CCO Gastric Cancer LL Slides
CCO Gastric Cancer LL Slides
CCO Gastric Cancer LL Slides
Core Faculty
Axel Grothey, MD
Professor, Oncology
Mayo Clinic
Rochester, Minnesota
Professor of Medicine
Weill Cornell Medical College
Attending Physician
Memorial Sloan Kettering Cancer Center
New York, New York
Faculty Disclosures
Axel Grothey, MD, has no real or apparent conflicts of
interest to report.
David Ilson, MD, PhD, has disclosed that he has
received consulting fees from Amgen, Lilly, Novartis,
and Taiho and funds for research support from Amgen
and Lilly.
Agenda
Program Overview
Choosing Optimal First-line Treatment for Patients With
Advanced or Metastatic Gastric Cancer
Selecting Effective Salvage Therapy for Patients With
Advanced or Metastatic Gastric Cancer Who Progress on
First or Later Lines of Treatment
Targeted Therapies for the Management of Advanced or
Metastatic Gastric Cancer
Promising Investigational Approaches in Metastatic or
Advanced Gastric Cancer
Closing Remarks, Question and Answer Session
Slide credit: clinicaloptions.com
5-yr update: 6% OS
increase vs resection
alone
US INT-113 (CF): N =
440[2]
No impact on OS or any
endpoint, including R0
rate
1. Allum WH, et al. J Clin Oncol. 2009;27:5062-5067.
2. Kelsen DP, et al. N Engl J Med. 1998;339:1979-1984.
3. Cunningham D, et al. ASCO 2015. Abstract 4002.
CF x 2 vs ECX x 4:
equivalent
No survival benefit with
additional cycles of ECX
Poor rates of R0
resection: 60% to 66%
Demonstrates no role for
anthracyclines in this
setting
Slide credit: clinicaloptions.com
M T W T F S S
M T W T F S S
M T W T F S S
M T W T F S S
M T W T F S S
Wk 1
Wk 2
Wk 3
Wk 4
Wk 5
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
XRT
CTX
Proportion Surviving
Proportion Surviving
1.0
CRT + surgery
Surgery alone
0.8
0.6
0.4
0.2
0
P = .003
0
1.0
12
24
Mos
36
48
60
0.8
Squamous: 49%
0.6
0.4
Adenocarcinoma: 23%
0.2
0
12
24
AC, P = .049
SCC, P = .011
36
48
60
Mos
van Hagen P, et al. N Engl J Med. 2012;366:2074-2078.
First-line Chemotherapy
Other regimens
Fluoropyrimidine + cisplatin
(category 1) or oxaliplatin (2A)
DCF (category 1)
ECF (category 1)
Fluorouracil + irinotecan
(category 1)
HER2-positive disease
Trastuzumab + cisplatin/
fluoropyrimidine (category 1)
Trastuzumab + other agents
(2B)
1. NCCN. Guidelines: gastric cancer. v.3.2015.
Docetaxel + irinotecan
(category 2B)
Fluoropyrimidine
Docetaxel
Paclitaxel
*2-drug regimens preferred due to lower toxicity,
reserving triplet therapy for younger, medically fit pts.
Cape:
EOX or
EOF[1]
ECX or
EOX[1]
489
513
ORR,
%
44
TTP,
mo
OS,
mo
DCF
2-Drug Regimens
ECF
S-1
Cis
[3]
XP[4]
FLO[5]
FOLFIRI[6]
221
126
160
112
209
305
45
37
45
46
35
39
54
6.7
6.5
5.6
7.4
5.6
5.8
5.3
6.0
10.4
10.9
9.2
8.9
10.5
10.7
9.5
13.0
[2]
[7]
DCF
Docetaxel 75 mg/m2 IV over 1 hr on Day 1 +
Cisplatin 75 mg/m2 IV over 1-3 hrs on Day 1 +
5-FU 750 mg/m2/day by CIV over 5 days
q3w
(n = 227)
CF
Cisplatin 100 mg/m2 IV over 1-3 hrs on Day 1 +
5-FU 1000 mg/m2/day by CIV over 5 days
q4w
(n = 230)
DCF
(n = 221)*
CF
(n = 224)*
P Value
55
55
--
Metastatic disease, %
96
97
--
ORR, %
37
25
.01
5.6
3.7
.001
9.2
8.6
.02
DCF
(n = 221)
CF
(n = 224)
Grade 3/4
Stomatitis
21
27
Diarrhea
19
Nausea
14
17
Vomiting
14
17
Neutropenia
82
57
29
12
Toxic deaths
3.6
5.4
49
37
TTF (Proportion)
1.0
0.8
0.6
Median PFS:
5.3 vs 5.8 mos
0.4
0.2
0
Median OS:
9.5 vs 9.7 mos
ECX
FOLFIRI
Pts at Risk, n
209
ECX
FOLFIRI 207
145
157
108
123
61
81
8
10
Mos
33
50
14
28
12
14
16
8
19
5
9
4
6
FLO
FLP
P Value
Median PFS,
mos
5.8
3.9
.077
ORR (ITT), %
42
16
.012
ECX (n = 241)
Epirubicin
Cisplatin
5-FU
Epirubicin
Cisplatin
Capecitabine
50 mg/m2 IV q3w
60 mg/m2 IV q3w
200 mg/m2/d IV given
continuously
50 mg/m2 IV q3w
60 mg/m2 IV q3w
625 mg/m2 PO BID
continuously
EOF (n = 235)
EOX (n = 239)
Epirubicin
Oxaliplatin
Capecitabine
2 x 2 randomization, 8 cycles
50 mg/m2 IV q3w
130 mg/m2 IV q3w
625 mg/m2 PO BID
continuously
100
80
60
5-FU
Capecitabine
40
20
0
484
480
178
206
37
52
8
12
Slide credit: clinicaloptions.com
100
80
60
40
Oxaliplatin
20
0
Cisplatin
490
474
187
198
41
48
10
10
Slide credit: clinicaloptions.com
Modified DCF
Docetaxel 40 mg/m2 IV on Day 1 +
Cisplatin 40 mg/m2 IV on Day 2 or 3 +
5-FU 1000 mg/m2/day IVCI X 2 days q2w
(n = 57)
Parent DCF
Docetaxel 75 mg/m2 IV over 1 hr on Day 1 +
Cisplatin 75 mg/m2 IV over 1-3 hrs on Day 1 +
5-FU 750 mg/m2/day by IVCI over 5 days with
GCSF q3w
(n = 33)
Probability of PFS
1.0
mDCF
Parent DCF
0.8
.2
Parameter
mDCF
(n = 54)
Parent
DCF
(n = 31)
Median cycles,
n (range)
5.7
(3.4-6.8)
4.0
(2.5-6.3)
6-mo PFS, %
63
53
6-mo TTF, %
56
51
1-yr OS, %
63
55
2-yr OS, %
30
12
ORR (CR +
PR), %
49
33
0.6
0.4
0.2
0
12
18
24
Mos
30
1.0
Probability of OS
9.7
6.5
mDCF
Parent DCF
0.8
36
42
Median
OS, Mos
18.8
12.6
P
.007
0.6
0.4
0.2
0
12
18
24 30 36 42
Mos
Shah MA, et al. J Clin Oncol. 2015;[Epub ahead of print].
mDCF
(n = 54)
Parent
DCF
(n = 31)
Anorexia
13
Nausea
Vomiting
Hematologic
AE, %
mDCF
(n = 54)
Parent
DCF
(n = 31)
Anemia
11
39
23
Leukopenia
22
48
19
Fatigue
11
13
Neutropenia
(afebrile)
56
45
Neuropathy
13
16
Hypophosphatemia
Febrile
neutropenia
13
32
Hypokalemia
13
TEE
20
19
Second-line/Salvage Therapy
Other regimens
Irinotecan and cisplatin
(category 2A)
Irinotecan and
fluoropyrimidine (category
2B)
Docetaxel and irinotecan
(category 2B)
Alternative regimens
(category 2B)
Mitomycin and irinotecan
Mitomycin and fluorouracil
0.8
0.6
0.4
50
25
0.2
0
Docetaxel
Active symptom control
75
OS (%)
Survival Probability
1.0
12
15
18
Mos
10
12
14
16
18
Docetaxel vs BSC[2]
Targeted Therapies
296 Esophageal/Gastric
Cancers; 190 CRCs
Amplified genes in 37% of
gastroesophageal tumors
EGFR
MET
FGFR1-2
KRAS
***
***
n.s.
***
***
60
40
20
Colorectal
Gastric
Esophageal
Multilevel Events
per Sample (n)
HER2
80
***
Amplifications
Deletions
Multicopy Alterations
***
***
*
n.s.
**
**
1
0
Multicopy
Amplifications
Multicopy
Deletions
Targeted Therapies
Conventional, cytotoxic chemotherapy has limited
benefit
Targeted agents: designed to block specific tumor
growth pathways
Monoclonal antibodies
Tyrosine kinase inhibitors
Pts with
advanced
gastric cancer
screened for
HER2 status
(N = 3803)
R
(n = 584)
5-FU or Capecitabine* +
Cisplatin 80 mg/m2 q3w x 6 +
Trastuzumab 6 mg/kg q3w until PD
(8 mg/kg loading dose)
(n = 294)
5-FU or Capecitabine* +
Cisplatin 80 mg/m2 q3w x 6
(n = 290)
*Selected
Primary
endpoint:
OS 5-FU 800 mg/m 2/day infusional on Days 1-5 q3w x 6;
at investigators
discretion:
capecitabine 1000 mg/m 2 BID on Days 1-14 q3w x 6.
Bang YJ, et al. Lancet. 2010;376:687-697.
Survival Probability
Median
Events, OS,
mos HR
n
FC + T
FC
11.1
0
167
182
13.8
11.1
95% CI P Value
0.74 0.60-0.91
.0046
13.8
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Mos
Pts at Risk, n
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
Survival Probability
Exploratory analysis
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Median
Events, OS,
n
mos HR
FC + T
FC
11.8
0
120
136
16.0
11.8
95% CI
0.65 0.51-0.83
16.0
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Mos
Pts at Risk, n
228 218 196 170 142 122 100 84
218 198 170 141 112 96 75 53
65
39
51
28
39
20
28
13
20
11
12
4
11
3
5
3
4
0
1
0
0
0
Primary endpoint: OS
Secondary endpoints: PFS, ORR, DoR, CBR, safety/toxicity, QoL,
molecular and pharmacogenetics analyses
Hecht J, et al. J Clin Oncol. 2015;[Epub ahead of print].
CapeOx + P
(n = 238)
12.2 (10.6-14.2)
10.5 (9.0-11.3)
Cumulative Survival
Probability
1.0
Median OS, Mos (95% CI)
0.8
HR (95% CI)
0.6
0.4
0.2
CapeOx + L
CapeOx + P
0.0
0
10
15
20
25
30
35
40
45
3
7
3
2
249
238
199
189
133
106
83
53
47
34
24
17
9
11
Second line
GATSBY: paclitaxel vs T-DM1 (planned N = 412)[3]
T-DM1 was no better than paclitaxel
1. ClinicalTrials.gov. NCT01774786.
2. ClinicalTrials.gov. NCT01450696.
3. ClinicalTrials.gov. NCT01641939.
Apatinib
Small-molecule multitargeted TKI with activity against
VEGFR
Phase III trial reported at ASCO 2014: median OS
significantly longer with
850 mg QD vs placebo (195 vs 140 days, respectively;
HR: 0.71)[2]
1. Ohtsu A, et al. J Clin Oncol. 2011;29:3968-3976.
2. Qin S, et al. ASCO 2014. Abstract 4003.
Treatment until
PD, unacceptable
toxicity, or death
Primary objective: OS
Secondary endpoints: PFS, 12-wk PFS, ORR, DoR, QoL, safety
Fuchs CS, et al. Lancet. 2014;383:31-39.
1.0
Ramucirumab
Placebo
Censored
0.8
0.6
Pts/events
Median, mos
(95% CI)
6-mo OS, %
12-mo OS, %
Ramucirumab
238/179
5.2 (4.4-5.7)
Placebo
117/99
3.8 (2.8-4.7)
42
18
32
11
Pts at Risk, n
Ramucirumab 238
Placebo
117
2 3
6 7
8 9 10 11 12 13 14 15 16 17 18 19 20
26 27 28
Mos
154
66
92
34
49
20
17
7
7
4
3
2
0
1
0
0
Ramucirumab
Placebo
Censored
0.8
Pts/events
Median, mos
(95% CI)
12-wk PFS, %
Ramucirumab
238/199
2.1 (1.5-2.7)
Placebo
117/108
1.3 (1.3-1.4)
40
16
3
49
3
23
0.6
ORR, %
DCR, %
0.4
0.2
0
0
10 11 12 13 14 15 16 17
Mos
Pts at Risk, n
Ramucirumab 238 213 113 65 61 45 30 18 18
Placebo
117 92 27 11 7 4 2 2 2
Fuchs CS, et al. Lancet. 2014;383:31-39.
11
2
5
2
4
1
2
1
1
0
1
0
1
0
1
0
0
0
Ramucirumab (n = 236)
Placebo (n = 115)
Any Grade
Grade 3
Any Grade
Grade 3
Hypertension*
16
Bleeding/hemorrhage
13
11
Arteriothromboembolic
Venous thromboembolic
Proteinuria
<1
<3
<0
GI perforation
<1
<1
<1
<1
<1
<1
<1
<1
Infusion-related reaction
<1
Cardiac failure
<1
5.2
3.8
Docetaxel vs ASC[2]
(n = 131)
5.2
3.6
5.3
3.8
4.0
Irinotecan vs BSC[4]
(n = 40)
2.4
0
4-wk cycle
Treat until
PD or
intolerable
toxicity
Primary endpoint: OS
Secondary endpoints: PFS, ORR, TTP
Wilke H, et al. Lancet Oncol. 2014;15:1224-1235.
RAINBOW[1]
1.0
Ram/Pac
Pts/events, n
Median, mos
5.7)
(95% CI)
6-mo OS, %
12-mo OS, %
Probability of OS
0.8
0.6
Placebo/Pac
330/256
335/260
9.63 (8.48-10.81) 7.38 (6.31-8.38)
72
40
Ram
238/199
5.2 (4.4-
57
30
42
18
0.4
mOS = 2.3 mos
0.2
Ram + Pac
Placebo + Pac
Censored
0
0
12
Mos
16
20
24
28
Ram/Pac
Placebo/Pac
330/279
335/296
4.40 (4.24-5.32) 2.86 (2.79-3.02)
Pts/events, n
Median, mos
(95% CI)
6-mo PFS, %
12-mo PFS, %
ORR, %
DCR, %
0.9
0.8
Probability of PFS
REGARD[2]
RAINBOW[1]
0.7
0.6
36
22
28
80
17
10
16 P = .0001
64 P < .0001
Ram
238/199
2.1 (1.5-2.7)
3
49
0.5
0.4
0.3
0.2
Ram + Pac
Placebo + Pac
Censored
0.1
0
0
10
Mos
14
18
22
21-day
cycles
*Pts unable to take capecitabine receive 5-FU 800 mg/m 2/day Days 1-5.
Investigational Therapies
ECX +
Rilotumumab
R
N = 450
1:1
ECX alone
y
l
e
r
u
t
a
m
e
r
Primary endpoint: OS
p
d
e
p
p
sto
s
e
i
d
u
t
s
Both
MetGastric
[2]
ECX +
Rilotumumab
R
N = 800
1:1
ECX alone
Effector phase
(peripheral tissue)
T-cell migration
Dendritic
cell
MHC
TCR
TCR
CD28
Dendritic
cell
T cell
B7
Cancer
cell
T cell
T cell
T cell
MHC
PD-1
PD-L1
Cancer
cell
CTLA-4
PD-L1
Atezolizumab: 1 gastric cancer pt in expansion study had TTP of
9.8 mos[2]
Durvalumab: dose-expansion study (N = 28) showed 2 PRs and
12-wk DCR of 25%[3]
PD-1
Pembrolizumab: KEYNOTE-012: ORR 22% to 33%; 53% of pts
had reduction in size of target lesions[4]
1. Ralph C, et al. Clin Cancer Res. 2010;16:1662-1672. 2. Tabernero J,
et al. ASCO 2013. Abstract 3622. 3. Segal D, et al. ESMO 2014.
Abstract 1058PD. 4. Bang YJ, et al. ASCO 2015. Abstract 4001.
Discontinue treatment
CR
Pembrolizumab
10 mg/kg IV q2w
PR, SD
Confirmed
PD
Discontinue treatment
Outcomes
Response
ORR, % (95% CI)
Investigator
Review
(n = 39)
Central
Review
(n = 36)
33 (19-50)
22 (10-39)
CR
PR
13 (33)
8 (22)
SD
3 (8)
5 (14)
PD
23 (59)
19 (53)
No assessment
1 (3)
Not determined
3 (8)
4 of 8 responses ongoing at
time of data cutoff
Median response duration:
40 wks (range: 20+ to 48+)
Bang YJ, et al. ASCO 2015. Abstract 4001.
Metastatic disease
Fluorinated pyrimidine + platinum agent (standard chemo): FOLFOX, CAPOX,
capecitabine/cisplatin
Positive trials for VEGFR2 inhibitors as second-line therapy
Ramucirumab improves outcome alone and with paclitaxel
PD-1
PD-L1
Combo
Agent
Trial Details
NCT Number
Ipilimumab
Ph II maintenance ipi
NCT01585987
Pembrolizumab
NCT02370498
Pembrolizumab
NCT02494583
Pembrolizumab
KEYNOTE-059: Ph II pembro vs
pembro+ cis/5-FU
NCT02335411
Avelumab
NCT02625610
Avelumab
NCT02625623
Tremelimumab +
durvalumab
NCT02340975
Nivolumab +
ipilimumab
NCT01928394
clinicaloptions.com/oncology