New Agents in the Treatment of New Agents in the Treatment of Esophageal and Gastric CancersEsophageal and Gastric Cancers

Heinz-Josef Lenz, MDHeinz-Josef Lenz, MDProfessor of Medicine Professor of Medicine

USC/Norris Comprehensive Cancer CenterUSC/Norris Comprehensive Cancer CenterUniversity of Southern California University of Southern California

Keck School of MedicineKeck School of MedicineLos Angeles, CALos Angeles, CA

Can Gastric Cancer Can Gastric Cancer be the next GIST?be the next GIST?

Intestinal versus Intestinal versus Diffuse? Diffuse?

Critical PathwaysCritical Pathways

Her2Her2

VEGF/VEGFR VEGF/VEGFR

EGFR EGFR

IGFR1IGFR1

C-met C-met

PI3K/AKT PI3K/AKT

E-CadherinE-Cadherin

Frequent Genetic and Molecular Frequent Genetic and Molecular Abnormalities In Sporadic Gastric CancerAbnormalities In Sporadic Gastric Cancer

E-cadherin E-cadherin In 92%, down regulation or mutationIn 92%, down regulation or mutationFibroblast growth factorFibroblast growth factor 70% expression, esp. undifferentiated 70% expression, esp. undifferentiated

tumorstumorsTelomerase expressionTelomerase expression 85% of advanced tumors, poor 85% of advanced tumors, poor

prognosisprognosisVEGF/VEGFRVEGF/VEGFR about 50% overexpression poor about 50% overexpression poor

prognosisprognosisMET, c-metMET, c-met Over-expression in approximately 50%,Over-expression in approximately 50%, a marker for poor prognosisa marker for poor prognosisEpidermal Growth Factor (EGF)Epidermal Growth Factor (EGF) Over-expression in over 50% of Over-expression in over 50% of

advanced advanced cancerscancersPI3K Mutations PI3K Mutations 35% have PI3K mutations 35% have PI3K mutations HER2 over expression:HER2 over expression: 10-25% overexpression (FISH) 10-25% overexpression (FISH)

intestinal intestinal typetype

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?)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 2 4 6 8 10 12 14 16

Years Since Diagnosis of Resectable Gastric Cancer

Estim

ate

d

Re

cu

rre

nce

-Fre

e P

rob

ab

ility

White N=63

African American N= 1

Asian N=28

Hispanic N= 45

P for wald test = 0.026

Targeted TherapiesTargeted Therapies

Conventional, cytotoxic chemotherapy has Conventional, cytotoxic chemotherapy has limited benefitlimited benefit

Targeted agents: attempt to block specific Targeted agents: attempt to block specific tumor growth pathwaystumor growth pathways– Monoclonal antibodiesMonoclonal antibodies– Tyrosine kinase inhibitorsTyrosine kinase inhibitors– Soluble receptors/Ligands to growth factorsSoluble receptors/Ligands to growth factors– Inhibition of pathways involved in protein Inhibition of pathways involved in protein

synthesis and degradationsynthesis and degradation

Targeted Agents in Phase II Targeted Agents in Phase II

Phase II Phase II StudyStudy RegimenRegimen NN

Response Response (%)(%) TTP / OSTTP / OS

Bang et al Bang et al 20072007 SunitinibSunitinib 3838 3%3% NSNS

Muro 2008Muro 2008 RAD001RAD001 2424 0%0% NSNS

Gold 2008Gold 2008 CetuximabCetuximab 5555 2%2% 1.8 mos / 1.8 mos / 4 mos4 mos

Hecht 2008Hecht 2008

Iqbal 2007Iqbal 2007LapatinibLapatinib

2121

4747

0%0%

7%7%

----

2 mos/ 5 2 mos/ 5 mosmos

Advanced Gastric Cancer:Advanced Gastric Cancer:Targeted AgentsTargeted Agents

Phase II Phase II StudyStudy RegimenRegimen NN RR (%)RR (%) TTP / OSTTP / OS

Lordick et Lordick et al. 2006al. 200644 CetuximabCetuximab + + FUFOXFUFOX 2828 56%56% 8.1 / 28.2 8.1 / 28.2

mosmos

Di Fabio et Di Fabio et al. 2006al. 200622

CetuximabCetuximab + + FOLFIRIFOLFIRI 2727 52%52%

Pinto et al. Pinto et al. 2006200633

CetuximabCetuximab + + FOLFIRIFOLFIRI 2525 56%56% 8 / 16 mos8 / 16 mos

Jhawer 2009Jhawer 2009 Bev + Modified DCFBev + Modified DCF 3636 64%64% 12 mos / 12 mos / 16mos16mos

Shah et al. Shah et al. 2006200611

BevBev + + CisplatinCisplatin + + IrinotecanIrinotecan 3434 65%65% 8.3 / 12.3 8.3 / 12.3

mosmos

Enzinger et Enzinger et al. 2008al. 2008

Bev + Bev + Irino/Docet/CisplatinIrino/Docet/Cisplatin 2222 68%68% NSNS

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 IIITargeted Agents in Phase III(EGFR/VEGF/Her2)(EGFR/VEGF/Her2)

REAL 3:REAL 3: ECX + / - ECX + / - PanitumumabPanitumumab (U.K.)(U.K.)

EXPAND:EXPAND:Cape-Cis + / Cape-Cis + / CetuximabCetuximabAVAGAST:AVAGAST: Cape-Cisplatin + / - Cape-Cisplatin + / -

BevacizumabBevacizumabLOGIC:LOGIC: Cape-Ox + / - Cape-Ox + / - LapatinibLapatinib

(HER2+)(HER2+)

TOGA:TOGA: HER+HER+Cape-Cisplatin + / - Cape-Cisplatin + / - TrastuzumabTrastuzumab

Angiogenesis in GC & ECAngiogenesis in GC & EC

VEGF-A expressed in 51% GC specimens w/o VEGF-A expressed in 51% GC specimens w/o stage correlation (stage correlation (Feng, 2002) but w/ OS Feng, 2002) but w/ OS correlation (Maeda,1996) correlation (Maeda,1996) Serum VEGF-A correlated with OS in resected Serum VEGF-A correlated with OS in resected GC (Yoshikawa, 2000; Karayiannakis, 2002)GC (Yoshikawa, 2000; Karayiannakis, 2002)Serum VEGF-A increased in SCC EC and Serum VEGF-A increased in SCC EC and correlated with stage and response to CT/RT correlated with stage and response to CT/RT ((Shimada, 2001Shimada, 2001))VEGF-D & VEGFR-3 expression in GC correlated VEGF-D & VEGFR-3 expression in GC correlated with poor OS (all pts & pN+) (with poor OS (all pts & pN+) (Jüttner, 2006Jüttner, 2006))Tight correlation between VEGF and EGFR Tight correlation between VEGF and EGFR pathways in GC (Akagi, 2003)pathways in GC (Akagi, 2003)

VEGFD & VEGFR-3 in GCVEGFD & VEGFR-3 in GC

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

Total (n=91) pN+ (n=63)

CX

CR IL-1

R

Tumor associated angiogenesis

HIF1 NFkbARNTHIf1

NRP1V

EG

FR

Tumor cellDNA

EG

FR

VEGF

Endothelial cell

HypoxiaEGF

IL-8 IL-1 β

PA

R-

4 PA

R-

1

Endostatin

Platelet1-granules2-granules

Thrombin Thrombin

Overall Survival among different IL-8 Polymorphisms

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 2 4 6 8 10 12 14 16

Years Since Diagnosis of Resectable Gastric Cancer

Estim

ate

d

Re

cu

rre

nce

-Fre

e P

rob

ab

ility

Il-8 -251 T>A (rs4073)

T/T (n=50)

T/A (n=66)

Log-rank test p value <0.0001

A/A (n=21)

Lurje et al Annals of Oncology 2009

Overall Survival among different PAR-1 Polymorphisms

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 2 4 6 8 10 12 14 16

Years Since Diagnosis of Resectable Gastric Cancer

Est

imat

ed R

ecur

renc

e-F

ree

Pro

babi

lity

PAR-1 -506 ins/del (rs11267092)

Del/del (n=91)

Ins/del (n=34)

Ins/Ins (n=11)

Log-rank p value < 0.0001

Lurje et al Annals of Oncology 2009

Overall Survival among different Endostatin Polymorphisms

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 2 4 6 8 10 12 14 16

Years Since Diagnosis of Resectable Gastric Cancer

Est

ima

ted

Re

curr

en

ce-F

ree

Pro

ba

bili

ty

G/G (n=115)

G/A (n=18)

A/A (n=4)

Endostatin +4349 G>A (rs12483377)

Log-rank p value < 0.0001

Lurje et al Annals of Oncology 2009

EGF and PAR1 associated with Time to Tumor Recurrence in Esophageal Cancers (n=237)

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

0 2 4 6 8 10 12 14

Estim

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ecu

rre

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-Fre

e P

rob

ab

ility

Years Since Surgery of Localized Esophageal Adenocarcinoma

EGF +61 A>G & PAR-1 -506 ins/del Adjusted P value < 0.001

EGF +61 A/G or G/G and PAR-1 -506 del/del (n=95)

EGF +61 A/A and PAR-1 -506 ins/del or ins/ins (n=34)

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)

Anti VEGF (Bevacizumab) Anti VEGF (Bevacizumab) Shah, et al. JCO 2007Shah, et al. JCO 2007– Phase II met gastric or GEJ adenocaPhase II met gastric or GEJ adenoca– First line therapy – cisplatin/irinotecan/bevFirst line therapy – cisplatin/irinotecan/bev– N = 47, 34 with measurable diseaseN = 47, 34 with measurable disease– RR 65%, OS 12.3 moRR 65%, OS 12.3 mo

Enzinger, et al. ASCO 2008, Abstr 4552Enzinger, et al. ASCO 2008, Abstr 4552– Phase II met esophagogastric cancerPhase II met esophagogastric cancer– First line therapy – docetaxel/cisplatin/irinotecanFirst line therapy – docetaxel/cisplatin/irinotecan– N = 32N = 32– RR 63%RR 63%

Jhawer, et al. GI ASCO 2009, Abstr 10Jhawer, et al. GI ASCO 2009, Abstr 10– mDCF plus bevacizumabmDCF plus bevacizumab– N = 45N = 45– RR 67%, PFS 12 mo, OS 16.2 moRR 67%, PFS 12 mo, OS 16.2 mo

AVAGAST study accrual completedAVAGAST study accrual completed– XP +/- bevacizumabXP +/- bevacizumab– Following toxicities carefully – thrombosis, perforationFollowing toxicities carefully – thrombosis, perforation

Anti-VEGFR (Sorafenib)Anti-VEGFR (Sorafenib)

ASCO 2008, Abstr 4535, Sun, et al.ASCO 2008, Abstr 4535, Sun, et al.

ECOG 5203ECOG 5203

Phase II study of sorafenib, docetaxel, Phase II study of sorafenib, docetaxel, cisplatincisplatin

44 pts with advanced gastric or GE 44 pts with advanced gastric or GE junctional cancersjunctional cancers

RR 38.6%, PFS 5.8 mo, OS 14.9 moRR 38.6%, PFS 5.8 mo, OS 14.9 mo

Meyerhardt JA, Mayer RJ. N Engl J Med. 2005;352:476-487; Venook A. Oncologist. 2005;10:250-261.

Survival (anti-

apoptosis)

Gene transcriptionCell-cycle progression

MYC

MYC Cyclin D1

FOSJUN

PP

Cyclin D1

AngiogenesisInvasion andmetastasis

Chemotherapy/radiotherapy resistance

Proliferation/maturation

MAPK

MEK

RAS RAFSOS

GRB2

PTEN AKTSTAT

P13KpY

pY

Ligand: AREG, EREG

EGFR-TKTarget for EGFT-TK inhibitor

pY

EGF Receptor: A Rational Target for CRC Therapy

EGFR/HER-2 Expression in GE EGFR/HER-2 Expression in GE cancercancer

EGFR expression

Range Ref.

Esophageal 43-89% Herbst (2002)

Gastric 50-63%Rojo (2003)

Matsubara (2007)

HER-2/neu expression

Range Ref.

Esophageal36% IHC 2/3+ 22% FISH +

Safran (2006) Brien (2000)

Gastric0-43%

(20% GC, 34% GEJC)

Rojo (2003) Safran (2006)

Matsubara (2007) Kang (2008) Hecht (2008)

EGFR expression correlates with OS in EC (Kitagawa, 1996)EGFR expression correlates with OS in EC (Kitagawa, 1996)

EGFR and TGF-EGFR and TGF- expression correlate with OS in EC (Lihara, expression correlate with OS in EC (Lihara, 1993) and GC (Yonemura, 1992)1993) and GC (Yonemura, 1992)

HER2HER2 gene amplification correlates with OS in EC (adeno) gene amplification correlates with OS in EC (adeno) (Brien, 2000) (Brien, 2000)

EGFr Tyrosine Kinase Inhibitors: EGFr Tyrosine Kinase Inhibitors: Phase II, AdenocarcinomaPhase II, Adenocarcinoma

Gastric Gastric Number PatientsNumber Patients % Response% Response

Dragovich Dragovich (Erlotinib)(Erlotinib)

2525 0%0%

Doi (Gefitinib)Doi (Gefitinib) 7575 1%1%

GE JunctionGE Junction

Ferry (Gefitinib)Ferry (Gefitinib) 2727 11%11%

Janmaat (Gefitinib)Janmaat (Gefitinib) 2626 0%0%

Tew (Erlotinib)Tew (Erlotinib) 1717 0%0%

DragovichDragovich

(Erlotinib)(Erlotinib)

4343

Total: 7/113Total: 7/113

9%9%

6%6%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: EGFr Tyrosine Kinase Inhibitors: Phase II, Squamous CarcinomaPhase II, Squamous Carcinoma

Number Number PatientsPatients

% Response% Response

GefitinibGefitinib

JanmaatJanmaat

(Squamous)(Squamous)

99 11%11%

ErlotonibErlotonib

TewTew

(Squamous)(Squamous)

1313 15%15%

Janmaat JCO 24: 1612; 2006;Tew GI ASCO 2005;

EGFR/HER-2 inhibitors in GE cancerEGFR/HER-2 inhibitors in GE cancerShould Should KRASKRAS gene status be revisited? 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 1206Phase II CALGB 80403/ECOG 1206Completed, ASCO 2010Completed, ASCO 2010

Metastatic Esophagogastric

Cancer

Irinotecan +Cisplatin +Cetuximab

ECF +Cetuximab

FOLFOX +Cetuximab

• Primary end point: Response rate

Rationale for targeting other receptors & Rationale for targeting other receptors & downstream signaling proteinsdownstream signaling proteins

Insulin-like growth factor Insulin-like growth factor receptorreceptor– ILGF1R expression in GC: ILGF1R expression in GC:

77%. Correlation with 77%. Correlation with EGFR/HER2 expression, EGFR/HER2 expression, intestinal type and poor intestinal type and poor survival (Matsubara, 2007)survival (Matsubara, 2007)

– 9 EC cell lines sensitive to 9 EC cell lines sensitive to picropodophyllin (PPI), an picropodophyllin (PPI), an IGF1R TKI (Bergqvist, 2007)IGF1R TKI (Bergqvist, 2007)

CpG Island Methylator CpG Island Methylator Phenotype (CIMP)Phenotype (CIMP)

Tumor A:

Tumor B:

Tumor C:

Tumor D:

Tumor E:

Tumor F:

S9008 Progression-Free SurvivalBy Cimp

Treatment Arm

0%

20%

40%

60%

80%

100%

0 24 48 72 96 120Months After Registration

NY

N166

Events125

Medianin Months

4816

S9008 Progression-Free SurvivalBy Cimp

Observation Arm

0%

20%

40%

60%

80%

100%

0 24 48 72 96 120 144Months After Registration

NY

N104

Events84

Medianin Months

117

HER2 Inhibitors:HER2 Inhibitors:Trastuzumab and LapatinibTrastuzumab and Lapatinib

ASCO 2008, Abstr 4526, Bang, et al.ASCO 2008, Abstr 4526, Bang, et al.– Analysis of 2484 gastric cancer samples from the Ph III ToGA Analysis of 2484 gastric cancer samples from the Ph III ToGA

trialtrial– 21.9% HER2 positivity21.9% HER2 positivity

ASCO 2009, Abstr LBA 4509, ToGA TrialASCO 2009, Abstr LBA 4509, ToGA Trial– Rand Ph III, HER2+ gastric cancerRand Ph III, HER2+ gastric cancer– 5-FU/capecitabine + cisplatin +/- trastuzumab5-FU/capecitabine + cisplatin +/- trastuzumab– RR 47.3 vs. 34.5%, OS 13.5 vs. 11.1 mo (p = 0.0048)RR 47.3 vs. 34.5%, OS 13.5 vs. 11.1 mo (p = 0.0048)– HR 0.74 (0.60-0.91)HR 0.74 (0.60-0.91)– Practice changing!!!Practice changing!!!

LOGIC TrialLOGIC Trial– Rand Ph III, HER 2+ gastric cancerRand Ph III, HER 2+ gastric cancer– Capecitabine + oxaliplatin +/- lapatinibCapecitabine + oxaliplatin +/- lapatinib

Her2 gene expression associated with OS in patients with metastatic gastric cancer treated

with lapatinib

Overall Survivalby Her2 Expression Level

0%

20%

40%

60%

80%

100%

0 6 12 18 24Months After Registration

Above MedianBelow Median

N1717

Events1215

Median in months63

P = .005

Il-8 associated with PFS in patients with metastatic gastric cancer treated

with lapatinibOverall Survival

by IL8 T 251A Genotype

0%

20%

40%

60%

80%

100%

0 6 12 18 24Months After Registration

A/AT/AT/T

N141810

Events9

138

Median in months1053

P = .04

ToGA trial designToGA trial design

HER2-positiveadvanced GC

(n=584)

5-FU or capecitabinea + cisplatin(n=290)

R

aChosen at investigator’s discretion GEJ, gastroesophageal junction

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

Phase III, randomized, open-label, international, multicenter study

1Bang et al; Abstract 4556, ASCO 2009

3807 patients screened1

810 HER2-positive (22.1%)

Primary end point: OSPrimary 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: Secondary end point: tumor response ratetumor response rate

2.4%5.4%

32.1%

41.8%

34.5%

47.3%

Intent to treat

ORR= CR + PRCR, complete response; PR, partial response

p=0.0599

p=0.0145

F+C + trastuzumab

F+C

p=0.0017Patients (%)Patients (%)

CRCR PRPR ORRORR

Nucleotide excision repairNucleotide excision repair

30

40

50

60

70

80

90

% cell viability

cis (4 uM) oxali (2 uM) carbo (20 uM)

control

siRNA

Pre-clinical studies showing Pre-clinical studies showing ERCC1 to be a determinant of ERCC1 to be a determinant of

platinum efficacyplatinum efficacy

•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 ERCC1 mRNA Levels vs Response in Gastric Cancer Patients Receiving FPCancer Patients Receiving FP

Metzger R, et al. J Clin Oncol. 1998;16(1):309-316.

ERCC1: p=.004 by Kruskal-Wallis test.

ER

CC

1 E

xpre

ssio

n

20

16

12

8

4

0

Response No Response

Clinical Study

ERCC1 Threshold for Platin Sensitivity:

Response Genetics Scale

Percent Patients with Low ERCC1 Benefit Ref

NSCLC: GILT (Platin Doublets) ERCC1<1.7 53 RR=53% Cobo et al JCO 2007

NSCLC: MADeIT (Platin Doublets) ERCC1<1.44 50

RR=44%, Increased Survival Sim et al JCO 2007

CRC: FOLFOX ERCC1<1.7 80

Increased Survival

and Response Shirota et al JCO 2001

CRC: FOLFOX Validation ERCC1<1.7 80Increased Survival Lenz et al ASCO 2008

Gastric: 5-FU/Cis ERCC1<1.46 50Increased Survival Metzger et al JCO 1998

Gastric: FOLFOX ERCC1<1.79 64Increased Survival J Wei et al ASCO 2007

Gastric: FOLFOX ERCC1<2.2 80Increased Survival

J Wei et al British J of Cancer 2008

Gastric: Platin (S-1/Oxaliplatin) ERCC1<1.85 67

Increased RR and Survival

Matsubara et al British J of Cancer 2008

ERCC1 Thresholds and Increased Benefit from Platin Therapy (Low ERCC1)

ERCC-1 gene expression associated with ERCC-1 gene expression associated with overall survival in 76 patients with gastric overall survival in 76 patients with gastric

cancer treated with 5-FU/oxaliplatincancer treated with 5-FU/oxaliplatin

Wei Jia et al Br j Cancer 2008

n=99 Endpoints feasibility and increase of PFS

SWOG Prospective Trial Proposed ERCC1 of FOLFOX versus CPT11/Taxotere

PI: Iqbal

Genotypic ArmERCC1 Selection

High ERCC1 CPT11/Taxotere

ASSIGNMENT

RANDOM

Her2+ receive trastuzumab in both arms

Future Directions: Tailoring of Future Directions: Tailoring of TherapyTherapy

Molecular Signatures for Targeted Molecular Signatures for Targeted and Cytotoxic Therapiesand Cytotoxic Therapies– Her2Her2– ERCC-1ERCC-1

Identification of critical pathways in Identification of critical pathways in Gastric Cancer (IGFR, cmet, HSP90) Gastric Cancer (IGFR, cmet, HSP90) to introduce novel therapiesto introduce novel therapiesIdentification of Predictive and Identification of Predictive and Prognostic Markers Prognostic Markers – Tumor, Host, EnvironmentTumor, Host, Environment

Sharon Carpenter Laboratory