Overview of Targeted Overview of Targeted Therapies for Esophageal Therapies for Esophageal and Gastric Cancers and Gastric Cancers Johanna Bendell, MD Johanna Bendell, MD Director, GI Oncology Research Director, GI Oncology Research Associate Director, Drug Associate Director, Drug Development Unit Development Unit Sarah Cannon Research Institute Sarah Cannon Research Institute Nashville, TN Nashville, TN
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Overview of Targeted Therapies for Esophageal and Gastric Cancers Johanna Bendell, MD Director, GI Oncology Research Associate Director, Drug Development.
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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
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
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
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.
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
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)
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.
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!