Overview of Targeted Therapies Overview of Targeted Therapies for Esophageal and Gastric for Esophageal and Gastric

CancersCancers

Johanna Bendell, MDJohanna Bendell, MDDirector, GI Oncology ResearchDirector, GI Oncology Research

Associate Director, Drug Development UnitAssociate Director, Drug Development UnitSarah Cannon Research InstituteSarah Cannon Research Institute

Nashville, TNNashville, TN

Basic NumbersBasic Numbers

Esophageal cancerEsophageal cancer– 17,460 new cases in the U. S. 201217,460 new cases in the U. S. 2012– 15,070 deaths15,070 deaths

Gastric cancerGastric cancer– 21,320 new cases in the U. S. 201221,320 new cases in the U. S. 2012– 10,540 deaths10,540 deaths

5 year survival rate <5% for patients with 5 year survival rate <5% for patients with metastatic diseasemetastatic disease

Why targeted therapy?Why targeted therapy?

Going after what makes the Going after what makes the cancer a cancercancer a cancerOur drug development is Our drug development is catching up with the labcatching up with the labIdentification of certain pathways Identification of certain pathways that are key in cancer that are key in cancer development and survivaldevelopment and survivalWe are still learningWe are still learning– One set of targets does not One set of targets does not

fit allfit all– All of the pathways talk to All of the pathways talk to

each othereach other– Side effect profiles are Side effect profiles are

different, but can be just as different, but can be just as toxic to the patienttoxic to the patient

– Chronic cancer treatment?Chronic cancer treatment?

Can Targeted Therapies Can Targeted Therapies Improve Outcomes?Improve Outcomes?

Pathways with targeted therapies where Pathways with targeted therapies where we have data or are currently under later we have data or are currently under later stage studystage study– HER2HER2– VEGFVEGF– EGFEGF– mTORmTOR– MetMet

ToGA trial – HER2 + gastric cancer

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

3807 patients screened1

810 HER2-positive (22.1%)

Bang, Y., et al. Lancet, 2010Bang, Y., et al. Lancet, 2010

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, trastuzumabVan Cutsem ASCO 2009

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

Van Cutsem ASCO 2009

Bang, Y. Lancet, 2010Bang, Y. Lancet, 2010

ToGA: Overall Survival (FISH+ or IHC3+)

ToGA Survival: IHC 2+/FISH+ or IHC 3+(Post-hoc Exploratory Analysis)

Bang, Y. Lancet, 2010Bang, Y. Lancet, 2010

Secondary end point: tumor 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

Van Cutsem ASCO 2009

LOGiC Trial: Gastric CancerRandomized Phase III

Stratification₋Region of the world₋Prior neoadjuvant and/or adjuvant chemotherapy

Adenocarcinoma of the stomach, GEJ,

or esophagus

HER2 positive (FISH+, IHC 3+)

No previous treatment for

advanced disease

N = 545

CapOx (as above) +

Placebo daily

CapOx (Oxaliplatin 130 mg/m2 IV Day 1 for up to 8 cycles + Capecitabine 850 mg/m2

BID Days 1-14)+

Lapatinib 1250 PO daily

RANDOMIZE

TYTAN Trial: Second Line Gastric Cancer

Randomized Phase III

Stratification₋Prior gastrectomy₋Prior anti HER2 therapy

Adenocarcinoma of the stomach, GEJ,

or esophagus

HER2 positive

Second Line

China, Korea, Japan, Taiwan

N = 261

Paclitaxel 80 mg/m2 IV D1, 8, 15 of 28 day cycle

N = 131

Paclitaxel 80 mg/m2 IV D1, 8, 15 of 28 day cycle

+Lapatinib 1500 PO daily

N = 130

RANDOMIZE

Bang GI ASCO 2013

TYTANTYTAN

ITT PopulationITT PopulationT + L T

OS (mo) 11.0HR 0.84

[0.64,1.11]

8.9

PFS (mo) 5.4HR 0.85

[0.63,1.13]

4.4

HER2 IHC 3+HER2 IHC 3+T + L T

OS (mo) 14.0HR 0.59

[0.37,0.93]

7.6

PFS (mo) 5.6HR 0.54

[0.33,0.90]

4.2

Bang GI ASCO 2013

T-DM1 structureT-DM1 structureT-DM1 is a novel ADC

Average drug:antibody ratio 3.5:1≅

Highly potent cytotoxic agent

Monoclonal antibody: Trastuzumab

Systemically stable

Target expression: HER2

Cytotoxic agent: DM1

Linker: MCC

T-DM1

Trastuzumab

* Dose selection based on PK/safety/efficacy ** Investigator’s choice between paclitaxel 80 mg/m2/wk and docetaxel 75 mg/m2 q 3 wk

• Phase II: 3 arm; 2:2:1 randomization; endpoints: safety, PK, PFS, ORR; n=100• Phase II: 3 arm; 2:2:1 randomization; endpoints: safety, PK, PFS, ORR; n=100

2L Her2 positive mGCPS: 0 -1IHC 3+ or IHC 2+/ISH+Prior Ctx + prior HER2 N=412

Chemotherapy**

T-DM1 2.4 mg/kg/wk

T-DM1 3.6 mg/kg q3 wk

Phase IIn=100

22

22

11

Trastuzumab Emtansine: Phase II Study of 2L treatment for HER2+ Metastatic Gastric

Cancer

Stratified by: region, PS, prior gastrectomy, prior HER2-targeted tx

HER2 blockade for gastric cancers

TOGA trial shows survival benefit using trastuzumab for patients with advanced gastric cancer– We should be testing patients early– What is the definition of HER2 positivity?

IHC 3+ and/or FISH +

But do FISH+ with IHC 0/1+ benefit?

What are the next steps (follow breast cancer)?– Lapatinib– TDM-1– Trastuzumab plus lapatinib?– Pertuzumab combinations?– Neoadjuvant use?

AVAGAST: AVAGAST: A Randomized Double-Blind A Randomized Double-Blind

Placebo- Controlled Phase III Placebo- Controlled Phase III StudyStudy

Starting dose of bev/placebo: 30 minutes, subsequent doses: 15 minutes

Capecitabine*/Cisplatin (XP)

+ Placebo q3w

Capecitabine*/Cisplatin (XP)

+ Bevacizumab q3w

Locally advanced or metastatic gastric cancer

R

*5-FU also allowed if cape contraindicated

Cape 1000 mg/m2 oral bid, d1–14, 1-week rest

Cisplatin 80 mg/m2 d1

Bevacizumab 7.5 mg/kg d1

Maximum of 6 cycles of cisplatin

Cape and bevacizumab/placebo until PD

Stratification factors:

1. Geographic region

2. Fluoropirimidine backbone

3. Disease status

Kang ASCO 2010

Overall SurvivalOverall Survival

387387

343355

271291

204232

146178

98104

1519

XP + PlaceboXP + Bev

Number at risk

5450

00

XP + Placebo

XP + Bev

HR = 0.87

95% CI 0.73–1.03

p = 0.1002

Survival rate

3 9 15 18 21 240

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

6 12

Study month

10.1

12.1

Kang ASCO 2010

Progression-Free SurvivalProgression-Free Survival

387387

279306

145201

86123

5571

3238

33

1511

00

XP + PlaceboXP + Bev

Number at risk

XP + Placebo

XP + Bev

HR = 0.80

95% CI 0.68–0.93

p = 0.0037

Progression-free survival rate

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

3 9 15 18 21 240 6 12

5.3

6.7

Study month

Kang ASCO 2010

Best Overall Response: Best Overall Response: Measurable Measurable

Disease PopulationDisease Population

XP + PlaceboN=387

XP + BevN=387

Patients with measurable disease 297 311

Overall response 111 (37%) 143 (46%)

95% CI 31.9–43.1 40.3–51.7

Difference 9%

95% CI 0.6–16.6

P value (2) 0.0315

Complete response 3 (1%) 5 (2%)

Partial response 108 (36%) 138 (44%)

Stable disease 90 (30%) 93 (30%)

Progressive disease 63 (21%) 44 (14%)

Not assessable 33 (11%) 31 (10%)

Kang ASCO 2010

Regional Differences in EfficacyRegional Differences in Efficacy

RegionXP + PlaceboMedian, mo

XP + BevMedian, mo

Delta, mo

Hazard Ratio 95% CI

OS Asia 12.1 13.9 1.8 0.97 0.75–1.25

Europe 8.6 11.1 2.5 0.85 0.63–1.14

America 6.8 11.5 4.7 0.63 0.43–0.94

PFS Asia 5.6 6.7 1.1 0.92 0.74–1.14

Europe 4.4 6.9 2.5 0.71 0.54–0.93

America 4.4 5.9 1.5 0.65 0.46–0.93

Kang ASCO 2010

Patient Characteristics by Patient Characteristics by RegionRegion

% of patients Asia Europe Pan-America

Age <65 72 68 77

≥65 28 32 23

ECOG PS 0–1 97 91 96

2 3* 9 4

Primary site Stomach 94 78 84

GEJ 6 22 16

Extent of disease Metastatic 99 95 92

Locally advanced 1 5 8

Prior gastrectomy yes 32 23 27

no 68 77 73

Measurable lesion yes 73 88 77

no 27 12 23

Liver metastasis yes 27 37 42

no 73 63 58

*1 additional patient had an ECOG PS of 4Kang ASCO 2010

Gastric cancer typesGastric cancer types

Intestinal typeIntestinal type– Well-differentiatedWell-differentiated– Related to gastritis, gastric atrophy, intestinal metaplasiaRelated to gastritis, gastric atrophy, intestinal metaplasia– More common in in older men, East Asia, Eastern Europe, More common in in older men, East Asia, Eastern Europe,

Central and South AmericaCentral and South America– Decreasing incidenceDecreasing incidence

Diffuse typeDiffuse type– UndifferentiatedUndifferentiated– Related to pangastritisRelated to pangastritis– More common in younger patients, M = FMore common in younger patients, M = F– Increasing incidenceIncreasing incidence– Worse prognosisWorse prognosis

Gastric cancer by locationGastric cancer by locationGastric cardia tumorsGastric cardia tumors– Rapidly increasing incidence in the WestRapidly increasing incidence in the West– Correlates with the increasing incidence of esophageal Correlates with the increasing incidence of esophageal

and GE junction adenocarcinomaand GE junction adenocarcinoma– Poorer prognosis than distal stomachPoorer prognosis than distal stomach– Shares demographic and pathologic features of Barrett’s-Shares demographic and pathologic features of Barrett’s-

associated esophageal cancerassociated esophageal cancer– Not associated with atrophic gastritis and intestinal Not associated with atrophic gastritis and intestinal

metaplasiametaplasia– Different genetic polymorphisms seen between cardia and Different genetic polymorphisms seen between cardia and

non-cardia tumors, suggesting they have different biologynon-cardia tumors, suggesting they have different biology

El-Serag 2002, Powell 1992

AVAGAST ConclusionsAVAGAST Conclusions

Overall the study was negative for survival Overall the study was negative for survival benefitbenefit

However, looking at the Americas patients However, looking at the Americas patients there appears to be a benefit to using there appears to be a benefit to using bevacizumabbevacizumab

Highlights the difference in gastric cancers Highlights the difference in gastric cancers in different parts of the world – different in different parts of the world – different epidemiology, different survivals, different epidemiology, different survivals, different responses to treatmentresponses to treatment

REGARD: Randomized Phase REGARD: Randomized Phase III Trial 2III Trial 2ndnd Line Ramicirumab Line Ramicirumab

vs. Placebovs. Placebo

1:1

Second line metastatic gastric

and GEJ adenocarcinoma

R

Ramucirumab IVq 2 weeks

Placeboq 2 weeks

26

Primary EP: OSN = 355

Press release 10/12: met primary endpointof OS and secondary endpoint of PFSPress release 1/23/13: OS 5.2 vs. 2.6 moPFS 2.1 vs. 1.3 mo

RAINBOW: Randomized Phase RAINBOW: Randomized Phase III Trial 2III Trial 2ndnd Line Paclitaxel +/- Line Paclitaxel +/-

RamicirumabRamicirumab

1:1

Second line metastatic gastric

and GEJ adenocarcinoma

R

Paclitaxel 80 mg/m2 d1, 8, 15 +

Ramucirumab IVq 2 weeks

Paclitaxel 80 mg/m2 d1, 8, 15 +

Placeboq 2 weeks

27

Primary EP: OSN = 665

Randomized Phase II Trial 1Randomized Phase II Trial 1stst Line FOLFOX +/- RamucirumabLine FOLFOX +/- Ramucirumab

1:1First line metastatic

esophagogastric adenocarcinoma

R

Ramucirumab IV+ FOLFOX q 2 weeks

Placebo + FOLFOXq 2 weeks

28

Primary EP: PFS

REAL-3REAL-3

Waddell ASCO 2012

Waddell ASCO 2012

Waddell ASCO 2012

Waddell ASCO 2012

Waddell ASCO 2012

Waddell ASCO 2012

EXPAND: Randomized Phase III EXPAND: Randomized Phase III Trial 1Trial 1stst Line Capecitabine/Cisplatin Line Capecitabine/Cisplatin

+/- Cetuximab+/- Cetuximab

1:1

First line metastatic gastric and GEJ adenocarcinoma

N = 904R

Cetuximab IV+

Capecitabine/Cisplatin q 3 weeks

N = 455

Capecitabine/Cisplatinq 3 weeks

N = 449

35

Primary EP: PFSLordick ESMO 2012

EXPANDEXPAND

Lordick ESMO 2012Lordick ESMO 2012

Cape/Cis + Cetuximab(n = 455)

Cape/Cis (n = 449)

PFS (months) 4.45.6

HR 1.091 [0.92,1.29]

P = 0.316

OS (months) 9.4 10.7

RR 29% 30%

Gefitinib in advanced esophageal Gefitinib in advanced esophageal cancer progressing after cancer progressing after

chemotherapychemotherapy

Patients progressing following

chemotherapy

Planned: 18 months to recruit 450 patientsPrimary endpoint: Overall survival - powered to detect an increase in 1 year survival from 10 to 18%, 82.5% power, 5% significance level.Secondary endpoints: PFS, toxicity & PROs

Gefitinib 500mg od(n=225)

Gefitinib 500mg od(n=225)

Placebo (n=225)Placebo (n=225)

Simple randomisation

• Multi-centre• Double-blind – patients,

clinicians and trial office staff blinded to trial treatment

• Treated until progression

• Regular CT scans

Overall SurvivalOverall Survival

ESMO 29th Sept 2012 ESMO 29th Sept 2012

TreatmentHR= 0.90 (0.74 to 1.09)Log rank test p=0.285

0.00

0.25

0.50

0.75

1.00

Su

rviv

al P

rob

ab

ility

0 3 6 12 18 24Months from randomisation

Placebo - median OS=3.60m

Gefitinib - median OS=3.73m

By treatment

PS0 - HR=1.00PS1 - HR=1.40 (1.10, 1.78)PS2 - HR=2.98 (2.22, 3.98)Log rank test p<0.0001

0.00

0.25

0.50

0.75

1.00

Su

rviv

al P

rob

ab

ility

0 3 6 12 18 24Months from randomisation

PS0 - median OS=6.03m

PS1 - median OS=3.93m

PS2 - median OS=1.97m

By performance status

COG 2012

Progression free survivalProgression free survival

ESMO 29th Sept 2012 ESMO 29th Sept 2012

HR= 0.795 (95%CI, 0.657 to 0.962)Log rank test p=0.017

0.00

0.25

0.50

0.75

1.00

Surv

ival P

robabili

ty

222 51 21 6 3 0 0Placebo223 62 25 15 7 4 2Gefitinib

Number at risk

0 3 6 9 12 15 18Months from randomisation

Placebo - Median PFS=1.17mths

Gefitinib - Median PFS=1.60mths

COG 2012

Kaplan-Meier survival estimates

Days on protocol therapyPlacebo: median 35; IQR 27 to 62; range 0 to 372Gefitinib: median 42; IQR 27 to 91; range 0 to 680

EGFR Inhibition for Gastric EGFR Inhibition for Gastric CancersCancers

Three negative randomized trialsThree negative randomized trials

Anything to biomarkers?Anything to biomarkers?– REAL-3 does not show anything predictive, only prognostic, but REAL-3 does not show anything predictive, only prognostic, but

numbers are lownumbers are low– EXPAND – 97% tumor sample acquisition – will this help us EXPAND – 97% tumor sample acquisition – will this help us

learn anything?learn anything?– Gefitinib – biomarker studies also pending – are TKI’s different Gefitinib – biomarker studies also pending – are TKI’s different

than antibodies?than antibodies?

Squamous vs. adenocarcinomas?Squamous vs. adenocarcinomas?– Small randomized phase II of cetuximab for SCC showed Small randomized phase II of cetuximab for SCC showed

potential benefit – like head and neck?potential benefit – like head and neck?Lordick, et al, ASCO 2008, n = 66, RR 19 vs. 13%, PFS Lordick, et al, ASCO 2008, n = 66, RR 19 vs. 13%, PFS 5.7 vs. 3.6 mo, OS 9.5 vs. 5.5 mo5.7 vs. 3.6 mo, OS 9.5 vs. 5.5 mo

PI3K/Akt/mTOR Pathway in Gastric PI3K/Akt/mTOR Pathway in Gastric CancerCancer

The PI3K/Akt/mTOR pathway, The PI3K/Akt/mTOR pathway, a key regulator of cell a key regulator of cell proliferation, growth, survival, proliferation, growth, survival, metabolism, and angiogenesis, metabolism, and angiogenesis, is dysregulated in 50%-60% of is dysregulated in 50%-60% of gastric cancersgastric cancers1-31-3

Everolimus, an oral mTOR Everolimus, an oral mTOR inhibitor, showed efficacy in inhibitor, showed efficacy in preclinical models of gastric preclinical models of gastric cancercancer1,4-61,4-6

4141

mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase.1Xu DZ et al. BMC Cancer. 2010;10:536; 2Lang SA et al. Cancer. 2007;120:1803-10; 3Yu G et al. Clin Cancer Res. 2009;15:1821-29; 4Taguchi F et al. Invest New Drugs. 2011;29:1198-205; 5Cejka D et al. Anticancer Res. 2008;28:3901-08; 6Jaeger-Lansky A et al. Cancer Biol Ther. 2010;9:919-27; 7Doi T et al. J Clin Oncol. 2010;28:1904-1910.

• In a phase 2 study of 53 patients with previously treated advanced gastric cancer, everolimus showed promising efficacy and acceptable tolerability7

Phase 3 GRANITE-1 Study Phase 3 GRANITE-1 Study DesignDesign

Everolimus 10 mg PO daily

+ BSC*(n = 439)

Placebo PO daily+

BSC(n = 217)

Treatment until disease progression

or intolerable

toxicity

• Stratification by region: Asia vs rest of world• Stratification by number of lines of previous

systemic chemotherapy (1 vs 2)

Safety follow-up: EOT + 28 d

Survival follow-up: every 3 mo

BSC, best supportive care; EOT, end of treatment; PO, orally.

ClinicalTrials.gov identifier: NCT00879333.

2

1

Van Cutsem GI ASCO 2012

Overall Survival (FAS)Overall Survival (FAS)

Van Cutsem GI ASCO 2012Van Cutsem GI ASCO 2012

Pro

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f o

vera

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urv

ival

(%

) 100

80

60

40

20

00 2 4 6 8 10 12

Time (months)

14

Censoring TimesEverolimus + BSC (n/N = 352/439)Placebo + BSC (n/N = 180/217)

Kaplan-Meier medians Everolimus + BSC: 5.39 months Placebo + BSC: 4.34 months

Hazard ratio: 0.90 (95% CI, 0.75-1.08)Log-rank P value = 0.1244

No. of patients still at riskTime (months)EverolimusPlacebo

16 18 20 22 24

0 2 4 6 8 10 12 14 16 18 20 22 24

217 172 117 82 60 35 28 16 12 8 4 1 0439 355 253 195 139 87 52 30 13 6 3 1 0

Overall Survival by Stratification Overall Survival by Stratification Factors (FAS)Factors (FAS)

Van Cutsem GI ASCO 2012Van Cutsem GI ASCO 2012ROW, rest of world.

Priorchemotherapy

Region

Cross-class.of strata

Hazard Ratio(95% CI)

0.80.6Everolimus

10 mg/dPlacebo

In favor of

1.0 1.2 1.4

All (N = 656) 0.90 (0.75-1.08)

2 (n = 343) 0.90 (0.70-1.15)

Asia (n = 363) 0.96 (0.75-1.23)

ROW (n = 293) 0.85 (0.65-1.10)

1 prior chemo & ROW (n = 167) 0.91 (0.64-1.31)

2 prior chemo & ROW (n = 126) 0.74 (0.50-1.09)

1 (n = 313) 0.94 (0.73-1.23)

0.98 (0.71-1.35)2 prior chemo & Asia (n = 217)

0.94 (0.63-1.39)1 prior chemo & Asia (n = 146)

Progression-Free Survival (FAS)Progression-Free Survival (FAS)

Van Cutsem GI ASCO 2012Van Cutsem GI ASCO 2012

Pro

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%)

100

80

60

40

20

00 2 4 6 7 9 10

Time (months)

12

Censoring TimesEverolimus + BSC (n/N = 386/439)Placebo + BSC (n/N = 206/217)

Kaplan-Meier medians Everolimus + BSC: 1.68 months Placebo + BSC: 1.41 months

Hazard ratio: 0.66 (95% CI, 0.56-0.78)Log-rank P value < 0.0001

No. of patients still at riskTime (months)EverolimusPlacebo

14 15 17 21

0 2 4 5 7 9 11 12 14 16 17 20 21

217 55 23 17 7 3 2 2 2 2 2 1 0439 179

1

168367 92

3

28117 60

6

844 37 20

8

627 10

10

213 6 3 2

15

23

13

25 1

19

20

18

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18 2019161311851 3

Rationale for Targeting METRationale for Targeting MET Met is a receptor tyrosine kinase.Met is a receptor tyrosine kinase. Following binding to its only known ligand, hepatic Following binding to its only known ligand, hepatic

growth factor (HGF), Met receptors dimerize, leading growth factor (HGF), Met receptors dimerize, leading to growth, migration and survival signalsto growth, migration and survival signals

Met is amplified, mutated, overexpressed in many Met is amplified, mutated, overexpressed in many tumorstumors

Met expression is associated with a worse prognosis Met expression is associated with a worse prognosis in many cancers including NSCLC, colorectal, gastric, in many cancers including NSCLC, colorectal, gastric, and breast cancers and breast cancers

Met pathway also implicated in resistance to Met pathway also implicated in resistance to bevacizumab in colorectal cancer patients and bevacizumab in colorectal cancer patients and resistance to EGFR inhibitorsresistance to EGFR inhibitors

Activation of Met in CancerActivation of Met in Cancer

MUTANT MET AUTOCRINE HGFINCREASED MET

Other Focal Amp

Paracrine HGF Paracrine HGF

LUNGHCC (Childhood)

PAPIL. RENAL(Hereditary& Sporadic)

GLIOMAOSTEOSARCOMAPANCREATICGASTRIC

BREASTCOLORECTALESOPHAGEALGASTRICGLIOMAHNSCCLUNGMELANOMAMESOTHELIOMAOVARIANPANCREATICRENAL

GASTRICLUNGMet CRC

Met Pathway and Targeted Agents

Appleman (2011) JCO ePub

1+ 2+ 3+

Intensity of Met staining on tumor cells scored on 0–3+ scale

Development of Met IHC as aDevelopment of Met IHC as a Diagnostic Diagnostic

‘Met High’ is defined as: ≥50% tumor cells with a staining intensity of 2+ or 3+

1+ 2+ 3+

AMG-102 for gastric cancerAMG-102 for gastric cancer

Met receptor overexpression is associated with Met receptor overexpression is associated with poor prognosis for gastric cancer patientspoor prognosis for gastric cancer patients

Update on randomized phase II trialUpdate on randomized phase II trial– ECX plus AMG-102 (rilotumumab) at 7.5 or 15 mg/kg ECX plus AMG-102 (rilotumumab) at 7.5 or 15 mg/kg

(n = 82) vs. ECX plus placebo (n = 39)(n = 82) vs. ECX plus placebo (n = 39)

Met high defined as > 50% tumor cells positive Met high defined as > 50% tumor cells positive for Met expression (n = 27 vs. 11)for Met expression (n = 27 vs. 11)

Oliner ASCO 2012

0

20

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Ove

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Clinical Efficacy in the Intent-to-Treat Clinical Efficacy in the Intent-to-Treat Population*Population*

*Results based on the updated analysis with data cutoff of April 1, 2011. †Adjusted for baseline randomization stratification variables (ECOG status [0 or 1] and disease extent [locally advanced or metastatic]).Iveson T, et al. European Multidisciplinary Cancer Congress, September 23-27, 2011,Stockholm, Sweden; abstract #6504.

Median Months(80% CI)

HR†

(80% CI) P Value

Rilotumumab + ECX (n = 82) 5.6 (4.9–6.9) 0.64 (0.48–0.85) 0.045

Placebo + ECX (n = 39) 4.2 (3.7–4.6)

Progression-Free Survival

Overall Survival Median Months(80% CI)

HR†

(80% CI) P Value

Rilotumumab + ECX (n = 82) 11.1 (9.5–12.1) 0.73 (0.53–1.01) 0.215

Placebo + ECX (n = 39) 8.9 (5.7–10.6)

HR 0.64

HR 0.73

Oliner ASCO 2012

Improved PFS and OS in METImproved PFS and OS in METHighHigh Patients Patients

Progression-Free Survival

Overall Survival

*HR adjusted for baseline disease extent and ECOG PS.

Time (Months)0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

100

80

60

40

20

0

Pro

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%)

Median Months(80% CI)

HR*

(95% CI) P Value

Rilotumumab + ECX (n = 27) 6.9 (5.1–7.5) 0.51 (0.24–1.10) 0.085

Placebo + ECX (n = 11) 4.6 (3.7–5.2)

Median Months(80% CI)

HR+

(95% CI) P Value

Rilotumumab + ECX (n = 27) 11.1 (9.2–13.3) 0.29 (0.11–0.76) 0.012

Placebo + ECX (n = 11) 5.7 (4.5–10.4)

0

20

40

60

80

100

Time (Months)0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Ove

rall

Su

rviv

al (

%)

HR 0.51

HR 0.29

Oliner ASCO 2012

Targeted Agents for Gastric and Targeted Agents for Gastric and Esophageal CancersEsophageal Cancers

They are in testing, and some look They are in testing, and some look promisingpromising

We are going to have to come to terms We are going to have to come to terms with the epidemiology of this disease to with the epidemiology of this disease to target the right populations in trialstarget the right populations in trials

Biomarkers are essential, though we do Biomarkers are essential, though we do not quite know what we are doing yetnot quite know what we are doing yet

But we are continuing to move forward!But we are continuing to move forward!