Download ASCO_GI_2010_files/Lenz NewAgnets EsophGastric Educ

New Agents in the Treatment of
Esophageal and Gastric Cancers
Heinz-Josef Lenz, MD
Professor of Medicine
USC/Norris Comprehensive Cancer Center
University of Southern California
Keck School of Medicine
Los Angeles, CA
Can Gastric Cancer
be the next GIST?
Intestinal versus
Diffuse?
Critical Pathways
Her2
VEGF/VEGFR
EGFR
IGFR1
C-met
PI3K/AKT
E-Cadherin
Frequent Genetic and Molecular
Abnormalities In Sporadic Gastric Cancer
E-cadherin
Fibroblast growth factor
In 92%, down regulation or mutation
70% expression, esp. undifferentiated
tumors
Telomerase expression
85% of advanced tumors, poor prognosis
VEGF/VEGFR
about 50% overexpression poor prognosis
MET, c-met
Over-expression in approximately 50%,
a marker for poor prognosis
Epidermal Growth Factor (EGF) Over-expression in over 50% of advanced
cancers
PI3K Mutations
35% have PI3K mutations
HER2 over expression:
10-25% overexpression (FISH) intestinal
type
Hundahl, Macdonald, & Smalley Chapter 45: Stomach in Chang F et al (eds)
Oncology: An Evidence Based Approach, New York: Springer Verlag, 2008, Galizia W J Surg 31: 1458; 2007 Mammano Anticancer
Res 26: 3547; 2006 Lee Oncogene 22: 6942; 2003 Yano Oncol Rep 15: 65; 2006
Overall Survival among
Different Ethnicities (Differences
in Genetic Make up?)
P for wald test = 0.026
Estimated Recurrence-Free Probability
1.0
White N=63
African American N= 1
Asian N=28
Hispanic N= 45
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
2
4
6
8
10
12
Years Since Diagnosis of Resectable Gastric Cancer
14
16
Targeted Therapies
Conventional, cytotoxic chemotherapy has
limited benefit
Targeted agents: attempt to block specific
tumor growth pathways
–
–
–
–
Monoclonal antibodies
Tyrosine kinase inhibitors
Soluble receptors/Ligands to growth factors
Inhibition of pathways involved in protein
synthesis and degradation
Targeted Agents in Phase II
Phase II
Study
Regimen
N
Response
(%)
TTP / OS
Bang et al
2007
Sunitinib
38
3%
NS
Muro 2008
RAD001
24
0%
NS
Gold 2008
Cetuximab
55
2%
1.8 mos /
4 mos
Lapatinib
21
47
0%
7%
-2 mos/ 5
mos
Hecht 2008
Iqbal 2007
Phase II
Study
Advanced Gastric Cancer:
Targeted Agents
Regimen
N
RR (%)
TTP / OS
Cetuximab + FUFOX
28
56%
8.1 / 28.2
mos
Cetuximab +
FOLFIRI
27
52%
Pinto et al.
20063
Cetuximab +
FOLFIRI
25
56%
8 / 16 mos
Jhawer 2009
Bev + Modified DCF
36
64%
12 mos /
16mos
Shah et al.
20061
Bev + Cisplatin +
Irinotecan
34
65%
8.3 / 12.3
mos
Bev +
Irino/Docet/Cisplatin
22
68%
NS
Lordick et
al. 20064
Di Fabio et
al. 20062
Enzinger et
al. 2008
1. Shah et al. J Clin Oncol. 2006;24:5201; 2. Di Fabio et al. ESMO, 2006. Abstract 1077PD;
3. Pinto et al. Ann Oncol 2007; 4. Lordick et al. Ann Oncol 2008.
Targeted Agents in Phase III
(EGFR/VEGF/Her2)
REAL 3:
ECX + / - Panitumumab
(U.K.)
EXPAND: Cape-Cis + / Cetuximab
AVAGAST: Cape-Cisplatin + / Bevacizumab
LOGIC:
Cape-Ox + / - Lapatinib
(HER2+)
TOGA:
HER+Cape-Cisplatin + / -
Trastuzumab
Angiogenesis in GC & EC
VEGF-A expressed in 51% GC specimens w/o
stage correlation (Feng, 2002) but w/ OS
correlation (Maeda,1996)
Serum VEGF-A correlated with OS in resected
GC (Yoshikawa, 2000; Karayiannakis, 2002)
Serum VEGF-A increased in SCC EC and
correlated with stage and response to CT/RT
(Shimada, 2001)
VEGF-D & VEGFR-3 expression in GC
correlated with poor OS (all pts & pN+) (Jüttner,
2006)
Tight correlation between VEGF and EGFR
pathways in GC (Akagi, 2003)
VEGFD & VEGFR-3 in GC
Total (n=91)
pN+ (n=63)
 VEGF-D & VEGFR-3 expression was correlated with decreased survival in the total
population
 Combined analysis of VEGF-D & VEGFR-3 can be useful to identify patients with
favourable vs unfavourable outcome (even pN+)
Jüttner S, et al. JCO 2006
Hypoxia
EGF
EGFR
Thrombin
Tumor cell
1-granules
PAR-4
NFkb
PAR-1
HIf1 ARNT
HIF1
DNA
Thrombin
2-granules
Platelet
VEGF
IL-8
IL-1 β
VEGFR
IL-1R
CXCR
NRP1
Endothelial cell
Tumor associated angiogenesis
Endostatin
Overall Survival among different
IL-8 Polymorphisms
Il-8 -251 T>A (rs4073)
Log-rank test p value <0.0001
1.0
Estimated Recurrence-Free Probability
0.9
0.8
T/T (n=50)
0.7
0.6
0.5
0.4
0.3
T/A (n=66)
0.2
A/A (n=21)
0.1
0.0
0
2
4
6
8
10
12
Years Since Diagnosis of Resectable Gastric Cancer
Lurje et al Annals of Oncology 2009
14
16
Overall Survival among different
PAR-1 Polymorphisms
PAR-1 -506 ins/del
(rs11267092)
1.0
Estimated Recurrence-Free Probability
Log-rank p value < 0.0001
0.9
0.8
0.7
0.6
0.5
Del/del (n=91)
0.4
0.3
Ins/del (n=34)
0.2
Ins/Ins (n=11)
0.1
0.0
0
2
4
6
8
10
12
Years Since Diagnosis of Resectable Gastric Cancer
Lurje et al Annals of Oncology 2009
14
16
Overall Survival among different
Endostatin Polymorphisms
Endostatin +4349 G>A
(rs12483377)
1.0
Log-rank p value < 0.0001
Estimated Recurrence-Free Probability
0.9
0.8
0.7
0.6
0.5
0.4
G/G (n=115)
0.3
G/A (n=18)
0.2
0.1
A/A (n=4)
0.0
0
2
4
6
8
10
12
Years Since Diagnosis of Resectable Gastric Cancer
Lurje et al Annals of Oncology 2009
14
16
EGF and PAR1 associated with
Time to Tumor Recurrence in
Esophageal Cancers (n=237)
1,0
EGF +61 A>G & PAR-1 -506 ins/del
Adjusted P value < 0.001
Estimated Recurrence-Free Probability
0,9
0,8
0,7
0,6
EGF +61 A/G or G/G and
PAR-1 -506 del/del (n=95)
0,5
EGF +61 A/A and PAR-1 -506 del/del or
EGF +61 A/G or G/G and PAR-1 -506 in/del or ins/ins
(n=108)
0,4
0,3
0,2
EGF +61 A/A and
PAR-1 -506 ins/del or ins/ins (n=34)
0,1
0,0
0
2
4
6
8
10
12
Years Since Surgery of Localized Esophageal Adenocarcinoma
14
Anti VEGF (Bevacizumab)
Shah, et al. JCO 2007
– Phase II met gastric or GEJ adenoca
– First line therapy – cisplatin/irinotecan/bev
– N = 47, 34 with measurable disease
– RR 65%, OS 12.3 mo
Enzinger, et al. ASCO 2008, Abstr 4552
– Phase II met esophagogastric cancer
– First line therapy – docetaxel/cisplatin/irinotecan
– N = 32
– RR 63%
Jhawer, et al. GI ASCO 2009, Abstr 10
– mDCF plus bevacizumab
– N = 45
– RR 67%, PFS 12 mo, OS 16.2 mo
AVAGAST study accrual completed
– XP +/- bevacizumab
– Following toxicities carefully – thrombosis, perforation
Anti-VEGFR (Sorafenib)
ASCO 2008, Abstr 4535, Sun, et al.
ECOG 5203
Phase II study of sorafenib, docetaxel,
cisplatin
44 pts with advanced gastric or GE
junctional cancers
RR 38.6%, PFS 5.8 mo, OS 14.9 mo
EGF Receptor:
A Rational Target for CRC Therapy
Ligand: AREG, EREG
Target for EGFT-TK
inhibitor
P13K
EGFR-TK
pY
pY
GRB2
SOS
pY
RAS
STAT
RAF
MEK
AKT
PTEN
P
P
MAPK
Gene transcription
Cell-cycle progression
Cyclin D1
MYC
JUN FOS
Proliferation/
maturation
Chemotherapy/
radiotherapy resistance
MYC
Angiogenesis
Cyclin D1
Invasion and
metastasis
Survival
(antiapoptosis)
Meyerhardt JA, Mayer RJ. N Engl J Med. 2005;352:476-487; Venook A. Oncologist. 2005;10:250-261.
EGFR/HER-2 Expression in GE
cancer
HER-2/neu expression
EGFR expression
Range
Esophageal
Gastric
43-89%
50-63%
Ref.
Herbst (2002)
Rojo (2003)
Matsubara (2007)
Esophageal
Gastric
Range
Ref.
36% IHC
2/3+ 22%
FISH +
Safran (2006)
Brien (2000)
0-43%
(20% GC,
34% GEJC)
Rojo (2003)
Safran (2006)
Matsubara (2007)
Kang (2008)
Hecht (2008)
EGFR expression correlates with OS in EC (Kitagawa, 1996)
EGFR and TGF- expression correlate with OS in EC (Lihara,
1993) and GC (Yonemura, 1992)
HER2 gene amplification correlates with OS in EC (adeno)
(Brien, 2000)
EGFr Tyrosine Kinase Inhibitors:
Phase II, Adenocarcinoma
Gastric
Number Patients
% Response
Dragovich
(Erlotinib)
25
0%
Doi (Gefitinib)
75
1%
Ferry (Gefitinib)
27
11%
Janmaat (Gefitinib)
26
0%
Tew (Erlotinib)
17
0%
Dragovich
(Erlotinib)
43
Total: 7/113
9%
6%
GE Junction
Doi 1036 Proc ASCO 22, 2003; Ferry Clin Can Res 132:5869; 2007 Janmaat JCO 24: 1612; 2006;Tew GI ASCO 2005; Dragovich
JCO 24: 4922; 2006
EGFr Tyrosine Kinase Inhibitors:
Phase II, Squamous Carcinoma
Number
Patients
% Response
Janmaat
(Squamous)
Erlotonib
9
11%
Tew
(Squamous)
13
15%
Gefitinib
Janmaat JCO 24: 1612; 2006;Tew GI ASCO 2005;
EGFR/HER-2 inhibitors in GE cancer
Should KRAS gene status be revisited?
KRAS mutations
N
Ref.
Esophageal
9%
Janmaat (2006)
GE
3%
Gold (2008)
Gastric
7%
Gylling (2007)
 No major impact of KRAS gene status in patients with
esophageal and gastric cancer
Phase II CALGB 80403/ECOG 1206
Completed, ASCO 2010
Metastatic
Esophagogastric
Cancer
ECF +
Cetuximab
• Primary end point: Response rate
Irinotecan +
Cisplatin +
Cetuximab
FOLFOX +
Cetuximab
Rationale for targeting other receptors &
downstream signaling proteins
Insulin-like growth factor
receptor
– ILGF1R expression in
GC: 77%. Correlation
with EGFR/HER2
expression, intestinal
type and poor survival
(Matsubara, 2007)
– 9 EC cell lines sensitive
to picropodophyllin (PPI),
an IGF1R TKI (Bergqvist,
2007)
CpG Island Methylator
Phenotype (CIMP)
Tumor A:
Tumor B:
Tumor C:
Tumor D:
Tumor E:
Tumor F:
S9008 Progression-Free Survival
By Cimp
Treatment Arm
100%
N
Y
80%
N
16
6
Events
12
5
Median
in Months
48
16
60%
40%
20%
0%
0
24
48
72
Months After Registration
96
120
S9008 Progression-Free Survival
By Cimp
Observation Arm
100%
N
Y
80%
N
10
4
Events
8
4
Median
in Months
11
7
60%
40%
20%
0%
0
24
48
72
96
Months After Registration
120
144
HER2 Inhibitors:
Trastuzumab and Lapatinib
ASCO 2008, Abstr 4526, Bang, et al.
– Analysis of 2484 gastric cancer samples from the Ph III ToGA
trial
– 21.9% HER2 positivity
ASCO 2009, Abstr LBA 4509, ToGA Trial
–
–
–
–
–
Rand Ph III, HER2+ gastric cancer
5-FU/capecitabine + cisplatin +/- trastuzumab
RR 47.3 vs. 34.5%, OS 13.5 vs. 11.1 mo (p = 0.0048)
HR 0.74 (0.60-0.91)
Practice changing!!!
LOGIC Trial
– Rand Ph III, HER 2+ gastric cancer
– Capecitabine + oxaliplatin +/- lapatinib
Her2 gene expression associated with OS in
patients with metastatic gastric cancer treated
with lapatinib
Overall Survival
by Her2 Expression Level
100%
Above Median
Below Median
N
17
17
Events
12
15
Median in months
6
3
P = .005
80%
60%
40%
20%
0%
0
6
12
Months After Registration
18
24
Il-8 associated with PFS in patients
with metastatic gastric cancer treated
with lapatinib
Overall Survival
by IL8 T251A Genotype
100%
A/A
T/A
T/T
80%
N
14
18
10
Events
9
13
8
P = .04
Median in months
10
5
3
60%
40%
20%
0%
0
6
12
Months After Registration
18
24
ToGA trial design
Phase III, randomized, open-label, international, multicenter study
3807 patients screened1
810 HER2-positive (22.1%)
HER2-positive
advanced GC
(n=584)
5-FU or capecitabinea
+ cisplatin
(n=290)
R
5-FU or capecitabinea
+ cisplatin
+ trastuzumab
(n=294)
 Stratification factors
−
−
−
−
−
advanced vs metastatic
GC vs GEJ
measurable vs non-measurable
ECOG PS 0-1 vs 2
capecitabine vs 5-FU
aChosen
at investigator’s discretion
GEJ, gastroesophageal junction
1Bang
et al; Abstract 4556, ASCO 2009
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:
tumor response rate
Intent to treat
Patients
(%)
p=0.0017
p=0.0145
47.3%
41.8%
p=0.0599
32.1%
34.5%
5.4%
2.4%
CR
ORR= CR + PR
CR, complete response; PR, partial response
PR
ORR
F+C + trastuzumab
F+C
Nucleotide excision repair
Pre-clinical studies showing
ERCC1 to be a determinant of
platinum efficacy
90
80
70
% cell
viability
control
siRNA
60
50
40
30
cis (4 uM)
oxali (2 uM)
carbo (20 uM)
•Youn et al Oncogenic H-Ras Up-Regulates Expression of ERCC1 to Protect Cells from Platinum-Based
Anticancer Agents Cancer Res 2004:64, 4849-4857.
ERCC1 mRNA Levels vs Response in Gastric
Cancer Patients Receiving FP
20
ERCC1 Expression
16
12
8
4
0
Response
No Response
ERCC1: p=.004 by Kruskal-Wallis test.
Metzger R, et al. J Clin Oncol. 1998;16(1):309-316.
ERCC1 Thresholds and Increased Benefit
from Platin Therapy (Low ERCC1)
Clinical Study
NSCLC: GILT (Platin
Doublets)
NSCLC: MADeIT (Platin
Doublets)
CRC: FOLFOX
CRC: FOLFOX Validation
Gastric: 5-FU/Cis
Gastric: FOLFOX
Gastric: FOLFOX
Gastric: Platin
(S-1/Oxaliplatin)
ERCC1 Threshold for
Platin Sensitivity:
Response Genetics
Scale
Percent
Patients
with Low
ERCC1
Benefit
Ref
ERCC1<1.7
53
RR=53%
Cobo et al JCO 2007
50
RR=44%,
Increased
Survival
Sim et al JCO 2007
80
Increased
Survival
and
Response
Shirota et al JCO 2001
80
Increased
Survival
Lenz et al ASCO 2008
50
Increased
Survival
Metzger et al JCO 1998
64
Increased
Survival
J Wei et al ASCO 2007
80
Increased
Survival
J Wei et al British J of
Cancer 2008
67
Increased
RR and
Survival
Matsubara et al British J of
Cancer 2008
ERCC1<1.44
ERCC1<1.7
ERCC1<1.7
ERCC1<1.46
ERCC1<1.79
ERCC1<2.2
ERCC1<1.85
ERCC-1 gene expression associated with
overall survival in 76 patients with gastric
cancer treated with 5-FU/oxaliplatin
Wei Jia et al Br j Cancer 2008
SWOG Prospective Trial Proposed
ERCC1 of FOLFOX versus CPT11/Taxotere
PI: Iqbal
R
A
N
D
O
M
A
S
S
I
G
N
M
E
N
T
High ERCC1
CPT11/Taxotere
Genotypic
Arm
ERCC1
Selection
n=99 Endpoints feasibility and increase of PFS
Her2+ receive trastuzumab in both arms
Future Directions: Tailoring of
Therapy
Molecular Signatures for Targeted
and Cytotoxic Therapies
– Her2
– ERCC-1
Identification of critical pathways in
Gastric Cancer (IGFR, cmet, HSP90)
to introduce novel therapies
Identification of Predictive and
Prognostic Markers
– Tumor, Host, Environment
Sharon Carpenter Laboratory