manish a. shah, md director, gastrointestinal oncology weill cornell medical college...
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Manish A. Shah, MDDirector, Gastrointestinal OncologyWeill Cornell Medical CollegeNewYork-Presbyterian HospitalNew York, New York
Treatment of HER2-Positive Gastroesophageal Carcinoma
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Program Faculty
Program Director:Manish A. Shah, MDDirector, Gastrointestinal OncologyWeill Cornell Medical CollegeNewYork-Presbyterian HospitalNew 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 HER2- positive tumors
Second-line options[1]
– Trastuzumab + standard chemotherapy for HER2-positive 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
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.
(n = 584)
R
Patients with advanced
gastric cancer screened for HER2 status(N = 3803)
Stratified by ECOG PS, advanced vs metastatic, gastric vs GEJ,
measurable disease, capecitabine vs 5-FU
Patients with HER2-positive
advanced gastric cancer
(n = 810; 22% of successful screenings)
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)
Bang YJ, et al. Lancet. 2010;376:687-697.
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ToGA: Efficacy Outcome
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)
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
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)
All patients (N = 584) 13.8 vs 11.1 0.74 (0.60-0.91)
Preplanned analysis
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)
Exploratory analysis
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)
Bang YJ, et al. Lancet. 2010;376:687-697.
*HR < 1 favors chemotherapy + trastuzumab; HR > 1 favors chemotherapy alone.
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Events,n
120136
Mos
228218
218198
196170
170141
142112
12296
10075
8453
6539
5128
3920
2813
2011
124
113
53
40
10
00
Pts at Risk, n
11.8 16.0
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
Su
rviv
al P
rob
abili
ty FC + TFC
HR
0.65
95% CI
0.51-0.83
MedianOS, Mos
16.011.8
ToGA: OS in IHC 2+/FISH+ or IHC 3+ (Exploratory Analysis)
Bang YJ, et al. Lancet. 2010;376:687-697.
FC + TFC
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ToGA: Select Toxicities
Adverse Event, % Chemotherapy + Trastuzumab(n = 294)
Chemotherapy Alone(n = 290)
Grade 3/4 hematologic events
Neutropenia 27 30
Anemia 12 10
Grade 3/4 nonhematologic events
Diarrhea 9 4
Nausea 7 7
Cardiac events 6 6
Grade 3/4 1 3
LVEF reduction of ≥ 10% to absolute value < 50%*
5 1
Bang YJ, et al. Lancet. 2010;376:687-697.
*Chemotherapy plus trastuzumab: n = 237; chemotherapy alone: n = 187.
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ToGA: HER2 Positivity by IHC
*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.
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 cellNegative
1+
Faint or barely perceptiblemembranous 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
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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
Tafe LJ, et al. Arch Pathol Lab Med. 2011;135:1460-1465.
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)
Equivocal (HER2/CEP17 1.8-2.2) 2 (1.9; 2.0)* 2 (2.1; 1.8)* 1 (2.1)* 0 5 (4)
Failure 2 2 0 1 5 (4)
Total, n (%) 64 (48) 44 (33) 8 (6) 17 (13) 133
HER2 Testing in Gastroesophageal Cancer
*Data in parentheses show individual values, not percentages.
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Median OS Increased to > 1 Yr With Trastuzumab-Based Therapy
0 5 10 15Trastuzumab + XP/FP[8]
EOX[6]
XP[7]
ECX[6]
ECF[6]
DCF[4]
EOF[6]
IF[5]
CF[4]
FAMTX[2]
BSC[1]
C + S1[3]
Median OS in Patients With Advanced Gastric Cancer (Mos)
12 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
FISH+ (ratio > 2.0)
IHC 3+ or
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
– Similar survival benefit in this subset
OS
Pat
ien
ts (
%)
Macdonald JS, et al. N Engl J Med. 2001;345:725-730.
Mos After Registration
0
20
40
60
80
100
0 24 48 72 96 120
Surgery only
Chemoradiotherapy
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70
HR: 0.82 (95% CI: 0.76-0.90; P < .001)
GASTRIC Group, et al. JAMA. 2010;303:1729-1737.
Meta-analysis: Surgery vs Surgery + Any Adj CT in Resectable GC Survival benefit for addition of chemotherapy
Su
rviv
al (
%)
Yrs From Randomization
0
20
40
60
80
100
0 2 3 7 9
10
30
50
90
1 4 5 6 8 10
Any chemotherapySurgery alone
Pts at Risk, nAny chemotherapySurgery along
19241857
16881568
13851300
12171092
1080952
929782
709583
526407
390267
297172
243138
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Chemotherapy in Resectable Gastric Cancer Addition of pre/peri/postsurgery chemotherapy consistently
demonstrates benefit vs surgery alone
Study Regimens Primary Endpoint
Primary Endpoint Results
P Value
CLASSIC[1] Surgery vs surgery + adjuvant
capecitabine/oxaliplatin3-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
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
1. Fuchs CS, et al. ASCO 2011. Abstract 4003. 2. Lee J, et al. J Clin Oncol. 2012;30:268-273.
Study Regimens Primary Endpoint
PrimaryEndpointResults
P Value
CALGB 80101[1]
Postop 5-FU/LV CRT vs ECF CRT
OS 37 vs 38 mos .80
ARTIST[2] Postop CT vs CRT (capecitabine/cisplatin)
3-yr DFS 74% vs 78% .086
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RTOG 1010: Neoadjuvant Phase III Trial in Esophageal/GEJ Adenocarcinoma
Primary endpoint: DFS (15 → 27 mos; HR: 0.56)
Patients with confirmed HER2-overexpressing
esophageal or GEJ adenocarcinoma
(Planned N = 160)
Radiation (50.4 Gy) + Paclitaxel +
Carboplatin + Trastuzumab
Radiation (50.4 Gy) + Paclitaxel + Carboplatin
Stratified by presence of adenopathy and involved celiac nodes
Surgery 5-8 wks after radiation
completion
Surgery 5-8 wks after radiation
completion
Maintenance Trastuzumab
q3w x 13
Principal investigator: H. Safran, Providence, RI. ClinicalTrials.gov. NCT01196390.
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Patients with HER2-amplified locally advanced, unresectable, or metastatic gastric, esophageal, or
GEJ cancer(Planned N = 535)
CapeOx + Lapatinib
CapeOx + Placebo
ClinicalTrials.gov. NCT00680901.
LOGiC: Phase III Trial of Lapatinib + CapeOx in HER2+ Gastric Cancer
Primary endpoint: OS (was PFS)
Data expected mid-2012
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Pertuzumab & Trastuzumab Bind Distinct Epitopes on HER2 Extracellular Domain
Activates ADCC Prevents HER2 domain
cleavage Inhibits HER2-mediated
signaling pathways
Activates ADCC Has a major effect on role of
HER2 as a coreceptor with HER3 or EGFR
Inhibits multiple HER-mediated signaling pathways
TrastuzumabPertuzumab
Hubbard SR. Cancer Cell 2005;7:287-288.
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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
ClinicalTrials.gov. NCT00486954.
Primary endpoint
– Initial pilot analysis: tolerability to determine optimal dosing
– Randomized part: OS
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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 pre-operative 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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