Overview of Targeted Therapies for Esophageal and Gastric Cancers Johanna Bendell, MD Director, GI...
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Transcript of Overview of Targeted Therapies for Esophageal and Gastric Cancers Johanna Bendell, MD Director, GI...
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
bab
ilit
y o
f o
vera
ll s
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
bab
ilit
y o
fp
rog
res
sio
n-f
ree
su
rviv
al (
%)
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
21 0 0
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
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Pro
gre
ssio
n-F
ree
Su
rviv
al (
%)
Time (months)
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17Time (months)
Ove
rall
Su
rviv
al (
%)
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
gre
ssio
n-F
ree
Su
rviv
al (
%)
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!