Transcript Treatment of HER2-Positive Gastroesophageal Carcinoma

Treatment of HER2-Positive
Gastroesophageal Carcinoma
Manish A. Shah, MD
Director,
Gastrointestinal Oncology
Weill Cornell Medical College
NewYork-Presbyterian Hospital
New York, New York
This program is supported by an educational donation from
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Program Faculty
Program Director:
Manish A. Shah, MD
Director, Gastrointestinal
Oncology
Weill Cornell Medical College
NewYork-Presbyterian Hospital
New York, New York
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Faculty Disclosure
Manish A. Shah, MD, has disclosed that he has received
consulting fees and contracted research support from
Genentech and sanofi-aventis.
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Gastroesophageal Cancer: Treatment
Overview

Surgery is primary treatment for medically fit, resectable cases[1]

For advanced disease, treatment may include perioperative chemotherapy or
preoperative chemoradiation

Postoperative treatment options
– Chemoradiation (fluoropyrimidine-based or capecitabine)
– Palliative chemotherapy or best supportive care

Recurrent or metastatic disease
– Chemotherapy
– Palliative chemotherapy, clinical trial, or best supportive care

Significant need exists for deeper understanding of tumor subtypes,
biomarkers for treatment response[2]
1. NCCN. Clinical practice guidelines in oncology: gastric cancer, v2. 2011.
2. Power DG, et al. Cancer Treat Rev. 2010;36:384-392.
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Gastroesophageal Cancer: Systemic
Therapy for Metastatic Disease
 First-line options[1]
– DCF/modified DCF
– ECF/modified DCF
– Single agent or combination
regimens (fluoropyrimidine or
taxane based)
– Trastuzumab + standard
chemotherapy for HER2positive tumors
 Second-line options[1]
– Trastuzumab + standard
chemotherapy for HER2positive tumors if no first-line
trastuzumab
– Paclitaxel or docetaxel
– Single agent irinotecan or
irinotecan-based combination
– Phase III trials under way with
other targeted agents[2]
1. NCCN. Clinical practice guidelines in oncology: gastric cancer, v2. 2011.
2. Power DG, et al. Cancer Treat Rev. 2010;36:384-392.
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Targeted Therapies
 Conventional, cytotoxic chemotherapy has limited benefit
 Targeted agents: attempt to block specific tumor growth
pathways
– Monoclonal antibodies
– Tyrosine kinase inhibitors
– Soluble receptors to growth factors
– Inhibition of pathways involved in protein synthesis and
degradation
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Molecular Targets: Esophagogastric
Cancer
 KRAS mutation: < 5% to 10%[1,2]
 BRAF mutation: < 5%[1,2]
 EGFR overexpression: ~ 50% to 80%[3,4]
– TKIs inactive[4]
– Cetuximab monotherapy inactive[5]
 EGFR mutation: very low[4,6]
 HER2 overexpression: 10% to 25%[7]
 HGF/c-Met: over/aberrant expression reported in various human
cancers, including gastric cancer[8]
1. Lee SH, et al. Oncogene. 2003;22:6942-6945. 2. Kim IJ, et al. Hum Genet. 2003;114:118-120.
3. Galizia G, et al. World J Surg. 2007;31:1458-1468. 4. Dragovich T, et al. J Clin Oncol. 2006;24:4922-4927.
5. Chan JA, et al. Ann Oncol. 2011;22:1367-1373. 6. Mammano E, et al. Anticancer Res. 2006;26:3547-3550.
7. Yano T, et al. Oncol Rep. 2006;15:65-71. 8. Birchmeier C, et al. Nat Rev Mol Cell Biol. 2003;4:915-925.
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ToGA: Trastuzumab + Chemotherapy in
Advanced HER2+ Gastric Cancer
 Rationale: a subpopulation of gastric cancers overexpress HER2
Stratified by ECOG PS,
advanced vs metastatic, gastric vs GEJ,
measurable disease, capecitabine vs 5-FU
Patients with
advanced
gastric cancer
screened for
HER2 status
(N = 3803)
Patients with
HER2-positive
advanced
gastric cancer
(n = 810; 22% of
successful
screenings)
R
(n = 584)
5-FU or Capecitabine* +
Cisplatin 80 mg/m2 q3w x 6 +
Trastuzumab 6 mg/kg q3w until PD
(8 mg/kg loading dose)
(n = 294)
5-FU or Capecitabine* +
Cisplatin 80 mg/m2 q3w x 6
(n = 290)
 Primary endpoint: OS
*Selected at investigator’s discretion: 5-FU 800 mg/m2/day infusional on Days 1-5 q3w x 6;
capecitabine 1000 mg/m2 BID on Days 1-14 q3w x 6.
Bang YJ, et al. Lancet. 2010;376:687-697.
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ToGA: Efficacy Outcome
Outcome
Chemotherapy
+ Trastuzumab
(n = 294)
Chemotherapy
Alone
(n = 290)
HR (95% CI)
P Value
Median OS, mos
13.8
11.1
0.74 (0.60-0.91)
.0046
Median PFS, mos
6.7
5.5
0.71 (0.59-0.85)
.0002
ORR, %
47
35
--
.0017
 CR
5
2
--
.0599
 PR
42
32
--
.0145
 Preplanned subgroup analysis indicated improved OS benefit with
increasing HER2 expression by IHC
 Exploratory analysis of IHC 2+/FISH+ and IHC 3+ cohort
demonstrated a 4-mo increase in OS with trastuzumab
– HR: 0.65 (95% CI: 0.51-0.83)
Bang YJ, et al. Lancet. 2010;376:687-697.
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ToGA: OS by HER2 Status
HER2 Status Subgroup
Median OS, Mos
(CT + T vs CT Alone)
HR* (95% CI)
13.8 vs 11.1
0.74 (0.60-0.91)
 IHC 0/FISH+ (n = 61)
10.6 vs 7.2
0.92 (0.48-1.76)
 IHC 1+/FISH+ (n = 70)
8.7 vs 10.2
1.24 (0.70-2.20)
 IHC 2+/FISH+ (n = 159)
12.3 vs 10.8
0.75 (0.51-1.11)
 IHC 3+/FISH+ (n = 256)
17.9 vs 12.3
0.58 (0.41-0.81)
 IHC3+/FISH- (n = 15)
17.5 vs 17.7
0.83 (0.20-3.38)
 IHC 0 or 1+/FISH+ (n = 131)
10.0 vs 8.7
1.07 (0.70-1.62)
 IHC 2+/FISH+ or IHC 3+ (n = 446)
16.0 vs 11.8
0.65 (0.51-0.83)
All patients (N = 584)
Preplanned analysis
Exploratory analysis
*HR < 1 favors chemotherapy + trastuzumab; HR > 1 favors chemotherapy alone.
Bang YJ, et al. Lancet. 2010;376:687-697.
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Survival Probability
ToGA: OS in IHC 2+/FISH+ or IHC 3+
(Exploratory Analysis)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Events, Median
n OS, Mos HR
FC + T 120
136
FC
11.8
0
2
4
6
95% CI
0.65 0.51-0.83
16.0
11.8
16.0
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Mos
Pts at Risk, n
FC + T 228 218 196 170 142 122 100 84 65 51 39 28 20 12 11
FC 218 198 170 141 112 96 75 53 39 28 20 13 11 4 3
Bang YJ, et al. Lancet. 2010;376:687-697.
5
3
4
0
1
0
0
0
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ToGA: Select Toxicities
Adverse Event, %
Chemotherapy + Trastuzumab
(n = 294)
Chemotherapy Alone
(n = 290)
 Neutropenia
27
30
 Anemia
12
10
 Diarrhea
9
4
 Nausea
7
7
Cardiac events
6
6
 Grade 3/4
1
3
5
1
Grade 3/4 hematologic events
Grade 3/4 nonhematologic
events
LVEF reduction of ≥ 10% to
absolute value < 50%*
*Chemotherapy plus trastuzumab: n = 237; chemotherapy alone: n = 187.
Bang YJ, et al. Lancet. 2010;376:687-697.
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ToGA: HER2 Positivity by IHC
Score
Surgical Specimen
Staining Pattern
Biopsy Specimen Staining
Pattern
HER2 Overexpr.
Assessment
0
No reactivity or
membranous
reactivity in < 10% of
tumor cells
No reactivity or no
membranous reactivity
in any tumor cell
Negative
1+
Faint or barely perceptible
membranous reactivity in
≥ 10% of tumor cells; cells
are reactive only in part of
their membrane
Tumor cell cluster with faint or
barely perceptible membranous
reactivity regardless of % of
tumor cells stained
Negative
2+
Weak to moderate
complete, basolateral or
lateral membranous
reactivity in ≥ 10% of
tumor cells
Tumor cell cluster with weak to
moderate complete, basolateral
or lateral membranous reactivity
regardless of % of tumor cells
stained
Equivocal*
3+
Strong complete,
basolateral or lateral
membranous reactivity in
≥ 10% of tumor cells
Tumor cell cluster with strong
complete, basolateral or lateral
membranous reactivity
regardless of % of tumor cells
stained
Positive
*FISH or other in situ hybridization method recommended by NCCN guidelines panel.
Bang YJ, et al. Lancet. 2010;376:687-697. NCCN. Clinical practice guidelines in oncology: gastric cancer, v2. 2011.
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HER2 Testing in Gastroesophageal Cancer
 HER2 more heterogeneous in gastric vs breast cancer
 Objectives
– Evaluate IHC-FISH concordance in processed samples
– Determine applicability of ASCO/CAP HER2 breast cancer scoring system
to gastroesophageal carcinomas
FISH
IHC 0
IHC 1+
IHC 2+
IHC 3+
Total, n (%)
Positive (HER2/CEP17 > 2.2)
0
1
3
16 (100)
20 (15)
Negative (HER2/CEP17 < 1.8)
60 (97)
39 (93)
4
0
103 (77)
2 (1.9; 2.0)*
2 (2.1; 1.8)*
1 (2.1)*
0
5 (4)
2
2
0
1
5 (4)
64 (48)
44 (33)
8 (6)
17 (13)
133
Equivocal (HER2/CEP17 1.8-2.2)
Failure
Total, n (%)
*Data in parentheses show individual values, not percentages.
Tafe LJ, et al. Arch Pathol Lab Med. 2011;135:1460-1465.
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Median OS Increased to > 1 Yr With
Trastuzumab-Based Therapy
12 mos
BSC[1]
FAMTX[2]
C + S1[3]
CF[4]
IF[5]
EOF[6]
DCF[4]
ECF[6]
ECX[6]
XP[7]
EOX[6]
Trastuzumab + XP/FP[8]
HER2 IHC 2+/FISH+ or IHC 3+
15
10
5
0
Median OS in Patients With Advanced Gastric Cancer (Mos)
1. Murad AM, et al. Cancer. 1993;72:37-41. 2. Vanhoefer U, et al. J Clin Oncol. 2000;18:2648-2657.
3. Ajani JA, et al. J Clin Oncol. 2010;28:1547-1553. 4. Van Cutsem E, et al. J Clin Oncol. 2006;24:4991-4997.
5. Dank M, et al. Ann Oncol. 2008;19:1450-1457. 6. Cunningham D, et al. N Engl J Med. 2008;358:36-46.
7. Kang YK, et al. Ann Oncol. 2009;20:666-673. 8. Bang YJ, et al. Lancet. 2010;376:687-697.
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Definition of HER2 Positivity for
Gastroesophageal Carcinoma
HER2-Positivity Requirements for Approved Trastuzumab Use
US
European Union
IHC 3+ or
IHC 3+ or
FISH+ (ratio > 2.0)
IHC 2+ and FISH+ (ratio > 2.0)
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Prognostic Role of HER2 in Gastric Cancer
 Prognostic value of HER2 controversial with > 20 yrs of conflicting data
 Systematic literature analysis involving 12,749 patients in 42 studies[1]
– 71% of studies demonstrated association between HER2 positivity and
poor survival (40%) or clinicopathologic features (31%; eg, serosal
invasion, LN metastases, disease stage, or distant metastases)
– However, multivariate analyses performed in only ~ 50% of studies
 Systematic literature review involving 11,337 patients in 49 studies
included 35 studies evaluating effect of HER2 overexpression on survival[2]
– 57%: no effect on OS
– 6%: significantly longer OS with HER2 overexpression
– 37%: significantly poorer OS with HER2 overexpression
1. Jørgensen JT, et al. J Cancer. 2012;3:137-144. 2. Chua TC, et al. Int J Cancer. 2012;130:2845-2856.
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Gastric Cancer
 Surgical cure rates are high with lesions limited to the mucosa
or submucosa (ie, T1)
 However, for patients with stage II or higher, 5-yr survival
remains poor
 Patients increasingly presenting with T1 N0 disease, but
proportion remains low
 40% to 50% of patients will present with unresectable disease
 Overall 5-yr survival remains low
 This is a bad disease
– After surgery, chances of long-term survival for most patients
remains < 50%. Can we do better??
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Gastric INT 116: Postoperative
Chemoradiotherapy vs Surgery Alone
 20% were GEJ tumors
100
– Similar survival benefit in
this subset
OS
Patients (%)
80
60
Chemoradiotherapy
40
20
Surgery only
0
0
24
48
72
Mos After Registration
Macdonald JS, et al. N Engl J Med. 2001;345:725-730.
96
120
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Meta-analysis: Surgery vs Surgery + Any
Adj CT in Resectable GC
Survival (%)
 Survival benefit for addition of chemotherapy
100
90
80
70
60
50
40
30
20
10
0
Any chemotherapy
Surgery alone
HR: 0.82 (95% CI: 0.76-0.90; P < .001)
0
1
2 3 4 5
6 7 8
Yrs From Randomization
Pts at Risk, n
Any chemotherapy 1924 1688 1385 1217 1080 929
Surgery along
1857 1568 1300 1092 952 782
GASTRIC Group, et al. JAMA. 2010;303:1729-1737.
9
10
709 526 390 297 243
583 407 267 172 138
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Chemotherapy in Resectable Gastric
Cancer
 Addition of pre/peri/postsurgery chemotherapy
consistently demonstrates benefit vs surgery alone
Study
Primary
Endpoint
Primary Endpoint
Results
P Value
Surgery vs surgery +
adjuvant
capecitabine/oxaliplatin
3-yr DFS
59% vs 74%
< .0001
MAGIC[2]
Surgery vs surgery +
periop ECF
5-yr OS
23% vs 36%
.009
Sakuramoto
et al[3]
Surgery vs surgery +
adjuvant S-1
3-yr OS
70% vs 80%
.003
CLASSIC[1]
Regimens
1. Bang YJ, et al. Lancet. 2012;379:315-321. 2. Cunningham D, et al. N Engl J Med. 2006;355:11-20.
3. Sakuramoto S, et al. N Engl J Med. 2007;357:1810-1820.
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Chemotherapy in Resectable Gastric
Cancer
 However, resounding lack of progress in improving patient
outcomes with any specific CT/CRT regimen vs any other
chemotherapy regimen
Study
CALGB
80101[1]
ARTIST[2]
Regimens
Primary
Endpoint
Primary
Endpoint
Results
P Value
Postop 5-FU/LV CRT
vs ECF CRT
OS
37 vs 38 mos
.80
Postop CT vs CRT
(capecitabine/cisplatin)
3-yr DFS
74% vs 78%
.086
1. Fuchs CS, et al. ASCO 2011. Abstract 4003. 2. Lee J, et al. J Clin Oncol. 2012;30:268-273.
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RTOG 1010: Neoadjuvant Phase III Trial in
Esophageal/GEJ Adenocarcinoma
Stratified by presence of adenopathy
and involved celiac nodes
Patients with
confirmed HER2overexpressing
esophageal or GEJ
adenocarcinoma
(Planned N = 160)
Radiation (50.4 Gy) +
Paclitaxel +
Carboplatin +
Trastuzumab
Surgery 5-8
wks after
radiation
completion
Radiation (50.4 Gy) +
Paclitaxel +
Carboplatin
Surgery 5-8
wks after
radiation
completion
 Primary endpoint: DFS (15 → 27 mos; HR: 0.56)
Principal investigator: H. Safran, Providence, RI. ClinicalTrials.gov. NCT01196390.
Maintenance
Trastuzumab
q3w x 13
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LOGiC: Phase III Trial of Lapatinib +
CapeOx in HER2+ Gastric Cancer
Patients with HER2-amplified
locally advanced, unresectable, or
metastatic gastric, esophageal, or
GEJ cancer
(Planned N = 535)
 Primary endpoint: OS (was PFS)
 Data expected mid-2012
ClinicalTrials.gov. NCT00680901.
CapeOx + Lapatinib
CapeOx + Placebo
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Pertuzumab & Trastuzumab Bind Distinct
Epitopes on HER2 Extracellular Domain
Pertuzumab
Trastuzumab
 Activates ADCC
 Activates ADCC
 Prevents HER2 domain
cleavage
 Has a major effect on role of
HER2 as a coreceptor with
HER3 or EGFR
 Inhibits HER2-mediated
signaling pathways
Hubbard SR. Cancer Cell 2005;7:287-288.
 Inhibits multiple HERmediated signaling pathways
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Second-line Paclitaxel + Lapatinib vs
Paclitaxel for Advanced Gastric Cancer
Patients with HER2-amplified
gastric cancer and PD
after 1 previous 5-FU and/or
cisplatin regimen
(N = 273)
Paclitaxel + Lapatinib
Paclitaxel
 Primary endpoint
– Initial pilot analysis: tolerability to determine optimal dosing
– Randomized part: OS
ClinicalTrials.gov. NCT00486954.
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Phase II Studies of Targeted Agents in
HER2-Positive Disease
 PF-00299804, pan-EGFR inhibitor (NCT01152853)
 AUY922, Hsp90 inhibitor (NCT01402401)
 Pertuzumab + trastuzumab + chemotherapy
(NCT01461057)
 Bevacizumab + trastuzumab + docetaxel, oxaliplatin and
capecitabine chemotherapy (NCT01359397)
 Bevacizumab + trastuzumab + capecitabine and
oxaliplatin (NCT01191697)
 Afatinib (NCT01522768)
ClinicalTrials.gov.
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Summary
 HER2 represents the first validated target in gastric and
gastroesophageal junction adenocarcinoma
 All patients with metastatic gastric/GEJ adenocarcinoma
who are HER2 positive should be considered for
trastuzumab-based therapy
 There are few data on the use of trastuzumab in the preoperative or adjuvant setting, or on its continued use after
progression on trastuzumab-based therapy
 Drug development targeting HER2 in gastric cancer is
active and ongoing
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