mos)
OS (mos)
Docetaxel
Graziano 21 5% --
3.5
Giuliani 30
17%
6.0
Jo (S. Korea)
154
14%
2.6
7.2
Paclitaxel
Hironka (Japan) 38
24%
5.0
Vinorelbine
Kulke 29 7%
1.9
7.8

4. Second-Line Therapy in Gastric Cancer
Historically, few randomized phase III trials compared to BSC
Numerous phase II trials:
Variability in response to 1st-line therapy
Variability in prior 1st-line therapy
Publication bias
Small number of patients

5. Second-Line Therapy in Gastric Cancer
625 pts who received 1st-line therapy at 3 centers in Italy
28% (175) received 2nd-line therapy
RR = 16%
Median OS = 6 months
Predictors of poor survival:
ECOG PS  2
Hgb  11.5 g/l
CEA > 50 ng/ml
>3 to 4 metastatic sites
TTP for 1st-line  6 months
Catalano et al

6. Second-Line Therapy in Gastric Cancer
1,080 patients in three 1st-line phase III trials
20% received 2nd line therapy
RR for 2nd-line therapy = 13%
Median OS = 5.6 months
Independent poor prognostic factors:
ECOG PS ≥ 2
Liver mets
Peritoneal mets
Serum alkaline phosphatase ≥ 100 U/L
Chau et al J Clin Oncol 2004

7. Chau et al J Clin Oncol 2004

8. Irinotecan vs. Best Supportive Care in Second-line Gastric Cancer
Thuss-Patience et al. ASCO 2009
Median
Survival N
Irinotecan 250 mg/m2
q 3weeks 21
4.1 mos
P = 0.02
Best Supportive Care 19
2.4 mos
HR = (95% CI, )

9. Cougar-02: Randomized Trial of Docetaxel vs
Cougar-02: Randomized Trial of Docetaxel vs. BSC in Relapsed Esophagogastric Adenocarcinoma
168 patients : R A N D O M I Z E
Docetaxel 75 mg/m2 q 3 weeks
Primary Endpoint:
Overall
Survival
Best supportive care

10. Cougar-02: Randomized Trial of Docetaxel vs
Cougar-02: Randomized Trial of Docetaxel vs. BSC in Relapsed Esophagogastric Adenocarcinoma
Docetaxel
BSC
P value
Response rate 7% NR
Overall survival
5.2 months
3.6 months
0.01
Cook et al. ASCO 2013

11. EGFR Signal Transduction
Metastasis
Proliferation/Maturation
Survival/Apoptosis
Angiogenesis
MAPK
MEK
Gene transcription
Cell-cycle progression
PI3-K
RAS
RAF
SOS
GRB2
PTEN
AKT
STAT pY K M G1 S G2

12. Ongoing Randomized Trials in Advanced Esophagogastric Adenocarcinoma
EOX
REAL-3 Trial
730 patients
EOX
Panitumumab
Capecitabine
Cisplatin R A N D O M I Z E
EXPAND Trial
870 patients
Capecitabine
Cisplatin
Cetuximab

13. PI3K/Akt/mTOR Pathway in Gastric Cancer
The PI3K/Akt/mTOR pathway, a key regulator of cell proliferation, growth, survival, metabolism, and angiogenesis, is dysregulated in 50%-60% of gastric cancers1-3
Everolimus, an oral mTOR inhibitor, showed efficacy in preclinical models of gastric cancer1,4-6
In a phase 2 study of 53 patients with previously treated advanced gastric cancer, everolimus showed promising efficacy and acceptable tolerability7
mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase.
1Xu DZ et al. BMC Cancer. 2010;10:536; 2Lang SA et al. Cancer. 2007;120: ; 3Yu G et al. Clin Cancer Res ;15: ; 4Taguchi F et al. Invest New Drugs. 2011;29: ; 5Cejka D et al. Anticancer Res. 2008;28: ; 6Jaeger-Lansky A et al. Cancer Biol Ther. 2010;9:919-27; 7Doi T et al. J Clin Oncol. 2010;28:

14. Phase 3 GRANITE-1 Study Design
Everolimus 10 mg PO daily BSC*
(n = 439)
RANDOMIZE
(N = 656)
SCREEN
Treatment until disease progression or intolerable toxicity
Safety follow-up: EOT + 28 d
Survival follow-up: every 3 mo 2 1
Placebo PO daily +
BSC
(n = 217)
Stratification by region: Asia vs rest of world
Stratification by number of lines of previous systemic chemotherapy (1 vs 2)
BSC, best supportive care; EOT, end of treatment; PO, orally.
ClinicalTrials.gov identifier: NCT

15. 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)
Kaplan-Meier medians
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

16. Role of VEGF Pathway in Tumor Growth Endothelial cell membrane
Ramucirumab (IMC-1121B; RAM) is a recombinant human IgG1 monoclonal antibody receptor antagonist designed to bind the extracellular domain of VEGF Receptor-2, thereby blocking the binding of VEGF ligands and inhibiting receptor activation.
VEGF-C VEGF-D
Angiogenesis
Tumor growth
VEGF-A
VEGFR2
Ligand binding activates VEGFR2 and p44/p42 MAP kinases
Ramucirumab
No signaling
Inhibit new blood vessel formation and tumor growth
Ramucirumab binds to VEGFR2, blocks VEGF ligand binding
VEGF binds to VEGFR2 receptor; VEGF-C, -D compete for binding to VEGFR2
VEGF-C VEGF-D
Endothelial cell membrane

17. Tumor assessment, survival, and safety follow-up
REGARD Study Design
Ramucirumab 8 mg/kg q2wk +
BSC (n = 238) R A N D O M I Z E
Treatment
until disease
progression or
intolerable
toxicity
Tumor assessment, survival, and safety follow-up
2:1 S C R E EN
Placebo q2wk +
BSC (n = 117)
N = 355
Multicenter, randomized, double-blind, placebo-controlled, phase 3 trial
Gastric or GEJ adenocarcinoma
Stratification factors: region, weight loss (≥10% vs. <10% over 3 months), location of primary tumor (gastric vs. GEJ)
Global: 6 continents, 30 countries, 120 study centers
Abbreviations: BSC=best supportive care; GEJ= gastroesophageal junction
Fuchs et al. Lancet 2013

18. REGARD: Overall Survival
HR (95% CI) = (0.603, 0.998)
Log rank P-value (stratified) =
Ramucirumab
Placebo
Patients / Events
238 / 179
117 / 99
Median (mos) (95% CI)
5.2 (4.4, 5.7)
3.8 (2.8, 4.7)
6-month OS
42%
32%
12-month OS
18%
11%
No. at Risk
Ram
238
154 92 49 17 7 3
Plcb
117 66 34 20 4 2 1
Fuchs et al. Lancet 2013

19. Tumor Response Ramucirumab N=238 Placebo N=117 P-value n (%)
Best Overall Response
Complete response (CR) 1
(0.4)
Partial response (PR) 7
(2.9) 3
(2.6)
Stable disease (SD)
108
(45.4) 24
(20.5)
Progressive disease 78
(32.8) 63
(53.8)
Not evaluable / Not assessed 44
(18.5) 27
(23.1)
Response rate: CR + PR 8
(3.4)
0.756
Disease control rate: CR + PR + SD
116
(48.7)
<0.0001

20. REGARD: Progression-free Survival
HR (95% CI) = (0.376, 0.620)
Log rank P-value (stratified) = ≤0.0001
Ramucirumab
Placebo
Patients / Events
238 / 199
117 / 108
Median (mos) (95% CI)
2.1 (1.5, 2.7)
1.3 (1.3, 1.4)
12-week PFS
40%
16%
No. at Risk
Ram
238
213
113 65 61 45 30 18 11 5 4 2 1
Plcb
117 92 27 7
Fuchs et al. Lancet 2013

21. Treatment Emergent Adverse Events *
Ramucirumab (N=236)
Placebo (N=115)
TEAEs*
Any Grade (%)
Grade ≥3 (%)
 Any Grade (%)
Fatigue 36 6 40 10
Abdominal pain 29 28 3
Decreased appetite 24 23
Vomiting 20 25 4
Constipation 15
<1
Anemia 8
Dysphagia 11 2
Dyspnea 9 13

22. Adverse Events of Special Interest
Ramucirumab (N=236)
Placebo (N=115)
Category of event
Any Grade
Grade ≥3
 Any Grade
(%)
Hypertension * † 16 8 3
Bleeding/Hemorrhage 13 11
Arteriothromboembolic 2 1
Venous thromboembolic 4 7
Proteinuria
<1
GI perforation
Fistula (GI and non-GI)
Infusion-related reaction
Cardiac failure
† No Grade 4 hypertension was observed among ramucirumab-treated patients
Fuchs et al. Lancet 2013

23. REGARD: Time to Performance Status Deterioration*
Ramucirumab
Placebo
Median
5.1 mos
2.4 mos
*Time to deterioration in ECOG PS score of 2 or worse
Fuchs et al. Lancet 2013

24. Median OS in randomized 2nd-line gastric cancer studies presented/published in 2009-2013
Ramucirumab vs PBO (BSC) 1
(n=355)
5.2
3.8
Docetaxel vs ASC2
(n=131)
5.2
3.6
CTX [Docetaxel or Irinotecan] vs BSC3
(n=202)
5.3
Irinotecan vs BSC4
(n=40)
1. Fuchs et al. Lancet 2013
2. Ford et al. Proc Gastrointestinal Cancer Symp LBA4.
3. Kang et al. J Clin Oncol 30: , 2012
4. Thuss-Patience et al. EUR J CANCER 47: (2011)

25. Response Rates in randomized 2nd-line gastric cancer studies presented/published in 2009-2013
Ramucirumab vs PBO (BSC)1
(n=355)
Docetaxel vs ASC2
(n=131)
CTX [Docetaxel or Irinotecan] vs BSC3
(n=202)
Irinotecan vs BSC4
(n=40)
1. Fuchs et al. Lancet 2013
2. Ford et al. Proc Gastrointestinal Cancer Symp LBA4.
3. Kang et al. J Clin Oncol 30: , 2012
4. Thuss-Patience et al. EUR J CANCER 47: (2011)

26. RAINBOW: Study Design 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)
* GEJ= gastroesophageal junction; gastric and GEJ will be summarized under the term GC

27. ToGA: A Randomized, Open Label Multicenter Phase III Study
Capecitabine1 or iv 5-FU2† + cisplatin (n=290)
HER2-positive* advanced gastric or GEJ cancer
(n=584)
3807 patients screened
810 HER2-positive (22.1%) R
Capecitabine or iv 5-FU2† + cisplatin3 + trastuzumab (n=294)
Stratification factors
Advanced vs. metastatic disease
GC vs. GEJ
Measurable vs. non-measureable
ECOG PS 0-1 vs. 2
Capecitabine vs. 5-FU
†Chosen at investigator’s discretion
mg/m2 bid d1-14 q3w x 6 cycles
2 800 mg/m2/day continuous iv infusion d1-5 q3w x 6 cycles
3 80 mg/m2 q3w x 6 cycles
4 8 mg/kg loading dose followed by 6 mg/kg q3w until disease progression
*IHC 3+ or FISH+ 5-FU=5-fluorouracil; GEJ=gastroesophageal junction; R=randomization;
ECOG PS =Eastern Cooperative Oncology Group performance score.
Bang YJ, et al. Lancet ;376: 27 27 27

28. ToGA Primary Endpoint: Overall Survival
Events
Median OS (mo) HR
95% CI
p-value
FC + Trastuzumab
167
13.8
0.74
0.60, 0.91
0.0046 FC
182
11.1
1.0
0.9
0.8
0.7
0.6
F+C+Trastuzumab
F+C
0.5
Probability
0.4
0.3
0.2
11.1
13.8
0.1
0.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Time (months)
No. at risk
294
290
277
266
246
223
209
185
173
143
147
117
113 90 90 64 71 47 56 32 43 24 30 16 21 14 13 7 12 6 6 5 4 1
F=fluoropyrimidine (either fluorouracil or capecitabine); C=cisplatin.
Bang YJ, et al. Lancet ;376: 28 28 28

29. T-DM1 structure Cytotoxic agent: DM1 Highly potent cytotoxic agent
T-DM1 is a novel ADC
Trastuzumab
Highly potent cytotoxic agent
Monoclonal antibody: Trastuzumab
Systemically stable
Target expression: HER2
Cytotoxic agent: DM1
Linker: MCC
T-DM1
Average drug: antibody ratio ≅3.5:1

30. Phase III Study of T-DM1 Versus Taxane in Patients With HER-2 Gastric Cancer
412 HER-2 pts following first-line therapy: R A N D O M I Z E
T-DM1
q 3 weeks
Primary endpoint:
Overall Survival
T-DM1
weekly
Paclitaxel or Docetaxel

31. MET Amplification as a Predictor of Drug Sensitivity in Gastric and Esophageal Adenocarcinoma
Graziano et al J Clin Onc 2011:
230 pts: 10% MET amplifications
Worse prognosis
Yapp et al J Clin Onc 2011:
Phase I trial of ARQ197
Minor regression in gastric cancer
Smollen et al PNAS, 2006

32. Second-Line Therapy for Gastric Cancer: 2014
For all patients, 2nd-line ramucirumab significantly improves overall survival
Survival benefit for ramucirumab appears comparable to 2nd-line docetaxel or irinotecan
Addition of ramucirumab to 2nd-line paclitaxel significantly improves overall survival
Other novel targeted approaches that may emerge:
HER-2 directed therapy
C-MET pathway directed therapy
Ongoing mining of genomic data may generate the next generation of targets

33. Back-up Slides

34. Post-discontinuation Treatment
Ramucirumab (N=238)
Placebo (N=117) n
(%) %
Patients with any PDT* 75
(31.5) 46
(39.3)
Chemotherapy 69
(29.0) 44
(37.6)
Biologic therapy 6
(2.5) 1
(0.9)
Radiotherapy 4
(1.7)
(5.1)
Surgery 2
(0.8)
*Each patient may have received more than one regimen.
PDT = Post-discontinuation Treatment 34

35. Progression-free Interval
REGARD: Subgroup Analysis for OS
238
156 82
169 69
181 39 18
218 20
199 99 92 37
201
179 59
165 55 41
197 67
171 96 52 90
163 75 64
174
132 65
N (Ram)
<65
≥65
Male
Female
White
Asian
Other
Yes No
First-Line
Adjuvant/Neo
Doublets
Triplets
≥10%
<10%
Gastric
GEJ NA LA
Asia
Hispanic
Not Hispanic ≥1
Diffuse
Intestinal
Unknown
0-2 ≥3
<6 months
≥6 months
Subgroup
Age Group
Sex
Overall
Race
Ethnicity
ECOG PS
Measurable Tumor
Prior Therapy
First-Line Type
Hist. Subtype
# Metastatic Sites
Peritoneal
Progression-free Interval
Weight Loss
Primary Tumor
Geo Region
Category
117 71 46 79 38 91 17 9
106 11
103 14 63 36
100 85 32 80 29 8 19 98 31 86 44 35 45 72 74 28
N (Plcb)

36. Progression-free Interval
REGARD: Subgroup Analysis for PFS
238
156 82
169 69
181 39 18
218 20
199 99 92 37
201
179 59
165 55 41
197 67
171 96 52 90
163 75 64
174
132 65
N (Ram)
<65
≥65
Male
Female
White
Asian
Other
Yes No
First-Line
Adjuvant/Neo
Doublets
Triplets
≥10%
<10%
Gastric
GEJ NA LA
Asia
Hispanic
Not Hispanic ≥1
Diffuse
Intestinal
Unknown
0-2 ≥3
<6 months
≥6 months
Subgroup
Age Group
Sex
Overall
Race
Ethnicity
ECOG PS
Measurable Tumor
Prior Therapy
First-Line Type
Hist. Subtype
# Metastatic Sites
Peritoneal
Progression-free Interval
Weight Loss
Primary Tumor
Geo Region
Category
117 71 46 79 38 91 17 9
106 11
103 14 63 36
100 85 32 80 29 8 19 98 31 86 44 35 45 72 74 28
N (Plcb)