Novel Biologic Therapies for
Second-Line Gastric Cancer
Charles S. Fuchs, MD
Dana-Farber Cancer Institute
Harvard Medical School
Boston, MA
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
Phase II Studies of Taxanes as SecondLine Therapy for Gastric Cancer
Drug
Author
No. of Pts
RR
PFS
(mos)
OS (mos)
Docetaxel
Graziano
21
5%
--
3.5
Docetaxel
Giuliani
30
17%
--
6.0
Docetaxel
Jo (S. Korea)
154
14%
2.6
7.2
Paclitaxel
Hironka (Japan)
38
24%
--
5.0
Vinorelbine
Kulke
29
7%
1.9
7.8
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
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. 2008
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
Chau et al J Clin Oncol 2004
Irinotecan vs. Best Supportive Care in
Second-line Gastric Cancer
Thuss-Patience et al. ASCO 2009
Irinotecan 250 mg/m2
q 3weeks
N
Median
Survival
21
4.1 mos
P = 0.02
Best Supportive Care
19
2.4 mos
HR = 0.48 (95% CI, 0.25-0.92)
Cougar-02: Randomized Trial of Docetaxel vs. BSC
in Relapsed Esophagogastric Adenocarcinoma
168 patients :
R
A
N
Docetaxel 75
mg/m2 q 3 weeks
Primary Endpoint:
Overall
Survival
D
O
M
I
Z
E
Best supportive
care
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
EGFR Signal Transduction
RAS RAF
PI3-K pY
SOS
K K
pY
GRB2
MEK
pY
PTEN
AKT
STAT
MAPK
Gene transcription
Cell-cycle progression
Proliferation/Maturation
G2
M
S
G1
Survival/Apoptosis
Angiogenesis
Metastasis
Ongoing Randomized Trials in Advanced
Esophagogastric Adenocarcinoma
REAL-3 Trial
730 patients
EXPAND Trial
870 patients
R
A
N
D
O
M
I
Z
E
R
A
N
D
O
M
I
Z
E
EOX
EOX
Panitumumab
Capecitabine
Cisplatin
Capecitabine
Cisplatin
Cetuximab
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;120:1803-10; 3Yu G et al. Clin Cancer Res.
2009;15:1821-29; 4Taguchi F et al. Invest New Drugs. 2011;29:1198-205; 5Cejka D et al. Anticancer Res. 2008;28:3901-08;
13
6Jaeger-Lansky A et al. Cancer Biol Ther. 2010;9:919-27; 7Doi T et al. J Clin Oncol. 2010;28:1904-1910.
RANDOMIZE
(N = 656)
SCREEN
Phase 3 GRANITE-1 Study Design
2
1
Everolimus 10 mg PO
daily
+
BSC*
(n = 439)
Placebo PO daily
+
BSC
(n = 217)
Treatment
until disease
progression
or
intolerable
toxicity
Safety
follow-up:
EOT + 28 d
Survival
follow-up:
every 3 mo
• 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: NCT00879333.
14
Overall Survival (FAS)
Probability of overall survival (%)
100
Censoring Times
Everolimus + BSC (n/N = 352/439)
Placebo + BSC (n/N = 180/217)
80
Kaplan-Meier medians
Everolimus + BSC: 5.39 months
Placebo + BSC: 4.34 months
60
Hazard ratio: 0.90 (95% CI, 0.75-1.08)
Log-rank P value = 0.1244
40
20
0
0
2
4
6
8
10
12
14
16
18
20
22
24
16
13
12
18
6
8
20
3
4
22
1
1
24
0
0
Time (months)
No. of patients still at risk
Time (months) 0
Everolimus
439
217
Placebo
2
355
172
4
253
117
6
195
82
8
139
60
10
87
35
12
52
28
14
30
16
15
Role of VEGF Pathway in Tumor Growth
 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
VEGF-A
Ramucirumab
VEGF binds to
VEGFR2 receptor;
VEGF-C, -D compete
for binding to
VEGFR2
VEGF-A
VEGF-C
VEGF-D
Ramucirumab binds to
VEGFR2, blocks VEGF
ligand binding
VEGFR2
Endothelial cell membrane
Ligand binding
activates VEGFR2 and
p44/p42 MAP kinases
VEGFR2
No signaling
Angiogenesis
Tumor growth
Inhibit new blood vessel
formation and tumor growth
REGARD Study Design
S
C
R
E
E
N
R
A
N
D
O
M
I
Z
E
N = 355
2:1
Ramucirumab 8 mg/kg
q2wk
+
BSC (n = 238)
Placebo q2wk
+
BSC (n = 117)
Treatment
until disease
progression
or
intolerable
toxicity
Tumor
assessment,
survival,
and safety
follow-up
• 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
REGARD: Overall Survival
HR (95% CI) = 0.776 (0.603, 0.998)
Log rank P-value (stratified) = 0.0473
1.0
Ramucirumab
Placebo
238 / 179
117 / 99
5.2 (4.4, 5.7)
3.8 (2.8, 4.7)
6-month OS
42%
32%
12-month OS
18%
11%
Patients / Events
0.8
Overall Survival
Median (mos) (95% CI)
0.6
0.4
0.2
Ramucirumab
Placebo
Censored
Censored
0.0
0
1
2
3
4
5
6
7
8
9
238
117
11
12
13
14
15
16
17
18
19
20
26
27
28
0
1
0
0
Months
No. at Risk
Ram
Plcb
10
154
66
92
34
49
20
17
7
7
4
3
2
Fuchs et al. Lancet 2013
Tumor Response
REGARD: Progression-free Survival
1.0
HR (95% CI) = 0.483 (0.376, 0.620)
Progression-free Survival
Log rank P-value (stratified) = ≤0.0001
0.8
Patients / Events
Median (mos) (95% CI)
0.6
Ramucirumab
Placebo
238 / 199
117 / 108
2.1 (1.5, 2.7)
1.3 (1.3, 1.4)
40%
16%
12-week PFS
0.4
0.2
Ramucirumab
Placebo
Censored
Censored
0.0
0
1
2
3
4
5
6
7
8
9
10
11
5
2
4
1
12
13
14
15
16
17
2
1
1
0
1
0
1
0
1
0
0
0
Months
No. at Risk
Ram
Plcb
238
117
213
92
113
27
65
11
61
7
45
4
30
2
18
2
18
2
11
2
Fuchs et al. Lancet 2013
Treatment Emergent Adverse Events *
Ramucirumab (N=236)
Placebo (N=115)
TEAEs*
Any Grade
(%)
Grade ≥3
(%)
Any Grade Grade ≥3
(%)
(%)
Fatigue
36
6
40
10
Abdominal pain
29
6
28
3
Decreased appetite
24
3
23
3
Vomiting
20
3
25
4
Constipation
15
<1
23
3
Anemia
15
6
15
8
Dysphagia
11
2
10
4
Dyspnea
9
2
13
6
Adverse Events of Special Interest
Ramucirumab (N=236)
Placebo (N=115)
Any Grade
Grade ≥3
Any Grade
Grade ≥3
(%)
(%)
(%)
(%)
Hypertension * †
16
8
8
3
Bleeding/Hemorrhage
13
3
11
3
Arteriothromboembolic
2
1
0
0
Venous thromboembolic
4
1
7
4
Proteinuria
3
<1
<1
<1
GI perforation
<1
<1
<1
<1
Fistula (GI and non-GI)
<1
<1
<1
<1
Infusion-related reaction
<1
0
2
0
Cardiac failure
<1
0
0
0
Category of event
† No
Grade 4 hypertension was observed among ramucirumab-treated patients
Fuchs et al. Lancet 2013
REGARD: Time to Performance
Status Deterioration*
Median
*Time to deterioration in ECOG PS score of 2 or worse
Ramucirumab
Placebo
5.1 mos
2.4 mos
Fuchs et al. Lancet 2013
Median OS in randomized 2nd-line gastric cancer
studies presented/published in 2009-2013
Median OS (months) by study arm
Ramucirumab vs PBO (BSC) 1
Ramucirumab vs BSC (n=355)
(n=355)
5.2
3.8
Docetaxel vs ASC2
Docetaxel vs ASC (n=131)
(n=131)
5.2
3.6
CTX
CTX[Docetaxel
[Docetaxel ororIrinotecan]
Irinotecan]vsvsBSC
BSC3
(n=202)
(n=202)
5.3
3.8
4.0
Irinotecan
vs BSC4
Irinotecan
vs BSC (n=40)
(n=40)
2.4
0
Active Treatment
1. Fuchs et al. Lancet 2013
2. Ford et al. Proc Gastrointestinal Cancer Symp 2013. LBA4.
3. Kang et al. J Clin Oncol 30:1513-1518, 2012
4. Thuss-Patience et al. EUR J CANCER 47: (2011) 2306-2314.
1
2
BSC
3
4
5
6
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)
3%
7%
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 2013. LBA4.
3. Kang et al. J Clin Oncol 30:1513-1518, 2012
4. Thuss-Patience et al. EUR J CANCER 47: (2011) 2306-2314.
9%
0%
RAINBOW: Study Design
1:1
S
C
R
E
E
N
R
A
N
D
O
M
I
Z
E
Ramucirumab 8 mg/kg day 1&15
+ Paclitaxel 80 mg/m2 day 1,8 &15
of a 28-day cycle
N = 330
Placebo day 1&15
+ Paclitaxel 80 mg/m2 day 1,8 &15
N = 335
Treat until
disease
progression
or
intolerable
toxicity
Survival and
safety
follow-up
•
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
ToGA: A Randomized, Open Label
Multicenter Phase III Study
3807 patients screened
810 HER2-positive
(22.1%)
HER2-positive*
advanced
gastric or GEJ
cancer
(n=584)
• Stratification factors
• Advanced vs. metastatic disease
• GC vs. GEJ
• Measurable vs. non-measureable
• ECOG PS 0-1 vs. 2
• Capecitabine vs. 5-FU
Capecitabine1 or iv 5-FU2†
+ cisplatin3
(n=290)
R
Capecitabine or iv 5-FU2†
+ cisplatin3 + trastuzumab
(n=294)
†Chosen
1 1000
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. 2010;376:687-697.
27
ToGA Primary Endpoint:
Overall Survival
Events
Median
OS (mo)
1.0
0.9
FC +
Trastuzumab
167
13.8
0.8
FC
182
11.1
HR
95% CI
0.74 0.60, 0.91
p-value
0.0046
Probability
0.7
0.6
F+C+Trastuzumab
F+C
0.5
0.4
0.3
0.2
11.1
0.1
0.0
0
2
4
6
8
13.8
10 12 14 16 18 20 22 24 26 28 30 32 34 36
Time (months)
No.
at risk
294 277 246 209 173 147 113 90
290 266 223 185 143 117 90 64
71
47
56
32
43
24
30
16
21
14
13
7
12
6
6
5
4
0
1
0
0
0
F=fluoropyrimidine (either fluorouracil or capecitabine); C=cisplatin.
Bang YJ, et al. Lancet. 2010;376:687-697.
28
T-DM1 structure
T-DM1 is a novel ADC
Trastuzumab
Target expression: HER2
Monoclonal antibody: Trastuzumab
Cytotoxic agent: DM1
Highly potent cytotoxic agent
T-DM1
Linker: MCC
Systemically stable
Average drug:
antibody ratio ≅3.5:1
Phase III Study of T-DM1 Versus Taxane in Patients
With HER-2 Gastric Cancer
412 HER-2 pts following first-line therapy:
R
T-DM1
A
q 3 weeks
N
D
O
M
Overall Survival
T-DM1
weekly
I
Z
E
Primary endpoint:
Paclitaxel or Docetaxel
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
Smollen et al PNAS, 2006
Minor regression in gastric cancer
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
Back-up Slides
Post-discontinuation Treatment
Ramucirumab (N=238)
Patients with any PDT*
Chemotherapy
Biologic therapy
Radiotherapy
Surgery
Placebo (N=117)
n
(%)
n
%
75
69
6
4
2
(31.5)
(29.0)
(2.5)
(1.7)
(0.8)
46
44
1
6
0
(39.3)
(37.6)
(0.9)
(5.1)
0
*Each patient may have received more than one regimen.
PDT = Post-discontinuation Treatment
REGARD: Subgroup Analysis for OS
Category
Subgroup
Overall
N
N
(Ram) (Plcb)
HR
(95% CI)
238
117
0.776 (0.603, 0.998)
Age Group
<65
≥65
156
82
71
46
0.846 (0.611, 1.171)
0.722 (0.471, 1.106)
Sex
Male
Female
169
69
79
38
0.676 (0.499, 0.916)
1.431 (0.852, 2.405)
Race
White
Asian
Other
181
39
18
91
17
9
0.784 (0.590, 1.042)
0.636 (0.306, 1.321)
1.426 (0.448, 4.539)
Ethnicity
Hispanic
41
Not Hispanic 197
19
98
0.563 (0.296, 1.072)
0.814 (0.617, 1.072)
ECOG PS
0
≥1
67
171
31
86
1.075 (0.638, 1.810)
0.682 (0.508, 0.915)
Measurable
Tumor
Yes
No
218
20
106
11
0.808 (0.620, 1.054)
0.434 (0.143, 1.313)
Prior Therapy
First-Line
199
Adjuvant/Neo 39
103
14
0.793 (0.605, 1.041)
0.784 (0.372, 1.654)
First-Line Type
Doublets
Triplets
99
92
63
36
0.756 (0.517, 1.105)
0.790 (0.510, 1.224)
Hist. Subtype
Diffuse
Intestinal
Unknown
96
52
90
44
35
38
0.560 (0.366, 0.857)
1.009 (0.583, 1.745)
0.908 (0.579, 1.423)
# Metastatic
Sites
0-2
≥3
163
75
71
46
0.751 (0.541, 1.042)
0.795 (0.516, 1.225)
Peritoneal
Yes
No
64
174
45
72
0.871 (0.556, 1.366)
0.800 (0.582, 1.101)
Progression-free
Interval
<6 months
≥6 months
132
65
74
28
0.876 (0.631, 1.216)
0.660 (0.389, 1.119)
Weight Loss
≥10%
<10%
37
201
17
100
0.883 (0.425, 1.834)
0.728 (0.554, 0.957)
Primary Tumor
Gastric
GEJ
179
59
85
32
0.823 (0.608, 1.114)
0.756 (0.472, 1.211)
Geo Region
NA
LA
Asia
165
55
18
80
29
8
0.896 (0.667, 1.205)
0.464 (0.265, 0.813)
0.694 (0.265, 1.818)
0.1
0.5
Favors Ramucirumab
1
1.5
2
3
Favors Placebo
4
5
REGARD: Subgroup Analysis for PFS
Category
Subgroup
Overall
N
N
(Ram) (Plcb)
HR
(95% CI)
238
117
0.483 (0.376, 0.620)
Age Group
<65
≥65
156
82
71
46
0.450 (0.327, 0.620)
0.490 (0.319, 0.752)
Sex
Male
Female
169
69
79
38
0.377 (0.277,0.515)
0.805 (0.504,1.288)
Race
White
Asian
Other
181
39
18
91
17
9
0.450 (0.338, 0.599)
0.735 (0.356, 1.517)
0.651 (0.209, 2.030)
Ethnicity
Hispanic
41
Not Hispanic 197
19
98
0.335 (0.174, 0.648)
0.502 (0.381, 0.661)
ECOG PS
0
≥1
67
171
31
86
0.571 (0.338, 0.965)
0.423 (0.315, 0.569)
Measurable
Tumor
Yes
No
218
20
106
11
0.484 (0.371, 0.631)
0.277 (0.081, 0.948)
Prior Therapy
First-Line
199
Adjuvant/Neo 39
103
14
0.531 (0.406, 0.694)
0.431 (0.194, 0.958)
First-Line Type
Doublets
Triplets
99
92
63
36
0.479 (0.331, 0.694)
0.531 (0.337, 0.837)
Hist. Subtype
Diffuse
Intestinal
Unknown
96
52
90
44
35
38
0.487 (0.318, 0.746)
0.456 (0.267, 0.778)
0.550 (0.347, 0.870)
# Metastatic
Sites
0-2
≥3
163
75
71
46
0.460 (0.334, 0.635)
0.599 (0.386, 0.927)
Peritoneal
Yes
No
64
174
45
72
0.695 (0.438, 1.103)
0.423 (0.308, 0.580)
Progression-free
Interval
<6 months
≥6 months
132
65
74
28
0.535 (0.385, 0.743)
0.465 (0.282, 0.769)
Weight Loss
≥10%
<10%
37
201
17
100
0.421 (0.199, 0.893)
0.480 (0.367, 0.629)
Primary Tumor
Gastric
GEJ
179
59
85
32
0.513 (0.384, 0.685)
0.386 (0.229, 0.649)
Geo Region
NA
LA
Asia
165
55
18
80
29
8
0.474 (0.352, 0.639)
0.456 (0.270, 0.771)
0.690 (0.268, 1.773)
0.1
0.5
Favors Ramucirumab
1
1.5
2
Favors Placebo
2.5