The new era in gastric cancer treatment: targeting HER2 to improve survival

1
The new era in gastric cancer treatment
targeting HER2 to improve survival
2
Gastric cancer overview

• Gastric cancer is the fourth most commonly
  diagnosed cancer and the second most common cause
  of cancer-related deaths worldwide1,2,4
• Despite an overall decrease in gastric cancer
  there is a growing incidence of gastro-esophageal
  (GE) junction tumours in US and Western
  countries3
• Metastatic gastric cancer has a poor prognosis
• Median 5-year survival rate of around 201,2

1. Kamangar F, et al. J Clin Oncol 2006
2421372150 2. Garcia M, et al. Global Cancer
Facts and Figures 2007. Atlanta GA American
Cancer Society 2007
3. Kusano C, et al. J Gastroenterol Hepatol
2008 2316621665. 4. Gravalos C, et al. J Clin
Oncol 2008 19 (9) 1523-1529
3
Rationale for Herceptin in HER2-positive gastric
cancer

• Unmet need for new treatment options5
• No universal standard treatment5
• Some gastric adenocarcinomas are HER2-positive4
• HER2 positive status in GC appears to be
  associated with poorer prognosis, more aggressive
  disease, and shorter survival7
• Herceptin is effective against HER2-overexpressing
  gastric cancer cell lines in vitro and in vivo6

4. Gravalos C Jimeno A. Annals of Oncology
2008 1915231529. 5. Van Cutsem E, et al. J
Clin Oncol 2009 27Abstract 4509 6.
Fujimoto-Ouchi K, et al. Cancer Chemother
Pharmacol 2007 59795805. 7. Rüschoff et al.
Virchows Arch 2010 epub published online.
4
HER2 and trastuzumab mechanism of action
HER2 receptor
trastuzumab

• Trastuzumab
• Inhibits HER2-mediated signalling in
  HER2-positive tumors
• Prevents HER2 activation by blocking
  extracellular domain cleavage
• Activates antibody-dependent cellular cytotoxicity

5. Van Cutsem E, et al. J Clin Oncol 2009
27Abstract 4509
5
Herceptin in 1st line mGC and mGE junction
cancer EU approval

• EU commission approval was granted in January
  2010
• EMA (European Medicines Agency) full indication
• Herceptin in combination with capecitabine or
  5-fluorouracil and cisplatin is indicated for the
  treatment of patients with HER2-positive
  metastatic adenocarcinoma of the stomach or
  gastro-esophageal junction who have not received
  prior anti-cancer treatment for their metastatic
  disease
• Herceptin should only be used in patients with
  metastatic gastric cancer whose tumours have HER2
  overexpression as defined by IHC2 and a
  confirmatory SISH or FISH result, or IHC 3, as
  determined by an accurate and validated assay
• Approval based on the results of the ToGA trial

8. Herceptin EUSmPChttp//www.ema.europa.eu/docs/
en_GB/document_library/EPAR_Product_Information/hu
man/000278/WC500074922.pdf
6
Herceptin efficacy results in 1st line mGC and
mGE junction cancer

• Herceptin provides survival benefits in
  HER2-positive metastatic gastric cancer5
• Herceptin is well tolerated in HER2-positive
  metastatic gastric cancer5,9
• Herceptin is setting a new standard in
  HER2-positive gastric cancer care5,10

5. Van Cutsem E, et al. J Clin Oncol 2009
27Abstract 4509. 9. Satoh T, et al. ASCO GI
2010 Abstract 7. 10. Bang YJ, et al. J Clin
Oncol 2009 27Abstract 4556.
7
ToGA results presented at ASCO 2009 now published
in The Lancet
8
ToGA screening

• Patients (N3883) with locally advanced,
  recurrent and/or metastatic gastric or
  gastro-oesophageal (GE) junction cancer were
  screened for HER2 expression in a central
  laboratory
• Assessment was by immunohistochemistry (IHC) and
  fluorescence in situ hybridisation (FISH)
• Patients who tested IHC 3 and/or FISH were
  eligible for randomisation into the ToGA trial

5. Van Cutsem E, et al. J Clin Oncol 2009
27Abstract 4509.10. Bang YJ, et al. J Clin
Oncol 2009 27Abstract 4556.
9
HER2 screening results
n
Patients consented to enter screening 3,883
Total patients screened (Aug 2005Nov 2008) 3,807
Successful screenings FISH or IHC 3,667
Successful screenings FISH and IHC 3,280
HER2-negative by FISH and IHC 2,855
HER2-positive by FISH and/or IHC 810
HER2-positivity 22.1 according to protocol
(based on 3,667 successful screenings)
5. Van Cutsem E, et al. J Clin Oncol 2009
27Abstract 4509. 10. Bang YJ, et al. J Clin
Oncol 2009 27Abstract 4556. 11. Bang YJ Van
Cutsem E et al. The Lancet, 2010 376687-97
10
Breakdown of successful HER2 IHC and FISH
screening
HER2 status of cases with both IHC and FISH
results (n3280)
IHC 0 n () IHC 1 n () IHC 2 n () IHC 3 n () Total n ()
FISH 94 (4.9) 96 (15.7) 212 (54.6) 354 (94.9) 756 (23)
FISH 1815 (95.1) 514 (84.3) 176 (45.4) 19 (5.1) 2524 (77)
Total 1909 (100) 610 (100) 388 (100) 373 (100) 3280 (100)
Out of 2519 IHC 0/1 cases, 7.5 scored FISHOut
of 761 IHC 2/3 cases, 74.4 scored FISH
10. Bang YJ, et al. J Clin Oncol 2009
27Abstract 4556. 11. Bang YJ Van Cutsem E et
al. The Lancet, 2010 376687-97
11
Breakdown of all HER2-positive cases (n810)
IHC 0 IHC 1 IHC 2 IHC 3 No IHC
FISH 94 96 212 354 10
FISH 19
No FISH result 25

• 810 cases (out of 3667 successfully tested for
  HER2)were HER2-positive according to the ToGA
  protocol (?22)
• 610 cases had high HER2 protein expression (?16)
• 594 patients fulfilled the protocol eligibility
  criteria and were randomised in ToGA

10. Bang YJ, et al. J Clin Oncol 2009
27Abstract 4556. 11. Bang YJ Van Cutsem E et
al. The Lancet, 2010 376687-97
12
The HER2 rate is higher in GE junction tumours
Gastric cancer GEJcancer
HER2 ve () 20.9 33.2
Patients
10. Bang YJ, et al. J Clin Oncol 2009
27Abstract 4556.
plt0.001
13
The HER2 rate is higher in intestinal tumours
Intestinal Diffuse Mixed Total
HER2-positive, n 607 67 130 804
HER2-negative, n 1277 1031 507 2815
Total, n 1884 1098 637 3619
HER2-positive, 32.2 6.1 20.4 22.2
plt0.001 vs diffuse
10. Bang YJ, et al. J Clin Oncol 2009
27Abstract 4556.
14
ToGA trial design
Capecitabineor 5-FU cisplatin (XP/FP) (n290)
HER2-positivelocally advanced or recurrent
and/or metastatic GC (n584)
3,807 patients screened 810 HER2-positive
R
Capecitabineor 5-FU cisplatin (XP/FP)
Herceptin (n294)

• Primary objective OS
• Secondary endpoints included PFS, TTP, ORR,
  duration of response, safety

Total recruited 594 patients (10 patients did
not receive study drug and were excluded from
analyses). 5-FU, 5-fluorouracil GC, gastric
cancer R, randomised.
10. Bang YJ, et al. J Clin Oncol 2009
27Abstract 4556. 11. Bang YJ Van Cutsem E et
al. The Lancet, 2010 376687-97
15
Main patient selection criteria

• Inclusion criteria
• Adenocarcinoma of stomach or GE junction
• Inoperable locally advanced, recurrent and/or
  metastatic disease
• Measurable disease (RECIST) or non-measurable
  evaluable disease
• HER2-positive tumour (centrally assessed)
• IHC 3 or FISH
• Adequate organ function ECOG performance status
  2
• Written informed consent
• Exclusion criteria
• Chemotherapy for advanced disease
• History of congestive heart failure or baseline
  LVEF lt50
• Creatinine clearance lt 60 mL/min

ECOG, Eastern Cooperative Oncology Group FISH,
fluorescence in situ hybridisationIHC,
immunohistochemistry LVEF, left ventricular
ejection fraction.
10. Bang YJ, et al. J Clin Oncol 2009
27Abstract 4556. 11. Bang YJ Van Cutsem E et
al. The Lancet, 2010 376687-97
16
Treatment regimens

• Herceptin
• 8 mg/kg loading dose followed by 6 mg/kg
• q3w until disease progression
• Cisplatin
• 80 mg/m2, d1
• q3w x 6
• Xeloda
• 1,000 mg/m2 bid, d114
• q3w x 6

• 5-FU
• 800 mg/m2/day continuous iv infusion, d15
• q3w x 6

or
5. Van Cutsem E, et al. J Clin Oncol 2009
27Abstract 4509. 11. Bang YJ Van Cutsem E et
al. The Lancet, 2010 376 687-97
17
Patient demographics and baseline characteristics
Characteristic Herceptin XP/FP(n294) XP/FP(n290)
Sex, male/female 77/23 75/25
Age, median (range), years 61 (2383) 59 (2182)
Weight, median (range), kg 61.5 (35110) 60.3 (28105)
Region, n ()
Asia 158 (53) 166 (56)
C/S America 27 (9) 26 (9)
Europe 99 (33) 95 (32)
Other 14 (5) 9 (3)
Type of gastric cancer(central assessment),
Intestinal 76.8 74.2
Diffuse 8.9 8.7
Mixed 14.3 17.1
Prior gastrectomy, 24.1 21.4
n293 n287.
5. Van Cutsem E, et al. J Clin Oncol 2009
27Abstract 4509. 11. Bang YJ Van Cutsem E et
al. The Lancet, 2010 376 687-97
18
Stratification factors at randomisation
Characteristic Herceptin XP/FP(n294) XP/FP(n290)
Extent of disease,
Locally advanced 3 3
Metastatic 97 97
Measurable disease, 91 89
Primary site,
Stomach 80 83
GE junction 20 17
ECOG performance status,
01 90 91
2 10 9
Chemotherapy regimen,
XP 87 88
FP 13 12
5. Van Cutsem E, et al. J Clin Oncol 2009
27Abstract 4509. 11. Bang YJ Van Cutsem E et
al. The Lancet, 2010 376 687-97
19
Herceptin XP/FP improves OS vs XP/FP alone
Median OS HR 95 CI p-value
Herceptin XP/FP 167 13.8 mo 0.74 0.60, 0.91 0.0046
XP/FP 182 11.1 mo
Events
1.0
0.9
0.8
0.7
0.6
0.5
Probability
0.4
0.3
0.2
11.1
13.8
0.1
0.0
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
Time (months)
No. at risk
294 290
277 266
246 223
209 185
173 143
147 117
113 90
90 64
71 47
56 32
43 24
30 16
21 14
13 7
12 6
6 5
4 0
1 0
0 0
5. Van Cutsem E, et al. J Clin Oncol 2009
27Abstract 4509. 11. Bang YJ Van Cutsem E et
al. The Lancet, 2010 376 687-97
20
Efficacy OS subgroup analysis
5. Van Cutsem E, et al. J Clin Oncol 2009
27Abstract 4509. 11. Bang YJ Van Cutsem E et
al. The Lancet, 2010 376 687-97
21
Herceptin XP/FP improves PFS vs XP/FP alone
Median PFS HR 95 CI p-value
Herceptin XP/FP 226 6.7 mo 0.71 0.59, 0.85 0.0002
XP/FP 235 5.5 mo
Events
1.0
0.9
0.8
0.7
0.6
0.5
Probability
0.4
0.3
0.2
5.5
6.7
0.1
0.0
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
Time (months)
No. at risk
294 290
258 238
201 182
141 99
95 62
60 33
41 17
28 7
21 5
13 3
9 3
8 2
6 2
6 1
6 1
4 0
2 0
0 0
PFS, progression free survival.
5. Van Cutsem E, et al. J Clin Oncol 2009
27Abstract 4509. 11. Bang YJ Van Cutsem E et
al. The Lancet, 2010 376 687-97
22
Herceptin improves all efficacy parameters
Herceptin XP/FP(n294)
XP/FP(n290)
Endpoint
HR(95 CI)
p-value
13.8
11.1
OS, median months
0.74 (0.60, 0.91)
0.0046
6.7
5.5
0.0002
PFS, median months
0.71 (0.59, 0.85)
7.1
5.6
0.0003
0.70 (0.58, 0.85)
TTP, median months
47
0.0017
35
ORR,
1.70 (1.22, 2.38)
6.9
lt0.0001
4.8
DoR, median months
0.53 (0.39, 0.73)
Odds ratio TTP, time-to-progression ORR,
overall response rate DoR, duration of response.
Odds ratio.
5. Van Cutsem E, et al. J Clin Oncol 2009
27Abstract 4509. 11. Bang YJ Van Cutsem E et
al. The Lancet, 2010 376 687-97
23
OS by HER2 status
Subgroup
Median OS (months)
HR
95 CI
N
All
11.1
13.8
vs
0.74
0.60, 0.91
584
Pre-planned analysis
IHC 0/FISH IHC 1/FISH IHC 2/FISH IHC
3/FISH IHC 3/FISH-
7.2 10.2 10.8 12.3 17.7
10.6 8.7 12.3 17.9 17.5
vs vs vs vs vs
0.92 1.24 0.75 0.58 0.83
0.48, 1.76 0.70, 2.20 0.51, 1.11 0.41, 0.81 0.20,
3.38
61 70 159 256 15
Exploratory analysis
8.7 11.8
10.0 16.0
vs vs
1.07 0.65
0.70, 1.62 0.51, 0.83
131 446
IHC 0 or 1/FISH IHC 2/FISH or IHC 3
Risk ratio
Favours H
Favours no H
5. Van Cutsem E, et al. J Clin Oncol 2009
27Abstract 4509. 11. Bang YJ Van Cutsem E et
al. The Lancet, 2010 376 687-97
24
OS in the IHC 2/FISH and IHC 3 subgroup
(exploratory analysis)
Median OS HR 95 CI
Herceptin XP/FP 120 16.0 mo 0.65 0.51, 0.83
XP/FP 136 11.8 mo
Events
1.0
0.9
0.8
0.7
0.6
0.5
Probability
0.4
0.3
0.2
0.1
11.8
16.0
0.0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
0
Time (months)
No. at risk
0 0
1 0
11 3
218 198
4 0
5 3
12 4
20 11
228 218
196 170
170 141
142 112
12296
100 75
84 53
65 39
51 28
39 20
28 13
5. Van Cutsem E, et al. J Clin Oncol 2009
27Abstract 4509. 11. Bang YJ Van Cutsem E et
al. The Lancet, 2010 376 687-97
25
Herceptin does not impact on the overall safety
profile (1)
Adverse event, Herceptin XP/FPn294 Herceptin XP/FPn294 XP/FPn290 XP/FPn290
Adverse event, All grades Grade 3/4 All grades Grade 3/4
Nausea 67 7 63 7
Anorexia 46 6 46 6
Vomiting 50 6 46 8
Constipation 26 1 32 2
Fatigue 35 4 28 2
Diarrhoea 37 9 28 4
Handfoot syndrome 26 1 22 2
Asthenia 19 5 18 3
Stomatitis 24 1 15 2
Weight decrease 23 2 14 2
Abdominal pain 22 2 19 2
Occurring in gt10 of patients occurring in gt5
of patients.
5. Van Cutsem E, et al. J Clin Oncol 2009
27Abstract 4509. 11. Bang YJ Van Cutsem E et
al. The Lancet, 2010 376 687-97
26
Herceptin does not impact on the overall safety
profile (2)
Adverse event, Herceptin XP/FPn294 Herceptin XP/FPn294 XP/FPn290 XP/FPn290
Adverse event, All grades Grade 3/4 All grades Grade 3/4
Renal impairment 16 1 13 1
Pyrexia 18 1 12
Dehydration 6 2 6 2
Dyspnoea 3 lt1 6 2
Mucosal inflammation 13 2 6 1
Nasopharyngitis 13 6
Haematological AEs
Neutropenia 53 27 57 30
Anaemia 28 12 21 10
Thrombocytopenia 16 5 11 3
Occurring in gt10 of patients occurring in gt5
of patients.
5. Van Cutsem E, et al. J Clin Oncol 2009
27Abstract 4509. 11. Bang YJ Van Cutsem E et
al. The Lancet, 2010 376 687-97
27
Herceptin does not impact on the cardiac safety
profile
Cardiac adverse event, n () Herceptin XP/FPn294 Herceptin XP/FPn294 XP/FPn290 XP/FPn290
Cardiac adverse event, n () All grades Grade 3/4 All grades Grade 3/4
Cardiac AEs, total 17 (6) 4 (1) 18 (6) 9 (3)
Cardiac failure 1 (lt1) 1 (lt1) 2 (lt1) 2 (lt1)
LVEF drops
lt50 14 (5.9) 14 (5.9) 2 (1.1) 2 (1.1)
lt50 and by 10 11 (4.6) 11 (4.6) 2 (1.1) 2 (1.1)
Cardiac AEsleading to death 2 (lt1)Acute MI angina unstable cardiac failure 2 (lt1)Acute MI angina unstable cardiac failure 2 (lt1)Cardiac arrest cardio respiratory arrest 2 (lt1)Cardiac arrest cardio respiratory arrest
Measured at baseline and every 12 weeks MI,
myocardial infarction.
5. Van Cutsem E, et al. J Clin Oncol 2009
27Abstract 4509. 11. Bang YJ Van Cutsem E et
al. The Lancet, 2010 376687-97
28
Summary

• Herceptin is the first biological to show a
  survival benefit in patients with locally
  advanced, recurrent and/or metastatic gastric and
  GE junction cancer
• Herceptin plus chemotherapy was well tolerated
• No difference in overall safety profile,
  including cardiac AEs, between treatment arms
• Herceptin in combination with chemotherapy is a
  new treatment option for patients with
  HER2-positive gastric adenocarcinoma

5. Van Cutsem E, et al. J Clin Oncol 2009
27Abstract 4509. 11. Bang YJ Van Cutsem E et
al. The Lancet, 2010 376 687-97
29
Conclusion

• Herceptin provides survival benefits in
  HER2-positive metastatic gastric cancer
• Herceptin is well tolerated in HER2-positive
  metastatic gastric cancer
• Herceptin is setting a new standard in
  HER2-positive gastric cancer care
• Reimbursement of Herceptin in GC and GE junction
  cancer effective since October 1st, 2010

5. Van Cutsem E, et al. J Clin Oncol 2009
27Abstract 4509. 9. Satoh T, et al. ASCO GI
2010 Abstract 7. 10. Bang YJ, et al. J Clin
Oncol 2009 27Abstract 4556.