CCO Gastric Cancer LL Slides

Expert Insight on Optimal
Treatment Selection for Patients

With Advanced Gastric Cancer
This program is supported by an educational grant from Lilly.
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Core Faculty
Axel Grothey, MD
Professor, Oncology
Mayo Clinic
Rochester, Minnesota
David H. Ilson, MD, PhD
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
Esophageal and Gastric Carcinoma:

US Incidence in 2015
Estimated 41,570 new cases (2.5% of all cancers)
Gastric: 24,590 (59%)
Esophagus: 16,980 (41%)
Decline in gastric cancer incidence

Increase in esophageal, GEJ, cardia adenocarcinoma
OS improvement, 1975-77, 1984-86, 1999-2006
Gastric: 16% 18% 27%
Esophageal: 5% 10% 19%
Siegel RL, et al. CA Cancer J Clin. 2015;65:5-29.
Adjuvant Therapy in Gastric Cancer

Improves OS
Postoperative RT + chemotherapy (US)[1]

Treatment: 5-FU/LV + RT (INT-0116 study)
10% 5-yr OS; HR: 0.76
Preop and postop chemo (UK) without RT[2]

Treatment: ECF (MAGIC study)
13% 5-yr OS; HR: 0.75
Postop chemo (Asia): 2 trials, 2000 pts, D2 resection, no RT

Treatment: S-1 (oral 5-FU) (ACTS-GC study)[3]
10% 5-yr OS; HR: 0.67
Treatment: postop capecitabine/oxaliplatin (CLASSIC trial)[4]

9% 5-yr OS; HR: 0.66
Survival improvements with all approaches similar, modest
1. Smalley SR, et al. J Clin Oncol. 2012;30:2327-2333.

2. Cunningham D, et al. N Engl J Med. 2006;355:11-20.
3. Sasako M, et al. J Clin Oncol. 2011;29:4387-4393.
4. Noh SH, et al. Lancet Oncol. 2014;15:1389-1396.
Esophageal and GEJ Adenocarcinoma:

Adjuvant Therapy
T2-3 or N+: Something more than surgery alone
should be done
Perioperative ECF, preoperative CF improves OS in
some but not all trials
MAGIC (perioperative ECF): 13% OS at 5 yrs; HR:
0.75 (esophageal, 120 pts), no increase in R0
resection[1]
FFCD/FNLC (preop CF): 14% OS at 5 yrs; HR: 0.69
(esophageal cancer, 180 pts) same as MAGIC, no
epirubicin, increase in R0 resection[2]
1. Cunningham D, et al. N Engl J Med. 2006;355:11-20.
2. Ychou M, et al. J Clin Oncol. 2011;29:1715-1721.
Esophageal Adenocarcinoma: Consensus

on Adjuvant Therapy
Preop chemotherapy
MRC OEO-2 (CF):
N = 802[1]
MRC OEO5 (CF vs ECX):

N = 900, EUS staged[3]
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
Preop CRT + Surgery vs Surgery Alone for

Esophageal or Junctional Cancer
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
Chemoradiotherapy followed by surgery compared with surgery alone (N = 368)
XRT
CTX
Paclitaxel 50 mg/m2 + carboplatin AUC 2 on Days 1, 8, 15, 22, and 29

Concurrent radiotherapy: 41.4 Gy in 23 fractions of 1.8 Gy
Surgery within 6 wks after completion of chemoradiotherapy
van Hagen P, et al. N Engl J Med. 2012;366:2074-2078.
Proportion Surviving
Proportion Surviving
Preop CRT + Surgery vs Surgery Alone for

Esophageal or Junctional Cancer: OS
OS by Treatment
1.0
CRT + surgery
Surgery alone
0.8
0.6
5-yr OS: 47% vs 34% with

surgery alone
0.4
0.2
0
Squamous HR: 0.453
P = .003
0
1.0
12
24
Mos
36
48
60
Adeno HR: 0.732
Pathologic CR with CRT +

surgery
OS by Tumor Type and

Treatment
0.8
Squamous: 49%
0.6
0.4
Adenocarcinoma: 23%
SCC, CRT + surgery

AC, CRT + surgery
AC, surgery alone
SCC, surgery alone
0.2
0
R0 resection increased from

69% w/surgery alone to 92%
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.
Considered a new standard of

care
First-line Chemotherapy
First-line Therapy Recommendations

Preferred regimens*
Other regimens
Fluoropyrimidine + cisplatin
(category 1) or oxaliplatin (2A)
Paclitaxel + cis- or carboplatin

(category 2A)
DCF (category 1)
Docetaxel with cisplatin

(category 2A)
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.
Trastuzumab should not be combined with

anthracyclines.
Advanced Esophagogastric Cancer

Chemotherapy: Which Regimen to Use?
3-Drug Regimens
Oxali:
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]
1. Cunningham D, et al. N Engl J Med. 2008;358:36-46. 2. Van Cutsem E, et al.

J Clin Oncol. 2006;24:4991-4997. 3. Webb A, et al. J Clin Oncol. 1997;15:261267.4. Kang YK, et al. Ann Oncol. 2009;20:666-673. 5. Al-Batran SE, et al. J
Clin Oncol. 2008;26:1435-1442. 6. Guimbaud R, et al. J Clin Oncol.
2014;32:3520-3526. 7. Koizumi W, et al. Lancet Oncol. 2008;9:215-221.
Phase III TAX325 Study: Docetaxel/

Cisplatin/5-FU vs Cisplatin/5-FU
Pts with advanced gastric

cancer and no previous
palliative chemotherapy
(N = 457)
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
5-FU 1000 mg/m2/day by CIV over 5 days
q4w
(n = 230)
Primary endpoint: TTP from 4 6 mos

Secondary endpoints: OS, RR, safety, QoL, clinical benefit
Van Cutsem E, et al. J Clin Oncol. 2006;24:4991-4997.
DCF vs CF in Advanced Gastric Cancer

(TAX-325): Efficacy
Parameter
DCF
(n = 221)*
CF
(n = 224)*
P Value
Median age, yrs
55
55
--
Metastatic disease, %
96
97
--
ORR, %
37
25
.01
Median TTP, mos
5.6
3.7
.001
Median OS, mos
9.2
8.6
.02
*Full analysis population (treated pts).
DCF vs CF in Advanced Gastric Cancer

(TAX-325): Toxicity
Adverse Event, %
DCF
(n = 221)
CF
(n = 224)
Grade 3/4
Stomatitis
21
27
Diarrhea
19
Nausea
14
17
Vomiting
14
17
Neutropenia
82
57
All-grade neutropenic fever and/or neutropenic

infection
29
12
Toxic deaths
3.6
5.4
Off therapy for adverse event or consent

withdrawal
49
37
Does Epirubicin Add Anything in

Advanced GE Cancer? FOLFIRI vs ECX
N = 416
Time to Treatment Failure
TTF (Proportion)
1.0
0.8
1/3 GEJ, 2/3 gastric
ORR: 39% vs 38%
HR: 0.77 (95% CI: 0.63-0.93;

P = .008)
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
Guimbaud R, et al. J Clin Oncol. 2014;32:3520-3526
TTF, toxicity favored

first-line FOLFIRI
over ECX
Phase III: 5-FU/LV + Either Oxaliplatin or

Cisplatin in Adv Gastric Cancer
N = 220
Treatment: 5-FU/LV q2w
plus either
FLO
FLP
P Value
Median PFS,
mos
5.8
3.9
.077
ORR (ITT), %
42
16
.012
Oxaliplatin 85 mg/m2 (FLO)

Cisplatin 50 mg/m2 (FLP)
Primary endpoint: PFS

Oxaliplatin noninferior to cisplatin
In pts 65 yrs, oxaliplatin showed superior PFS and OS
Al-Batran SE, et al. J Clin Oncol. 2008;26:1435-1442.
5-FU/LV + Oxaliplatin Docetaxel in Adv

Gastric Cancer: Results in Pts 65 Yrs
N = 143 pts; median age: 70 yrs
Treatment: FLO vs FLOT
5-FU/oxaliplatin docetaxel
ORR: 49% with FLOT vs 28% with FLO (P = .016)

PFS: 9 mos with FLOT vs 7 mos with FLO (P = .079)
OS: 17.3 mos with FLOT vs 14.5 mos with FLO (P = 0.39)
Toxicity: 82% grade 3/4 AEs with FLOT vs 39% with FLO;
worse QoL with FLOT
More toxicity with no survival benefit for FLOT vs FLO in pts
65 yrs
Al-Batran SE, et al. Eur J Cancer. 2013;49:835-842.
REAL-2 Trial: Capecitabine vs 5-FU,

Oxaliplatin vs Cisplatin
ECF (n = 249)
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 50 mg/m2 IV q3w

Oxaliplatin 130 mg/m2 IV q3w
5-FU
200 mg/m2/d IV given
continuously
Epirubicin
Oxaliplatin
Capecitabine
2 x 2 randomization, 8 cycles
Cunningham D, et al. N Engl J Med. 2008;358:36-46.
50 mg/m2 IV q3w
130 mg/m2 IV q3w
625 mg/m2 PO BID
continuously
Noninferiority of X over F and O over C

with 1-yr survival of 35% (1-side of 5%)
REAL 2: OS, 5-FU vs Capecitabine

Probability of Survival (%)
100
80
60
5-FU
Capecitabine
40
20
0
Yrs Since Randomization

Pts at Risk, n
5-FU
Capecitabine
484
480
178
206
37
52
8
12
REAL 2: OS, Cisplatin vs Oxaliplatin

Probability of Survival (%)
100
80
60
40
Oxaliplatin
20
0
Cisplatin
Yrs Since Randomization

Pts at Risk, n
Cisplatin
Oxaliplatin
490
474
187
198
41
48
10
10
Parent DCF vs Modified DCF in Metastatic

Gastric Cancer
Randomized, multicenter phase II trial
Pts with previously

untreated metastatic or
GEJ adenocarcinoma
(N = 90)
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 +
5-FU 750 mg/m2/day by IVCI over 5 days with
GCSF q3w
(n = 33)
Primary endpoint: safety and 6-mo PFS
Secondary endpoints: response, median PFS, OS, 1- and 2-yr survival
Shah MA, et al. J Clin Oncol. 2015;[Epub ahead of print].

Gastric Cancer: Efficacy
Median
PFS, Mos
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

Gastric Cancer: Grade 3/4 AEs of Interest
Nonhematologic
AE, %
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
Pt Selection for Chemotherapy

Assess age, functional status, comorbidities
Combination chemotherapy preferred over single agents
Most pts are candidates for doublet chemo
Monotherapy with 5-FU, capecitabine, taxanes in elderly,
poor PS pts
Triplet: DCF or a modified schedule

High functional status, younger pts without comorbidities
Willingness to tolerate AEs
Access to frequent follow-up and toxicity assessment
Second-line/Salvage Therapy
Second-line Therapy Recommendations

Depends on prior therapy
and PS
Preferred regimens (all
category 1)
Ramucirumab + paclitaxel
Docetaxel
Paclitaxel
Irinotecan
Ramucirumab
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
NCCN Guidelines: gastric cancer. v.3.2015.
Improved OS in Phase III Trials of Secondline Chemo for Gastric Cancer

100
SLC
BSC
0.8
0.6
0.4
HR: 0.67 (95% CI: 0.49-0.92;

P = .01)
50
25
0.2
0
Docetaxel
Active symptom control
75
OS (%)
Survival Probability
1.0
12
15
18
Mos
Docetaxel or Irinotecan vs BSC[1]
1. Kang JH, et al. J Clin Oncol. 2012;30:1513-1518.

2. Ford HE, et al. Lancet Oncol. 2014;15:78-86.
10
12
14
16
18
Mos From Randomization
Docetaxel vs BSC[2]
Targeted Therapies
Genome Atlas Project: Gene Amplification

in Esophagogastric Cancer
Number of Focal Events per Sample
Focal Events per
Sample (n)
296 Esophageal/Gastric
Cancers; 190 CRCs
Amplified genes in 37% of
gastroesophageal tumors
EGFR
MET
FGFR1-2
KRAS
Targetable receptors and

receptor tyrosine kinases
Dulak AM, et al. Can Res. 2012;72:4383-4393.
***
***
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
Gastric Adenocarcinoma: 4 Genomic

Subsets
Genomically unstable (50%)
Intestinal, present in most GEJ tumors
High rate of p53 mutation, amplification of RTKs
MSI-high (22%): High rate of microsatellite instability, gene

mutation, and promoter hypermethylation
Genomically stable (20%)
Associated with diffuse histology, CHD-1 and RHOA mutation
High Epstein-Barr virus burden (9%)

High rate of PIK3CA mutation, PD-L1 and PD-L2 amplification,
strong IL-12 signaling indicating an immune presence
The Cancer Genome Atlas Research Network. Nature. 2014;513:202-209. Slide credit: clinicaloptions.com
Targeted Therapies
Conventional, cytotoxic chemotherapy has limited
benefit
Targeted agents: designed to block specific tumor
growth pathways
Monoclonal antibodies
Tyrosine kinase inhibitors
Receptor-associated tyrosine kinase mediated

pathways and downstream pathways
Phase III ToGA: Trastuzumab + Chemo in

Advanced HER2+ Gastric Cancer
Rationale: a subpopulation of gastric cancers overexpress HER2
Stratified by ECOG PS,
advanced vs metastatic, gastric vs GEJ,
measurable disease, capecitabine vs 5-FU
Pts with
advanced
gastric cancer
screened for
HER2 status
(N = 3803)
Pts with HER2+

advanced
gastric cancer
(n = 810; 22% of
successful
screenings)
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.
Phase III ToGA: OS

1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
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
Phase III ToGA: OS in Pts With IHC 3+ or

FISH+ and IHC 2+
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
Phase III LOGiC: CapeOx Lapatinib in

HER2+ Advanced Gastric Cancer
Stratified by prior neo/adjuvant therapy, region
(Asia vs North America vs rest of the world)
Pts with HER2-amplified locally
advanced, unresectable, or
metastatic gastric, esophageal, or
GEJ cancer
(N = 545)
CapeOx* + Lapatinib 1250 mg QD

21-day cycles
CapeOx* + Placebo
*Day 1: oxaliplatin 130 mg/m2, Days 2-14:
capecitabine 850 mg/m2 BID.
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 Lapatinib in HER2+ Advanced

Gastric Cancer (LOGiC): OS
CapeOx + L
(n = 249)
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)
0.91 (0.73-1.12) P = .3492
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
Mos Since Randomization

Pts at Risk, n
CapeOx + L
CapeOx + P
249
238
199
189
133
106
83
53
47
34
24
17
9
11
ITT analysis HR: 0.91

Hecht J, et al. J Clin Oncol. 2015;[Epub ahead of print].
Phase III Clinical Trials of HER2-Directed

Therapy in Gastric Cancer
First line
JACOB: capecitabine/cisplatin/trastuzumab
pertuzumab (planned N = 780)[1]
HELOISE: capecitabine/cisplatin + 2 dose levels of
trastuzumab (planned N = 400)[2]
Second line
GATSBY: paclitaxel vs T-DM1 (planned N = 412)[3]
T-DM1 was no better than paclitaxel
1. ClinicalTrials.gov. NCT01774786.
VEGF Revisited?: Second and Later Line

of Therapy
AVAGAST: capecitabine/cisplatin bevacizumab[1]
No OS benefit for addition of bevacizumab in first-line
setting
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.
Phase III REGARD Trial: BSC Ramucirumab

in Met Gastric or GEJ Cancer
Stratified by geographic region, weight loss (> vs < 10%
over 3 mos), location of primary tumor (gastric vs GEJ)
Pts with metastatic

gastric or GEJ
adenocarcinoma
progressing on first-line
platinum- and/or
fluoropyrimidinecontaining combination
therapy, ECOG PS 0-1
(N = 355)
Ramucirumab 8 mg/kg IV q2w +

BSC
(n = 238)
BSC + Placebo
(n = 117)
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.
BSC Ramucirumab in Metastatic Gastric

or GEJ Cancer (REGARD): OS
Proportion Remaining Alive
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
HR: 0.776 (95% CI: 0.603-0.998; P = .0473)

0.4
0.2
0
0 1
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
Proportion Without Progression

or GEJ Cancer (REGARD): PFS, Response
1.0
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
HR: 0.483 (95% CI: 0.376-0.620; P < .0001)
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
11
2
5
2
4
1
2
1
1
0
1
0
1
0
1
0
0
0

or GEJ Cancer (REGARD): AEs of Interest
AE, %
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
Fistula (GI and non-GI)
<1
<1
<1
<1
Infusion-related reaction
<1
Cardiac failure
<1
*Includes increased blood pressure.
No grade 4 hypertension observed among ramucirumab-treated pts.
Randomized Second-line Gastric Cancer

Studies (2009-2013): Median OS
Median OS by Study Arm, Mos
Ramucirumab vs BSC[1]
(n = 355)
5.2
3.8
Docetaxel vs ASC[2]
(n = 131)
5.2
3.6
Chemo (docetaxel or irinotecan) vs BSC[3]

(n = 202)
5.3
3.8
4.0
Irinotecan vs BSC[4]
(n = 40)
2.4
0
1. Fuchs CS, et al. Lancet. 2014;383:31-39.

Active treatment
BSC/ASC
2. Ford H, et al. ASCO GI 2013. Abstract LBA4.
3. Kang JH, et al. J Clin Oncol. 2012;30:1513-1518.
4. Thuss-Patience PC, et al. Eur J Cancer. 2011;47:2306-2314.
RAINBOW: Second-line Paclitaxel

Ramucirumab in Advanced Gastric Cancer
Randomized, double-blind phase III trial
Stratified by geographic region,
measurable vs nonmeasurable disease,
TTP on first-line therapy (< 6 vs 6 mos)
Pts with metastatic or locally

adv unresectable gastric or
GEJ cancer and progression
on first-line chemo*
(N = 665)
4-wk cycle
Ramucirumab 8 mg/kg Days 1, 15 +

Paclitaxel 80 mg/m2 Days 1, 8, 15
(n = 330)
Placebo Days 1, 15 +
Paclitaxel 80 mg/m2 Days 1, 8, 15
(n = 335)
Treat until
PD or
intolerable
toxicity
*Platinum agent plus fluoropyrimidine anthracycline.
Secondary endpoints: PFS, ORR, TTP
Wilke H, et al. Lancet Oncol. 2014;15:1224-1235.
2nd-Line Ramucirumab in Advanced

Gastric Cancer (RAINBOW): OS
REGARD[2]
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
HR: 0.807 (95% CI: 0.678-0.962; P = .0169)
0.4
mOS = 2.3 mos
0.2
Ram + Pac
Placebo + Pac
Censored
0
0
12
1. Wilke H, et al. Lancet Oncol. 2014;15:1224-1235.

Mos
16
20
24
28
Second-line Ramucirumab in Adv Gastric

Cancer (RAINBOW): PFS, Responses
1.0
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
HR: 0.635 (95% CI: 0.536-0.752; P < .0001)
0.5
0.4
0.3
0.2
Ram + Pac
Placebo + Pac
Censored
0.1
0
0
10
1. Wilke H, et al. Lancet Oncol. 2014;15:1224-1235.

Mos
14
18
22
RAINFALL: Capecitabine/5-FU + Cisplatin

Ramucirumab in Metastatic Gastric CA
Randomized, double-blind, phase III trial
Pts with
metastatic
gastric/GEJ CA
with no prior firstline therapy
(N = 616,
planned)
Ramucirumab 8 mg/kg IV Days 1, 8

Capecitabine* 1000 mg/m2 PO Days 1-14
Cisplatin 80 mg/m2 IV Day 1
Placebo IV Days 1, 8
Capecitabine* 1000 mg/m2 PO Days 1-14
Cisplatin 80 mg/m2 IV Day 1
21-day
cycles
*Pts unable to take capecitabine receive 5-FU 800 mg/m 2/day Days 1-5.
Primary endpoint: PFS

Secondary endpoints: OS, PFS2, ORR, DCR, TTP, DoR, QoL, PK
ClinicalTrials.gov. NCT02314117.
Investigational Therapies
Phase III Trials in Gastric Cancer:

EGFR-Targeted Agents
REAL3: ECX panitumumab (UK)[1]
Negative: panitumumab had inferior outcomes
EXPAND: capecitabine/cisplatin cetuximab (EU)[2]

Negative: cetuximab trended inferior
COG: BSC vs gefitinib (UK): negative[3]

Trials conducted with no biomarker selection of pts
No biomarker identified in esophagogastric cancer
1. Waddell T, et al. Lancet Oncol. 2013;14:481-489.
2. Lordick F, et al. Lancet Oncol. 2013;14:490-499.
3. Dutton SJ, et al. Lancet Oncol. 2014;15:894-904.
cMET Antibodies in Gastric Cancer:

Phase III Trials
RILOMET-1[1]
Locally advanced or metastatic
gastric and AEG Cancer, METpositive by
immunohistochemistry (IHC)
HER2 negative
ECX +
Rilotumumab
R
N = 450
1:1
ECX alone
y
l
e
r
u
t
a
m
e
r
p
d
e
p
p
sto
s
e
i
d
u
t
s
Both
MetGastric
[2]
Locally advanced or metastatic

gastric and AEG Cancer, METpositive by
immunohistochemistry (IHC)
HER2 negative
ECX +
Rilotumumab
R
N = 800
1:1
ECX alone
Primary endpoint: OS in the Met IHC 2+/3+ pt subgroup

1. ClinicalTrials.gov. NCT01697072. 2. ClinicalTrials.gov. NCT01662869.
Targeting Amplified Gene Signaling

Pathways in Gastric Cancer: FGFR
FGFR
Tyrosine kinase inhibitors alone or with chemotherapy
Phase I-II
Dovitinib
Nintedanib
Some phase I trials selecting pts with an FGFRactivating mutation or amplification
Immune Checkpoint Inhibitors
CTLA-4 and PD-1/L1 Checkpoint Blockade

Priming phase
(lymph node)
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
Ribas A. N Engl J Med. 2012;366:2517-2519.
Immune Checkpoint Inhibitors in

Esophagogastric Carcinoma
CTLA-4
Tremelimumab: phase II study (N = 18) showed 1 PR > 30 mos[1]
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.
KEYNOTE-012: Pembrolizumab in Gastric

Cancer Cohort
Multicenter, multicohort open-label phase Ib trial
Pts with PD-L1positive

recurrent or metastatic
adenocarcinoma
of the stomach or
gastroesophageal junction;
ECOG PS 0-1; no active
brain metastases
(N = 39)
Discontinue treatment
CR
Pembrolizumab
10 mg/kg IV q2w
PR, SD
Pembrolizumab 10 mg/kg IV q2w

for 24 mos or until progression or
intolerable toxicity
Confirmed
PD
Discontinue treatment
Endpoints: association of clinical response with PD-L1 expression

Assessment of response every 8 wks by RECIST v1.1
Assessment of PD-L1 expression by IHC
Bang YJ, et al. ASCO 2015. Abstract 4001.
Pembrolizumab in Gastric Cancer Cohort

(KEYNOTE-012): Responses
Pembrolizumab therapy
associated with PR in 13 of
39 pts by investigator review
and 8 of 36 pts by central
review
Outcomes
Response
ORR, % (95% CI)
Investigator
Review
(n = 39)
Central
Review
(n = 36)
33 (19-50)
22 (10-39)
Best response, n (%)
53% of pts had decrease in

lesion size
CR
PR
13 (33)
8 (22)
Median time to response:

8 wks
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+)
Pembrolizumab in Gastric Cancer Cohort

(KEYNOTE-012): Change in Tumor Size
Change From Baseline in

Sum of Longest Diameter
of Target Lesion (%)
Maximum Percentage Change From Baseline in Tumor Size

(RECIST v1.1, Central Review)
100
80
60
53.1% of pts experienced a
40
decrease in target lesions
20
0
-20
-40
-60
-80
-100
Gastric Cancer: Take Home Messages
Current adjuvant therapy achieves a limited survival improvement

Both perioperative and postoperative chemotherapy improve survival
Postoperative RT + chemotherapy needed for < D1 resection
Preoperative chemotherapy + RT preferred for GEJ and esophageal cancer
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
Failed trials targeting EGFR, MET

HER2+: trastuzumab added to first-line chemo
Immunotherapy trials ongoing
Immune Checkpoint Inhibitors in Adv.

Gastric CA: Ongoing Clinical Trials
Checkpoint
CTLA-4
PD-1
PD-L1
Combo
Agent
Trial Details
NCT Number
Ipilimumab
Ph II maintenance ipi
NCT01585987
Pembrolizumab
KEYNOTE-061: Ph III 2nd-line

pembro vs paclitaxel
NCT02370498
Pembrolizumab
KEYNOTE-062: Ph III first-line

pembro monotherapy
NCT02494583
Pembrolizumab
KEYNOTE-059: Ph II pembro vs
pembro+ cis/5-FU
NCT02335411
Avelumab
Ph III avelumab vs continuation of

first-line chemo
NCT02625610
Avelumab
Ph III avelumab vs chemo, 3rd-line
NCT02625623
Tremelimumab +
durvalumab
Ph Ib/II tremelimumab + durvalumab

vs treme vs durvalumab
NCT02340975
Nivolumab +
ipilimumab
Ph I/II nivolumab vs nivo/ipi
NCT01928394
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David H. Ilson, MD, PhD

Esophageal and Gastric Carcinoma:

Decline in gastric cancer incidence

Slide credit: clinicaloptions.com

Adjuvant Therapy in Gastric Cancer

Postoperative RT + chemotherapy (US)[1]

Preop and postop chemo (UK) without RT[2]

Postop chemo (Asia): 2 trials, 2000 pts, D2 resection, no RT

Treatment: postop capecitabine/oxaliplatin (CLASSIC trial)[4]

Survival improvements with all approaches similar, modest

1. Smalley SR, et al. J Clin Oncol. 2012;30:2327-2333.

Slide credit: clinicaloptions.com

Esophageal and GEJ Adenocarcinoma:

Slide credit: clinicaloptions.com

Esophageal Adenocarcinoma: Consensus

MRC OEO5 (CF vs ECX):

Preop CRT + Surgery vs Surgery Alone for

Chemoradiotherapy followed by surgery compared with surgery alone (N = 368)

Paclitaxel 50 mg/m2 + carboplatin AUC 2 on Days 1, 8, 15, 22, and 29

van Hagen P, et al. N Engl J Med. 2012;366:2074-2078.

Slide credit: clinicaloptions.com

Preop CRT + Surgery vs Surgery Alone for

5-yr OS: 47% vs 34% with

Squamous HR: 0.453

Adeno HR: 0.732

Pathologic CR with CRT +

OS by Tumor Type and

SCC, CRT + surgery

R0 resection increased from

Considered a new standard of

First-line Therapy Recommendations

Paclitaxel + cis- or carboplatin

Docetaxel with cisplatin

Trastuzumab should not be combined with

Advanced Esophagogastric Cancer

1. Cunningham D, et al. N Engl J Med. 2008;358:36-46. 2. Van Cutsem E, et al.

Phase III TAX325 Study: Docetaxel/

Pts with advanced gastric

Primary endpoint: TTP from 4 6 mos

Slide credit: clinicaloptions.com

DCF vs CF in Advanced Gastric Cancer

Median age, yrs

Median TTP, mos

Median OS, mos

*Full analysis population (treated pts).

Van Cutsem E, et al. J Clin Oncol. 2006;24:4991-4997.

Slide credit: clinicaloptions.com

DCF vs CF in Advanced Gastric Cancer

All-grade neutropenic fever and/or neutropenic

Off therapy for adverse event or consent

Van Cutsem E, et al. J Clin Oncol. 2006;24:4991-4997.

Slide credit: clinicaloptions.com

Does Epirubicin Add Anything in

1/3 GEJ, 2/3 gastric

ORR: 39% vs 38%

HR: 0.77 (95% CI: 0.63-0.93;

Guimbaud R, et al. J Clin Oncol. 2014;32:3520-3526