1. Treatment of HER2-Positive Gastroesophageal Carcinoma
Manish A. Shah, MD
Director,
Gastrointestinal Oncology Weill Cornell Medical College NewYork-Presbyterian Hospital New York, New York
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3. Program Faculty Program Director:
Manish A. Shah, MD Director, Gastrointestinal Oncology
Weill Cornell Medical College
NewYork-Presbyterian Hospital
New York, New York

4. Faculty Disclosure
Manish A. Shah, MD, has disclosed that he has received consulting fees and contracted research support from Genentech and sanofi-aventis.

5. 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, v Power DG, et al. Cancer Treat Rev. 2010;36:

6. 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]
DCF, docetaxel, cisplatin, and 5-fluorouracil; ECF, epirubicin, cisplatin, and 5-fluorouracil.
1. NCCN. Clinical practice guidelines in oncology: gastric cancer, v Power DG, et al. Cancer Treat Rev. 2010;36:

7. 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

8. 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]
EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor.
1. Lee SH, et al. Oncogene. 2003;22: Kim IJ, et al. Hum Genet. 2003;114: Galizia G, et al. World J Surg. 2007;31: Dragovich T, et al. J Clin Oncol. 2006;24: Chan JA, et al. Ann Oncol. 2011;22: Mammano E, et al. Anticancer Res. 2006;26: Yano T, et al. Oncol Rep. 2006;15: Birchmeier C, et al. Nat Rev Mol Cell Biol. 2003;4:

9. ToGA: Trastuzumab + Chemotherapy in Advanced HER2+ Gastric Cancer
Rationale: a subpopulation of gastric cancers overexpress HER2
Primary endpoint: OS
Stratified by ECOG PS, advanced vs metastatic, gastric vs GEJ, measurable disease, capecitabine vs 5-FU
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)
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
5-FU or Capecitabine* +
Cisplatin 80 mg/m2 q3w x 6
(n = 290)
5-FU, 5-fluorouracil; ECOG, Eastern Cooperative Oncology Group; GEJ, gastroesophageal junction; OS, overall survival; PD, progressive disease; PS, performance score; R, randomization.
(n = 584)
*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:

10. ToGA: Efficacy Outcome
Chemotherapy + Trastuzumab
(n = 294)
Chemotherapy Alone
(n = 290)
HR (95% CI)
P Value
Median OS, mos
13.8
11.1
0.74 ( )
.0046
Median PFS, mos
6.7
5.5
0.71 ( )
.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: )
CI, confidence interval; CR, complete response; FISH, fluorescence in situ hybridization; HR, hazard ratio; IHC, immunohistochemistry; PFS, progression-free survival; PR, partial response; ORR, overall response rate; OS, overall survival.
Bang YJ, et al. Lancet. 2010;376:

11. Median OS, Mos (CT + T vs CT Alone)
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 ( )
Preplanned analysis
IHC 0/FISH+ (n = 61)
10.6 vs 7.2
0.92 ( )
IHC 1+/FISH+ (n = 70)
8.7 vs 10.2
1.24 ( )
IHC 2+/FISH+ (n = 159)
12.3 vs 10.8
0.75 ( )
IHC 3+/FISH+ (n = 256)
17.9 vs 12.3
0.58 ( )
IHC3+/FISH- (n = 15)
17.5 vs 17.7
0.83 ( )
Exploratory analysis
IHC 0 or 1+/FISH+ (n = 131)
10.0 vs 8.7
1.07 ( )
IHC 2+/FISH+ or IHC 3+ (n = 446)
16.0 vs 11.8
0.65 ( )
CI, confidence interval; CT, chemotherapy; CT + T, chemotherapy + trastuzumab; FISH, fluorescence in situ hybridization; HR, hazard ratio; IHC, immunohistochemistry; OS, overall survival.
*HR < 1 favors chemotherapy + trastuzumab; HR > 1 favors chemotherapy alone.
Bang YJ, et al. Lancet. 2010;376:

12. ToGA: OS in IHC 2+/FISH+ or IHC 3+ (Exploratory Analysis)
1.0
Events, n
Median OS, Mos
0.9 HR
0.65
95% CI
0.8
FC + T
0.7 FC
0.6
Survival Probability
0.5
0.4
0.3
0.2
0.1
11.8
16.0
CI, confidence interval; FC, 5-fluorouracil, cisplatin; FC + T, 5-fluorouracil, cisplatin + trastuzumab; FISH, fluorescence in situ hybridization; HR, hazard ratio; IHC, immunohistochemistry; OS, overall survival. 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Mos
Pts at Risk, n
FC + T
228
218
218
198
122 96
100 75
84 53
65 39
51 28
39 20
28 13
20 11
12 4
11 3
5 3 4 1 FC
Bang YJ, et al. Lancet. 2010;376:

13. 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
Cardiac events 6
Grade 3/4 1 3
LVEF reduction of ≥ 10% to absolute value < 50%* 5
LVEF, left ventricular ejection fraction.
*Chemotherapy plus trastuzumab: n = 237; chemotherapy alone: n = 187.
Bang YJ, et al. Lancet. 2010;376:

14. ToGA: HER2 Positivity by IHC
Score
Surgical Specimen Staining Pattern
Biopsy Specimen Staining Pattern
HER2 Overexpr. Assessment
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 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, fluorescence in situ hybridization; IHC, immunohistochemistry.
*FISH or other in situ hybridization method recommended by NCCN guidelines panel.
Bang YJ, et al. Lancet. 2010;376: NCCN. Clinical practice guidelines in oncology: gastric cancer, v

15. 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) 1 3
16 (100)
20 (15)
Negative (HER2/CEP17 < 1.8)
60 (97)
39 (93) 4
103 (77)
Equivocal (HER2/CEP )
2 (1.9; 2.0)*
2 (2.1; 1.8)*
1 (2.1)*
5 (4)
Failure 2
64 (48)
44 (33)
8 (6)
17 (13)
133
ASCO/CAP, American Society of Clinical Oncology/College of American Pathologists; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry.
*Data in parentheses show individual values, not percentages.
Tafe LJ, et al. Arch Pathol Lab Med. 2011;135:

16. 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]
BSC, best supportive care; C + S1, cisplatin + S1; CF, cisplatin, 5-fluorouracil; DCF, docetaxel, cisplatin, 5-fluorouracil; ECF, epirubicin, cisplatin, 5-fluorouracil; ECX, epirubicin, cisplatin, capecitabine; EOF, epirubicin, oxaliplatin, 5-fluorouracil; EOX, epirubicin, oxaliplatin, capecitabine; FAMTX, methotrexate, 5-fluorouracil, doxorubicin; FISH, fluorescence in situ hybridization; IF, irinotecan, 5-fluorouracil; IHC, immunohistochemistry; OS, overall survival; XP, capecitabine, cisplatin; XP/FP, capecitabine or 5-fluorouracil plus cisplatin.
XP[7]
EOX[6]
Trastuzumab + XP/FP[8]
HER2 IHC 2+/FISH+ or IHC 3+ 5 10 15
Median OS in Patients With Advanced Gastric Cancer (Mos)
1. Murad AM, et al. Cancer. 1993;72: Vanhoefer U, et al. J Clin Oncol. 2000;18: Ajani JA, et al. J Clin Oncol. 2010;28: Van Cutsem E, et al. J Clin Oncol. 2006;24: Dank M, et al. Ann Oncol. 2008;19: Cunningham D, et al. N Engl J Med. 2008;358: Kang YK, et al. Ann Oncol. 2009;20: Bang YJ, et al. Lancet. 2010;376: 16 16

17. 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 2+ and FISH+ (ratio > 2.0)

18. 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: Chua TC, et al. Int J Cancer. 2012;130:

19. 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??

20. Gastric INT 116: Postoperative Chemoradiotherapy vs Surgery Alone
20% were GEJ tumors
Similar survival benefit in this subset
100 OS 80 60
Chemoradiotherapy
Patients (%) 40 20
Surgery only 24 48 72 96
120
Mos After Registration
Macdonald JS, et al. N Engl J Med. 2001;345:

21. Meta-analysis: Surgery vs Surgery + Any Adj CT in Resectable GC
Survival benefit for addition of chemotherapy
100
Any chemotherapy
Surgery alone 90 80 70 60
Survival (%) 50 40 30 20
HR: 0.82 (95% CI: ; P < .001) 10 1 2 3 4 5 6 7 8 9 10
Yrs From Randomization
Pts at Risk, n
Any chemotherapy
Surgery along
GASTRIC Group, et al. JAMA. 2010;303: 21

22. 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/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
1. Bang YJ, et al. Lancet. 2012;379: Cunningham D, et al. N Engl J Med. 2006;355: Sakuramoto S, et al. N Engl J Med. 2007;357:

23. 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
Regimens
Primary Endpoint
Primary Endpoint Results
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
1. Fuchs CS, et al. ASCO Abstract Lee J, et al. J Clin Oncol. 2012;30:

24. RTOG 1010: Neoadjuvant Phase III Trial in Esophageal/GEJ Adenocarcinoma
Stratified by presence of adenopathy and involved celiac nodes
Radiation (50.4 Gy) + Paclitaxel + Carboplatin + Trastuzumab
Surgery 5-8 wks after radiation completion
Maintenance Trastuzumab q3w x 13
Patients with confirmed HER2-overexpressing esophageal or GEJ adenocarcinoma (Planned N = 160)
Radiation (50.4 Gy) + Paclitaxel + Carboplatin
Surgery 5-8 wks after radiation completion
DFS, disease-free survival; GEJ, gastroesophageal junction; HR, hazard ratio; RTOG, Radiation Therapy Oncology Group.
Primary endpoint: DFS (15 → 27 mos; HR: 0.56)
Principal investigator: H. Safran, Providence, RI. ClinicalTrials.gov. NCT

25. LOGiC: Phase III Trial of Lapatinib + CapeOx in HER2+ Gastric Cancer
CapeOx + Lapatinib
Patients with HER2-amplified locally advanced, unresectable, or metastatic gastric, esophageal, or GEJ cancer (Planned N = 535)
CapeOx + Placebo
CapeOx, capecitabine + oxaliplatin; GEJ, gastroesophageal junction; OS, overall survival; PFS, progression-free survival.
Primary endpoint: OS (was PFS)
Data expected mid-2012
ClinicalTrials.gov. NCT

26. 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
ADCC, antibody-dependent cellular cytotoxicity; EGFR, epidermal growth factor receptor.
Hubbard SR. Cancer Cell 2005;7: 26

27. Paclitaxel + Lapatinib
Second-line Paclitaxel + Lapatinib vs Paclitaxel for Advanced Gastric Cancer
Paclitaxel + Lapatinib
Patients with HER2-amplified gastric cancer and PD after 1 previous 5-FU and/or cisplatin regimen (N = 273)
Paclitaxel
Primary endpoint
Initial pilot analysis: tolerability to determine optimal dosing
Randomized part: OS
ClinicalTrials.gov. NCT

28. Phase II Studies of Targeted Agents in HER2-Positive Disease
PF , pan-EGFR inhibitor (NCT )
AUY922, Hsp90 inhibitor (NCT )
Pertuzumab + trastuzumab + chemotherapy (NCT )
Bevacizumab + trastuzumab + docetaxel, oxaliplatin and capecitabine chemotherapy (NCT )
Bevacizumab + trastuzumab + capecitabine and oxaliplatin (NCT )
Afatinib (NCT )
ClinicalTrials.gov.

29. 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

30. Go Online for More CCO Coverage of Chicago 2012!
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