Beyond Trastuzumab: The potential for Lapatinib, Pertuzumab, T-DM1 and combinations in GE Adenocarcinoma
David H. Ilson, M.D., Ph.D.GI Oncology ServiceMemorial Sloan-Kettering Cancer CenterNew York, NY
DISCLOSURES
Grant/Research Support
– Amgen
– Bayer
– Bristol-Myers Squibb
Consultant
– Amgen
– Lilly
– Imclone
Speaker’s Bureau
– Genentech
Esophageal and Gastric CarcinomaUS 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
2012 Genentech USA, Inc. All rights reserved.6
HER signaling: The network begins with the 4 HER receptors
HER2HER1/EGFR HER4HER3
Transmembranedomain
Intracellular tyrosine kinase domain
Extracellular ligand-binding 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.7
FA
K
Dysregulated cancer signaling pathways: Tyrosine kinase signaling examples
AK
T
RAS
Raf
PI3K
PDK1mTOR
Cell cyclecontrol
Proliferation
↓ Apoptosis
↑ Survival
Angiogenesis
MAPK
MEK
MAPK
Src
Ligand-activated receptors
2012 Genentech USA, Inc. All rights reserved.8
8
AK
TPDK1
Targeted agents:Crossing the plasma membrane
RAS
SosGrb2 Shc
Raf
PI3K
Cell surface receptors
AK
TPDK1RAS
SosGrb2 Shc
Raf
PI3K
Cell surface receptors
Small-molecule inhibitors (SMIs)
• Generally, chemical agents (~400 daltons)
• Varying degrees of specificity
• Penetrate through the plasma membrane
• Cannot elicit immune response, eg, TKIs
Monoclonal antibodies (mAbs)
• Large proteins (~150,000 daltons)
• Highly specific• Cannot penetrate through the
plasma membrane• May elicit immune response:
ADCC
Adjei et al. J Clin Oncol. 2005;23:5386-5403. Imai et al. Nat Rev Cancer. 2006;6:714-727.
Targeting the HER2Targeting the HER2
Hynes et al, 2005; Garrett et al, 2003; Graus-Porta et al, 1997.
HER2 Does Not Require A Ligand To Be Primed
TrastuzumabTrastuzumab Humanized anti-HER2 antibody
HER2-neu as a biomarker and therapeutic target for gastroesophageal cancers
Junttila et al, 2009.
Targeting HER2Targeting HER2
Meric-Bernstam et al, 2006; Olayioye et al, 2000; Rowinski, 2003.
HER2 Expression in Gastric/GEJ CancerHER2 Expression in Gastric/GEJ Cancer
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.
Incidence of HER2 Expression by IHC or FISH1-5
All GC tumors ── 13% to 23%
Histology IntestinalDiffuseMixed
Unknown
16% to 34%6% to 7%
20%14%
Primary tumor location GEJGastric
25% to 34%9% to 20%
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
HER2-positiveadvanced GC
(n = 584)
5FU or capecitabine + cisplatin(n = 290)
R
5FU or capecitabine + cisplatin
+ trastuzumab(n = 294)
Phase III: Trastuzumab in HER2+ GEJ and Gastric Cancer
3807 patients screened 810 HER2-positive (22.1%)
• 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
ToGA: Efficacy OutcomeToGA: Efficacy Outcome
• 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)
Chemotherapy + Trastuzumab
(n = 294)
Chemotherapy Alone
(n = 290) HR (95% CI) P Value
Primary endpoint
Median OS, months 13.8 11.1 0.74 (0.60-0.91) .0046
Secondary endpoints
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
ORR, overall response rateBang Y, et al. Lancet. 2010;376(9742):687-697.
Primary end point: OS
Time (months)
294290
277266
246223
209185
173143
147117
11390
9064
7147
5632
4324
3016
2114
137
126
65
40
10
00
No. at risk
11.1 13.8
0.00.10.20.30.40.50.60.70.80.91.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Event
FC + TFC
Events
167182
HR
0.74
95% CI
0.60, 0.91
p value
0.0046
MedianOS
13.811.1
T, trastuzumab
Secondary end point: PFS
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Event
294290
258238
201182
14199
9562
6033
4117
287
215
133
93
82
62
61
61
40
20
00
5.5 6.7
No. at risk
0.00.10.20.30.40.50.60.70.80.91.0
Time (months)
FC + TFC
Events
226235
HR
0.71
95% CI
0.59, 0.85
p value
0.0002
MedianPFS
6.75.5
113
OS in IHC2+/FISH+ or IHC3+ (exploratory analysis)
1.0
0.8
0.6
0.4
0.2
0.0
363432302826242220181614121086420
Time (months)
11.8 16.0
FC + T
FC
Events
120136
HR
0.65
95% CI
0.51, 0.83
MedianOS
16.011.8
Event
0.1
0.3
0.5
0.7
0.9
218 198
40
53
124
2011
228 218
196 170
170 141
142 112
12296
10075
8453
6539
5128
10
00
No. at risk
3920
2813
RTOG 1010: Phase III Study of Neoadjuvant Trastuzumab and Chemoradiation for
Esophageal Adenocarcinoma (Siewert I, II)
RTOG 1010: Phase III Study of Neoadjuvant Trastuzumab and Chemoradiation for
Esophageal Adenocarcinoma (Siewert I, II)
‘
CHEMORADIATIONCHEMORADIATION
HER-2 (+)(FISH)
HER-2 (+)(FISH)
TRASTUZUMAB+
CHEMORADIATION
TRASTUZUMAB+
CHEMORADIATION
SURGERYSURGERY
SURGERY+
TRASTUZUMAB (1 YR)
SURGERY+
TRASTUZUMAB (1 YR)
HER-2 (-)(FISH)
HER-2 (-)(FISH)
ALTERNATIVE STUDIES
ALTERNATIVE STUDIES
Chemoradiation: Carboplatin, Paclitaxel + RT 5040 cGy SurgeryMaintenance trastuzumab post opOS Primary Endpoint
Targeting the Intracellular Domain Targeting the Intracellular Domain of HER2: Lapatinibof 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
RANDOMIZATION
Capox + LapatinibCapox
Gastric/GEJ Cancer, HER2+, 545 patients
Hecht JR, et al. J Clin Oncol. 2013;31(Suppl):Abstract LBA4001
Primary Endpoint: Overall Survival
CapeOx+L
CapeOx+P
1.0
0.8
0.6
0.4
0.2
0.0
Cum
ula
tive
sur
viva
l pro
babi
lity
0 5 10 15 20 25 30 35 40 45
Time since randomization (months)
PEP CapeOx+L
N=249
CapeOx+P
N=238
Median (95% CI) (mo)
12.2 (10.6, 14.2) 10.5 (9.0, 11.3)
HR (95% CI) 0.91 (0.73, 1.12) p=0.3492
Subjects at risk CapeOx+L 249 199 133 83 47 24 9 3 3CapeOx+P 238 189 106 53 34 17 11 7 2 2
ITT analysis HR 0.91
Presented at ASCO 2013
OS by Region
CapeOx+L
CapeOx+P
1.0
0.8
0.6
0.4
0.2
0.0
Cum
ula
tive
sur
viva
l pro
babi
lity
0 5 10 15 20 25 30 35 40 45
Time since randomization (months)
ASIA ROW
Subjects at riskCapeOx+L 100 93 70 49 25 16 7 3 3 141 101 59 30 19 6 2 CapeOx+P 93 77 47 28 19 11 7 5 1 136 104 53 21 12 4 2 1
CapeOx+L
N=100
CapeOx+P
N=93
Median (95% CI) (mo)
16.5 (13.3,20.2)
10.9 (9.0,14.9)
HR (95% CI) 0.68 (0.48,0.96)
CapeOx+L
N=141
CapeOx+P
N=136
Median (95% CI) (mo)
10.0 (8.0,12.0)
9.1 (8.3,10.9)
HR (95% CI) 1.04 (0.79,1.37)
1.0
0.8
0.6
0.4
0.2
0.0
Cum
ula
tive
sur
viva
l pro
babi
lity
0 5 10 15 20 25 30 35 40 45
Time since randomization (months)
CapeOx+L
CapeOx+P
Presented at ASCO 2013
Progression Free Survival (PEP)
CapeOx+L
N=249
CapeOx+P
N=238
Median (95% CI) (mo) 6.0 (5.6, 7.0) 5.4 (4.4, 5.7)
HR (95% CI) 0.86 (0.71, 1.04) p= 0.1026
Subjects at riskCapeOx+L 249 212 180 121 95 63 43 35 27 17 9 9 5 4 4 3 2 1 1 1 1 0 0 0 0CapeOx+P 238 205 157 91 54 36 25 20 18 15 11 9 7 6 6 6 5 4 3 2 1 1 1 1 0
Without Censoring
CapeOx+L
N=249
CapeOx+P
N=238
Median (95% CI) (mo) 6.0 (5.6, 7.0) 5.4 (4.4, 5.7)
HR (95% CI) 0.82 (0.68, 1.00) p=0.0381
With Censoring
CapeOx+L
CapeOx+P
1.0
0.8
0.6
0.4
0.2
0.0
Cum
ula
tive
sur
viva
l pro
babi
lity
0 4 10 14 18 26 30 34 38 46
Time since randomization (months)
2 6 8 22 42
Note: The curve displayed represents data without censoring
Presented at ASCO 2013
Best Overall ResponseCapeOx + Lapatinib
N=249
CapeOx + PlaceboN=238
Complete response 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%)
Overall RR 53% (95%CI : 46.6−59.3) 40% (95% CI : 33.6−46.4)
Median Duration of Response (month)
7.3 (95%CI : 6.4–8.4) 5.6 (95%CI : 4.8–6.0)
ORR by region
North America 63 % 56 %
Asia 65 % 39 %
ROW 44 % 40 %
Presented at ASCO 2013
TYTAN Trial: Gastric Cancer
RANDOMIZATION
Weekly Paclitaxel + LapatinibWeekly Paclitaxel
Gastric/GEJ Cancer POD prior FP, HER2+
Bang YJ, et al. J Clin Oncol. 2012;30(15S): Abstract 11
TYTAN Trial: OS, OS by IHC
2012 Genentech USA, Inc. All rights reserved.29
Receptor-ADC complex is internalized into cell
Potent cytotoxic is released once inside the cell
ADC binds to the receptor
Receptor-targeted Antibodies selectively deliver potent cytotoxics: TDM-1
ADCs=antibody-drug conjugates.
HER2-Directed Therapy TrialsHER2-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
2012 Genentech USA, Inc. All rights reserved.3131
eIF4B
Targeting mTOR
AK
TPDK1
↑Metabolism
PI3K
↑ Protein synthesis
Receptor
mTOR
PTEN
S6K
4EBP1
S6
Ribosomebiogenesis
Autophagy
mTOR: Everolimus in Gastric Cancer: GRANITE-1 Trial
RANDOMIZATION, 656 patients
BSC + Everolimus
Ohtsu A, et al. J Clin Oncol. 2013;31(31):3935-3943.
Refractory Gastric/GEJ Cancer
BSC + Placebo
Gastric Cancer: GRANITE-1, Everolimus
Gastric Cancer: GRANITE-1, Everolimus
• GRANITE-2: Paclitaxel + / - Everolimus second line
Ohtsu A, et al. J Clin Oncol. 2013;31(31):3935-3943.
2012 Genentech USA, Inc. All rights reserved.3434
Targeting the PI3K/AKT axis
AK
TPDK1
Cell cyclecontrol
Proliferation
↑Survival
PI3K
Cyclin D1
p27
BAD
GSK3
NFκB
↓Apoptosis
Receptor
mTOR
PTEN
S6K
4EBP1
Protein translation
Trials of Targeted Agents1st 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
2nd Line
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 Pac + / - Olap Planned
Esophagogastric Cancer: Targeted Agents
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
