Beyond Trastuzumab: The potential
for Lapatinib, Pertuzumab, T-DM1 and
combinations in GE Adenocarcinoma
David H. Ilson, M.D., Ph.D.
GI Oncology Service
Memorial Sloan-Kettering Cancer Center
New York, NY
DISCLOSURES

Grant/Research Support
– Amgen
– Bayer
– Bristol-Myers Squibb

Consultant
– Amgen
– Lilly
– Imclone

Speaker’s Bureau
– Genentech
Esophageal and Gastric Carcinoma
US Incidence in 2014

Globally
– Gastric Cancer second leading cause of cancer death

U.S. : 40,390 new cases
– Gastric: 22,220 (55%)
– Esophagus: 18,170 (45%)

Decline in Gastric Cancer Incidence

Increase in Esophageal , GE JX, cardia adeno

OS improvement, 1975-77, 1984-86, 1999-2006
– Gastric: 16%  18%  27%
– Esophageal: 5%  10%  19%
Siegel et al, CA 64: 9-29; 2014
Exome and Whole Genome Sequencing:
Esophageal Adenocarcinoma
149 Tumors Studied

26 significant genes
with Mutation or
Genomic loss

Targetable Genes
– CDKN2A
– PIK3CA
– SMAD4
– ARID1A
– TP53

Rarely mutated:
KRAS, BRAF ERBB2,
EGFR
Dulak AM et al Nat Genet 45: 478; 2013
Gene Amplification: The Driver in
Esophagogastric Cancer

296 Esophageal / Gastric
Cancers, 190 CRC

Amplified genes in 37% Gas /
Eso tumors
– FGFR1-2
– HER2
– EGFR
– MET

Targetable Receptors and
Receptor Tyrosine Kinases

KRAS also amplified

Similar data for a Chinese
series
Dulak AM et al Can Res 72: 4383; 2012
HER signaling:
The network begins with the 4 HER receptors
Extracellular ligand-binding domain
HER1/EGFR
HER2
HER3
HER4
Transmembrane
domain
Intracellular tyrosine kinase domain
HER=human epidermal growth factor receptor; EGFR=epidermal growth factor receptor.
Rowinsky EK. Oncologist. 2003;8:5-17. Yarden Y, Sliwkowski MX. Nat Rev Mol Cell Biol. 2001;2:127-137.
 2012 Genentech USA, Inc. All rights reserved.
6
Dysregulated cancer signaling pathways:
Tyrosine kinase signaling examples
Ligand-activated
receptors
RAS
Raf
FAK
PDK1
Src
AKT
PI3K
mTOR
MEK
MAPK
↓ Apoptosis
↑ Survival
Cell cycle
control
Angiogenesis
Proliferation
 2012 Genentech USA, Inc. All rights reserved.
7
Targeted agents:
Crossing the plasma membrane
Small-molecule inhibitors (SMIs)
Monoclonal antibodies (mAbs)
• Generally, chemical agents
(~400 daltons)
• Large proteins
(~150,000 daltons)
• Highly specific
• Cannot penetrate through the
plasma membrane
• May elicit immune response:
ADCC
• Varying degrees of specificity
• Penetrate through the plasma
membrane
• Cannot elicit immune response,
eg, TKIs
Cell surface
receptors
Cell surface
receptors
Sos
Sos
PI3K
Raf
Adjei et al. J Clin Oncol. 2005;23:5386-5403. Imai et al. Nat Rev Cancer. 2006;6:714-727.
RAS
Grb2 Shc
PI3K
PDK1
AKT
PDK1
AKT
RAS
Grb2 Shc
Raf
 2012 Genentech USA, Inc. All rights reserved.
8
Targeting the HER2
HER2 Does Not Require
A Ligand To Be Primed
Hynes et al, 2005; Garrett et al, 2003; Graus-Porta et al, 1997.
Trastuzumab

Humanized anti-HER2 antibody

HER2-neu as a biomarker and therapeutic target for
gastroesophageal cancers
Junttila et al, 2009.
Targeting HER2
Meric-Bernstam et al, 2006; Olayioye et al, 2000; Rowinski, 2003.
HER2 Expression in Gastric/GEJ Cancer
Incidence of HER2 Expression by IHC or FISH1-5
All GC tumors
Histology
Primary tumor location
──
13% to 23%
Intestinal
Diffuse
Mixed
Unknown
16% to 34%
6% to 7%
20%
14%
GEJ
Gastric
25% to 34%
9% to 20%
DFS, disease-free survival
1. Bang YJ, et al. Lancet. 2010;6736(10):61121-61132. 2. Gravalos C, et al. Ann Oncol. 2008;19:1523-1529. 3. Yano T, et
al. J Clin Oncol. 2004;22(14S): Abstract 4053. 4. Gravolos C, et al. Presented at: 2007 Gastrointestinal Cancer
Symposium; January 19-21, 2007: Orlando, Florida. Abstract 89. 5. Lordick F, et al. Eur J Cancer Suppl. 2007;5(4):
Abstract 3541.
Is HER2 Prognostic?

Mayo Clinic: 787 pts esophageal/GEJ cancer surgery only
– HER2+ 17%, better OS, but not independent of path stage
– HER3 strongly + in 40%

Utrecht: 156 pts esophageal/GEJ cancer surgery only
– HER2+ 18%, poorer OS, independent  SISH/IHC but not FISH

INT-116: GEJ and gastric cancer, + / - post op FU/RT
– HER2+ FISH 11% in 258 pts, IHC 12% in 148 pts
– Poorer OS in HER2+ receiving FU/RT: 24 vs 44 mos
– No difference in OS for HER2+ with / without FU/RT

MAGIC Trial: GEJ and gastric cancer, preop ECF
– HER2+ 11% in 156 pts
– HER2 neither prognostic for OS nor predictive of chemo benefit

EXPAND Trial: Cape-Cis + / - Cetuximab
– HER2+ 21% in 679 pts
– Superior OS on either arm
Yoon Cancer 120: 415; 2014 Prins Ann Oncol 24:1290; 2013 Gordon Ann Oncol 24:1754; 2103 Okines
Ann Oncol 24: 1253; 2013 Lordick Lancet Oncol 14: 490; 2013
ToGA Trial
Phase III: Trastuzumab in HER2+ GEJ and Gastric Cancer
3807 patients screened
810 HER2-positive (22.1%)
•
HER2-positive
advanced GC
(n = 584)
Stratification factors
─
─
─
─
─
Advanced vs metastatic
GC vs GEJ
Measurable vs nonmeasurable
ECOG PS 0-1 vs 2
Capecitabine vs 5-FU
Bang Y, et al. Lancet. 2010;376(9742):687-697
5FU or capecitabine
+ cisplatin
(n = 290)
R
5FU or capecitabine
+ cisplatin
+ trastuzumab
(n = 294)
ToGA: Efficacy Outcome
Chemotherapy
+ Trastuzumab
(n = 294)
Chemotherapy
Alone
(n = 290)
HR (95% CI)
P Value
13.8
11.1
0.74 (0.60-0.91)
.0046
Median PFS, months
6.7
5.5
0.71 (0.59-0.85)
.0002
ORR, %
47.3
34.6
-
.0017
•
CR
5.4
2.4
-
.0599
•
PR
41.8
32.1
-
.0145
Primary endpoint
Median OS, months
Secondary endpoints
• Preplanned subgroup analysis indicated improved OS benefit
with increasing HER2 expression by IHC
• Exploratory analysis of IHC 2+/FISH+ and IHC 3+ cohort
demonstrated a 4-month increase in OS with trastuzumab
− HR: 0.65 (95% CI: 0.51-0.83)
ORR, overall response rate
Bang Y, et al. Lancet. 2010;376(9742):687-697.
Primary end point: OS
Event
Median
Events OS
HR
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
FC + T
FC
11.1
0
2
4
6
167
182
13.8
11.1
95% CI
p value
0.74 0.60, 0.91
13.8
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
T, trastuzumab
71
47
56
32
43
24
30
16
21
14
13
7
12
6
6
5
4
0
1
0
0
0
0.0046
Secondary end point: PFS
Event
Median
Events PFS HR
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
FC + T
FC
5.5
0
2
4
226
235
6.7
5.5
95% CI
p value
0.71 0.59, 0.85
6.7
6
8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time (months)
No.
at risk
294 258 201 141 95
290 238 182 99 62
60
33
41
17
28
7
21
5
13
3
9
3
8
2
6
2
6
1
6
1
4
0
2
0
0
0
0.0002
OS in IHC2+/FISH+ or IHC3+
(exploratory analysis)
Event
Median
Events OS
HR
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
FC + T
FC
11.8
0
2
4
6
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
Time (months)
No.
at risk
228 218 196 170 142 122 100 84
218 198 170 141 112 96 75 53
65
39
51 39
28 20
28
13
20 12
11 4
11
3
5
3
4
0
1
0
0
0
RTOG 1010: Phase III Study of Neoadjuvant
Trastuzumab and Chemoradiation for
Esophageal Adenocarcinoma (Siewert I, II)
CHEMORADIATION
SURGERY
HER-2 (+)
(FISH)
TRASTUZUMAB
+
CHEMORADIATION
HER-2 (-)
(FISH)
SURGERY
+
TRASTUZUMAB (1 YR)
ALTERNATIVE
STUDIES
Chemoradiation: Carboplatin, Paclitaxel + RT 5040 cGy 
Surgery
Maintenance trastuzumab post op
OS Primary Endpoint
Targeting the Intracellular Domain
of HER2: Lapatinib

Oral dual TKI

Targets EGFR/HER2
– Both frequently
overexpressed in
various cancers
TKI = tyrosine kinase inhibitor; EGFR = epidermal growth factor receptor.
Yamauchi et al, 2009.
LOGIC Trial: Gastric Cancer
Gastric/GEJ Cancer, HER2+, 545 patients
RANDOMIZATION
Capox
Capox + Lapatinib
Hecht JR, et al. J Clin Oncol. 2013;31(Suppl):Abstract LBA4001
Cumulative survival probability
Primary Endpoint: Overall Survival
1.0
PEP
0.8
Median (95% CI)
(mo)
0.6
HR (95% CI)
CapeOx+L
N=249
CapeOx+P
N=238
12.2 (10.6, 14.2)
10.5 (9.0, 11.3)
0.91 (0.73, 1.12) p=0.3492
0.4
0.2
CapeOx+L
CapeOx+P
0.0
Subjects at risk
CapeOx+L
CapeOx+P
0
5
10
249
238
199
189
133
106
15
20
25
30
Time since randomization (months)
83
53
47
34
24
17
9
11
35
40
45
3
7
3
2
2
ITT analysis HR 0.91
Presented at ASCO 2013
OS by Region
ROW
1.0
Median
(95% CI) (mo)
0.8
CapeOx+L
N=100
CapeOx+P
N=93
16.5
(13.3,20.2)
10.9
(9.0,14.9)
HR (95% CI)
0.68 (0.48,0.96)
0.6
0.4
0.2
CapeOx+L
CapeOx+P
5
10
15
20
25
30
35
40
Time since randomization (months)
Subjects at risk
CapeOx+L 100
CapeOx+P 93
93
77
70
47
1.0
Median
(95% CI) (mo)
0.8
49
28
25
19
16
11
7
7
3
5
3
1
45
CapeOx+L
N=141
CapeOx+P
N=136
10.0
(8.0,12.0)
9.1
(8.3,10.9)
HR (95% CI)
1.04 (0.79,1.37)
0.6
0.4
0.2
CapeOx+L
CapeOx+P
0.0
0.0
0
Cumulative survival probability
Cumulative survival probability
ASIA
0
5
10
15
20
25
30
35
40
Time since randomization (months)
141 101
136 104
59
53
30
21
19
12
6
4
Presented at ASCO 2013
2
2
1
45
Progression Free Survival (PEP)
Cumulative survival probability
1.0
Without Censoring
Median (95% CI) (mo)
0.8
Median (95% CI) (mo)
0.4
5.4 (4.4, 5.7)
CapeOx+L
N=249
CapeOx+P
N=238
6.0 (5.6, 7.0)
5.4 (4.4, 5.7)
HR (95% CI)
0.82 (0.68, 1.00) p=0.0381
CapeOx+L
CapeOx+P
0 2 4
Subjects at risk
CapeOx+L
CapeOx+P
6.0 (5.6, 7.0)
0.86 (0.71, 1.04) p= 0.1026
With Censoring
0.0
CapeOx+P
N=238
HR (95% CI)
0.6
0.2
CapeOx+L
N=249
6
8 10
14
18
22
26
30
34
38
42
46
Time since randomization (months)
249 212 180 121
238 205 157 91
95
54
63 43 35 27 17 9
36 25 20 18 15 11
9
9
5
7
4
6
4
6
3
6
2
5
1
4
1
3
1
2
1
1
Note: The curve displayed represents data without censoring
Presented at ASCO 2013
0
1
0
1
0
1
0
0
Best Overall Response
CapeOx + Lapatinib
CapeOx + Placebo
N=249
N=238
6 (2%)
5 (2%)
Partial response
126 (51%)
90 (38%)
Stable Disease
70 (28%)
94 (39%)
Disease Progression
20 (8%)
22 (9%)
Not evaluable/unknown
27 (11%)
27 (11%)
53% (95%CI : 46.6−59.3)
40% (95% CI : 33.6−46.4)
7.3 (95%CI : 6.4–8.4)
5.6 (95%CI : 4.8–6.0)
North America
63 %
56 %
Asia
65 %
39 %
ROW
44 %
40 %
Complete response
Overall RR
Median Duration of
Response (month)
ORR by region
Presented at ASCO 2013
TYTAN Trial: Gastric Cancer
Gastric/GEJ Cancer POD prior FP, HER2+
RANDOMIZATION
Weekly Paclitaxel Weekly Paclitaxel + Lapatinib
Bang YJ, et al. J Clin Oncol. 2012;30(15S): Abstract 11
TYTAN Trial: OS, OS by IHC
Receptor-targeted Antibodies selectively
deliver potent cytotoxics: TDM-1
ADC binds to the
receptor
Receptor-ADC
complex is
internalized
into cell
ADCs=antibody-drug conjugates.
Potent cytotoxic
is released once
inside the cell
 2012 Genentech USA, Inc. All rights reserved.
29
HER2-Directed Therapy Trials
• Ongoing HER2 Trials
– Second-line:
- GATSBY: Paclitaxel vs TDM-1
– First-line
- JACOB: Cape-Cis-Trastuzumab + / - Pertuzumab
(HER2-3), 780 patients
- HELOISE: Cape-Cis + 2 dose levels of Trastuzumab,
400 patients
Targeting mTOR
Receptor
PI3K
AKT
PDK1
PTEN
↑ Protein
synthesis
S6
↑Metabolism
eIF4B
S6K
mTOR
Autophagy
4EBP1
Ribosome
biogenesis
 2012 Genentech USA, Inc. All rights reserved.
31
3
mTOR: Everolimus in Gastric
Cancer: GRANITE-1 Trial
Refractory Gastric/GEJ Cancer
RANDOMIZATION, 656
patients
BSC + Everolimus
Ohtsu A, et al. J Clin Oncol. 2013;31(31):3935-3943.
BSC + Placebo
Gastric Cancer: GRANITE-1,
Everolimus
•
GRANITE-2: Paclitaxel + / - Everolimus
second line
Ohtsu A, et al. J Clin Oncol. 2013;31(31):3935-3943.
Targeting the PI3K/AKT axis
Receptor
PI3K
AKT
PDK1
PTEN
S6K
Protein translation
GSK3b
mTOR
4EBP1
NFκB
BAD
Cyclin D1
p27
↓Apoptosis
Cell cycle
control
↑Survival
Proliferation
 2012 Genentech USA, Inc. All rights reserved.
34
3
Trials of Targeted Agents
1st Line
Target
Agent
Trial
Regimen
Number Status
HER2
Pertuzumab
JACOB
XP + T +/Pertuzumab
780
Ongoing
HER2
Trastuzumab
HELOISE
XP + T (2 doses) 400
Ongoing
CMET
Rilotumumab
Rilomet-1
ECX + / - Rilo
650
Ongoing
CMET
Onartuzumab MetGastric FOLFOX + /- O
800
Ongoing
EGFr
Panitumumab
NCT01627379
5-FU-Cis + / Pan
300
Ongoing
VEGFr
Pazopanib
PaFLO
FLO + / - Pazop
75
Ongoing
mTOR
Everolimus
AIOST00111
Pac + / - Evero
665
Ongoing
HER2
TDM-1
GATSBY
Pac vs TDM-1
412
Ongoing
EGFr
Nimotuzumab
NCT01813253
Irino + / - Nimo
400
Ongoing
PARP
Olaparib
2nd Line
Pac + / - Olap
Planned
Esophagogastric Cancer:
Targeted Agents
• Biomarkers to identify patients more likely to respond
• Gene amplification > mutation in esophagogastric
cancer: EGFr and HER2 are key pathways
• EGFR
– Negative trials in EG Cancer
- No Biomarker
• Trastuzumab: improves outcome in HER2+ / amplified
esophagogastric cancers
• Lapatinib + chemo: failed to improve OS
• Newer HER2 agents, TDM-1 and pertuzumab, will be
studied