Manish A. Shah, MD

1
Treatment of HER2-Positive Gastroesophageal
Carcinoma

• Manish A. Shah, MD
• Director,
• Gastrointestinal OncologyWeill Cornell Medical
  CollegeNewYork-Presbyterian HospitalNew York,
  New York

This program is supported by an educational
donation from
2
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3
Program Faculty

• Program Director
• Manish A. Shah, MDDirector, 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 cases1
• 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
  response2

1. NCCN. Clinical practice guidelines in
oncology gastric cancer, v2. 2011. 2. Power DG,
et al. Cancer Treat Rev. 201036384-392.
6
Gastroesophageal Cancer Systemic Therapy for
Metastatic Disease

• First-line options1
• DCF/modified DCF
• ECF/modified DCF
• Single agent or combination regimens
  (fluoropyrimidine or taxane based)
• Trastuzumab standard chemotherapy for HER2-
  positive tumors

• Second-line options1
• 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
  agents2

1. NCCN. Clinical practice guidelines in
oncology gastric cancer, v2. 2011. 2. Power DG,
et al. Cancer Treat Rev. 201036384-392.
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 lt 5 to 101,2
• BRAF mutation lt 51,2
• EGFR overexpression 50 to 803,4
• TKIs inactive4
• Cetuximab monotherapy inactive5
• EGFR mutation very low4,6
• HER2 overexpression 10 to 257
• HGF/c-Met over/aberrant expression reported in
  various human cancers, including gastric cancer8

1. Lee SH, et al. Oncogene. 2003226942-6945. 2.
Kim IJ, et al. Hum Genet. 2003114118-120. 3.
Galizia G, et al. World J Surg.
2007311458-1468. 4. Dragovich T, et al. J Clin
Oncol. 2006244922-4927. 5. Chan JA, et al. Ann
Oncol. 2011221367-1373. 6. Mammano E, et al.
Anticancer Res. 2006263547-3550. 7. Yano T, et
al. Oncol Rep. 20061565-71. 8. Birchmeier C, et
al. Nat Rev Mol Cell Biol. 20034915-925.
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)
(n 584)
Selected at investigators 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. 2010376687-697.
10
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. 2010376687-697.
11
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)
HR lt 1 favors chemotherapy trastuzumab HR gt 1
favors chemotherapy alone.
Bang YJ, et al. Lancet. 2010376687-697.
12
ToGA OS in IHC 2/FISH or IHC 3 (Exploratory
Analysis)
1.0
Events,n 120136
MedianOS, Mos 16.011.8
0.9
HR 0.65
95 CI 0.51-0.83
0.8
FC T
0.7
FC
0.6
0.5
Survival Probability
0.4
0.3
0.2
11.8
16.0
0.1
0
0
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
196170
170141
142112
12296
10075
8453
6539
5128
3920
2813
2011
124
113
53
4 0
1 0
0 0
FC
Bang YJ, et al. Lancet. 2010376687-697.
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 7
Cardiac events 6 6
Grade 3/4 1 3
LVEF reduction of 10 to absolute value lt 50 5 1
Chemotherapy plus trastuzumab n 237
chemotherapy alone n 187.
Bang YJ, et al. Lancet. 2010376687-697.
14
ToGA HER2 Positivity by IHC
Score Surgical Specimen Staining Pattern Biopsy Specimen Staining Pattern HER2 Overexpr. Assessment
0 No reactivity or membranous reactivity in lt 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. 2010376687-697. NCCN.
Clinical practice guidelines in oncology gastric
cancer, v2. 2011.
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 gt 2.2) 0 1 3 16 (100) 20 (15)
Negative (HER2/CEP17 lt 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
Data in parentheses show individual values, not
percentages.
Tafe LJ, et al. Arch Pathol Lab Med.
20111351460-1465.
16
Median OS Increased to gt 1 Yr With
Trastuzumab-Based Therapy
12 mos
BSC1
FAMTX2
C S13
CF4
IF5
EOF6
DCF4
ECF6
ECX6
XP7
EOX6
Trastuzumab XP/FP8
5
10
15
0
Median OS in Patients With Advanced Gastric
Cancer (Mos)
1. Murad AM, et al. Cancer. 19937237-41. 2.
Vanhoefer U, et al. J Clin Oncol.
2000182648-2657.3. Ajani JA, et al. J Clin
Oncol. 2010281547-1553. 4. Van Cutsem E, et al.
J Clin Oncol. 2006244991-4997.5. Dank M, et
al. Ann Oncol. 2008191450-1457. 6. Cunningham
D, et al. N Engl J Med. 200835836-46. 7. Kang
YK, et al. Ann Oncol. 200920666-673. 8. Bang
YJ, et al. Lancet. 2010376687-697.
17
Definition of HER2 Positivity for
Gastroesophageal Carcinoma
HER2-Positivity Requirements for Approved Trastuzumab Use HER2-Positivity Requirements for Approved Trastuzumab Use
US European Union
IHC 3 or FISH (ratio gt 2.0) IHC 3 or IHC 2 and FISH (ratio gt 2.0)
18
Prognostic Role of HER2 in Gastric Cancer

• Prognostic value of HER2 controversial with gt 20
  yrs of conflicting data
• Systematic literature analysis involving 12,749
  patients in 42 studies1
• 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
  survival2
• 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.
20123137-144. 2. Chua TC, et al. Int J Cancer.
20121302845-2856.
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 lt 50. Can we do better??

20
Gastric INT 116 Postoperative Chemoradiotherapy
vs Surgery Alone

• 20 were GEJ tumors
• Similar survival benefit in this subset

OS
100
80
60
Chemoradiotherapy
Patients ()
40
20
Surgery only
0
0
24
48
72
96
120
Mos After Registration
Macdonald JS, et al. N Engl J Med.
2001345725-730.
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 0.76-0.90 P lt .001)
10
0
0
2
3
7
9
1
4
5
6
8
10
Yrs From Randomization
Pts at Risk, n Any chemotherapy Surgery along
19241857
16881568
13851300
12171092
1080952
929782
709583
526407
390267
297172
243138
GASTRIC Group, et al. JAMA. 20103031729-1737.
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
CLASSIC1 Surgery vs surgery adjuvant capecitabine/oxaliplatin 3-yr DFS 59 vs 74 lt .0001
MAGIC2 Surgery vs surgery periop ECF 5-yr OS 23 vs 36 .009
Sakuramoto et al3 Surgery vs surgery adjuvant S-1 3-yr OS 70 vs 80 .003
1. Bang YJ, et al. Lancet. 2012379315-321. 2.
Cunningham D, et al. N Engl J Med.
200635511-20. 3. Sakuramoto S, et al. N Engl J
Med. 20073571810-1820.
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 PrimaryEndpointResults P Value
CALGB 801011 Postop 5-FU/LV CRT vs ECF CRT OS 37 vs 38 mos .80
ARTIST2 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. 201230268-273.
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

• Primary endpoint DFS (15 ? 27 mos HR 0.56)

Principal investigator H. Safran, Providence,
RI. ClinicalTrials.gov. NCT01196390.
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

• Primary endpoint OS (was PFS)
• Data expected mid-2012

ClinicalTrials.gov. NCT00680901.
26
Pertuzumab Trastuzumab Bind Distinct Epitopes
on HER2 Extracellular Domain
Trastuzumab
Pertuzumab

• 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

Hubbard SR. Cancer Cell 20057287-288.
27
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. NCT00486954.
28
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.
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
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