Metastatic Gastric Cancer

1
Metastatic Gastric Cancer

• John L. Marshall, MD
• Lombardi Cancer Center
• Georgetown University
• Washington DC

2
Gastric cancer a global disease

• 4th most common malignant disease 930,000
• 2nd most common cause of cancer-related death
  worldwide 700,000
• Falling incidence of distal gastric cancer
• Increasing incidence of proximal gastric cancer
• Wide geographical variation

Incidence (males)
?20 / 100 000
?10 - ?20 / 100 000
lt10 / 100 000
www.cancer.gov Kamangar F et al. J Clin Oncol
200624213750
3
Neo-adjuvant and adjuvant therapy for gastric
cancer different strategies
Peri-operative Chemotherapy (ECF- 5FU/cisplatin)
Post-operative Chemoradiotherapy (trend to
perioperative CT in academic centers)
Postoperative CT
Post-operative Chemotherapy (5FU/Xeloda or
combination)
4
North American Perspective

• We see more proximal tumors
• Surgery first dominates in community hospitals
• Chemotherapy first dominates in academic centers
• We are unsure what to do with radiation
• Our patients are typically quite ill from the
  beginning

5
State of the Art

• More than one disease
• Gastric- low acid
• Esophageal tobacco, alcohol
• GE Junction- high acid
• Different cancers in different parts of the world
• Asia ? Western
• No regional or global standards
• Surgical differences
• Chemotherapy differences
• Sequence of therapy differences
• (Chemo, Surgery, Radiation)

6
Esophagogastric Cancer Siewart Classification
From Siewart, J Surg Onc 2005, v. 90 139
7
Role of Docetaxel V 325 Phase III
Stratification Factors
Docetaxel 75 mg/m2 IV over 1 hr
Cisplatin 75 mg/m2 IV over 1-3 hrsboth on Day 1
only
Liver Involvement
5-FU 750 mg/m2/day by CIV over5 days Days 1-5
Prior Gastrectomy

Cycles repeated every 3 weeks
Measurable vsEvaluable Disease
Cisplatin 100 mg/m2/IV over 1-3 hrs
Weight Loss (gt5) inPrior 3 Months
5-FU 1000 mg/m2/day by CIV over5 days Days 1-5
Cycles repeated every 4 weeks
Centers
Adequate hydration and anti-emetics required,
No Prophylactic Growth FactorsResponse
assessment every 8 weeks independent of treatment
schedule
8
Results TAX 325
DCF (227) CF (230)
36.7 ORR (P0.02) 25.4
5.6 months Med. TTP (p0.0004) 3.7 months
9.2 months Med. Survival (HR1.29, p0.02) 8.6 months
40.2 1-yr. Survival 31.6
18.4 2-yr. Survival 8.8
9
Toxicity TAX 325
DCF (221) Gr. 3-4 Toxicity ( of Pts) CF (224)
82 Neutropenia 57
66 Received GCSF 20
30 Neutro. Fever/Infect. 13
20 Diarrhea 8
21 Stomatitis 27
15 Vomiting 19
8 Neurologic 3
3.6 Death from Toxicity 5.4
10
DCF is too toxic- and not worth itmDCF vs
DCFShah et al ASCO 4014, 2010

• DCF is spicy- requires G-CSF
• mDCF less so
• 72 patients randomized
• mDCF had a better survival
• Does dose intensity matter in GI cancers?

11
Advanced Gastric Cancer REAL-2 Cunningham, NEJM
2008, v 358, p. 36

• 1002 pts with unresectable esophageal/ gastric
  cancer enrolled 6/00-5/05
• 63 yo (22-83)
• 81 male
• 78 metastatic
• 40 gastric, 35 esophageal, 25 GEJ
• 90 adenoCA
• 11 PS2
• Primary endpoint
• Survival
• non-inferiority design (23 boundary)

12
REAL-2

• 2x2 design (ECF, EOF, ECX, EOX)
• Cycles repeated every 21 days
• Epirubicin 50 mg/m2 IV D1
• Cisplatin 60 mg/m2 IV D1 or Oxaliplatin 130
  mg/m2 IV D1
• 5-Fluorouracil 200 mg/m2/d IVCI or Capecitabine
  625 mg/m2 PO BID

13
Cunningham, NEJM 2008, v358, p. 42
14
Cunningham, NEJM 2008, v 358, p. 41
15
Cunningham, NEJM 2008, v358, p 44
16
CALGB 80403 / ECOG E1206 Schema
ARM A (ECF cetuximab) 1 cycle 21
days Cetuximab 400 ? 250mg/m2 IV,
weekly Epirubicin 50 mg/m2 IV, day 1 Cisplatin
60mg/m2 IV, day 1 Fluorouracil 200mg/m2/day, days
1-21
ARM B (IC cetuximab) 1 cycle 21
days Cetuximab 400 ? 250mg/m2 IV,
weekly Cisplatin 30 mg/m2 IV, days 1 and
8 Irinotecan 65 mg/m2 IV, days 1 and 8
Stratification ECOG 0-1 vs 2 ADC vs. SCC
ARM C (FOLFOX cetuximab) 1 cycle 14
days Cetuximab 400 ? 250mg/m2 IV,
weekly Oxaliplatin 85 mg/m2 IV, day 1 Leucovorin
400 mg/m2, day 1 Fluorouracil 400 mg/m2 IV bolus,
day 1 Fluorouracil 2400 mg/m2 IV over 46hrs (days
1-2)
17
CALGB 80403/ECOG 1206 Response
RECIST - confirmed restaging every 6 weeks
18
CALGB 80403/ECOG 1206 Overall Survival by Arm
19
The ToGA trial A phase III study of trastuzumab
added to standard chemotherapy in first-line
human epidermal growth factor receptor 2
(HER2)-positive advanced gastric cancer
20
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

21
The Rules for EGFR Targeting

• Breast- HER2 overexpression
• Colon- KRAS
• Lung- ATP binding site mutations
• Gastric- Do we actually know?

22
HER2 testing

• HER2 testing in breast cancer is well established
• Recent evidence shows that same techniques with
  some modifications are also valid for assessing
  HER2 status in stomach cancer

1. Hoffmann 2008
23
HER2 testing 2 main methods

• Immunohistochemistry (IHC)
• Shows how much of the HER2 protein is present in
  the tumour sample

HER2-negative
HER2-positive
24
HER2 testing 2 main methods

• Fluorescence in-situ hybridization (FISH)
• Measures the amount of the HER2/neu gene in each
  cell

HER2-negative
HER2-positive
25
ToGA trial design

• Phase III, randomized, open-label, international,
  multicenter study

5-FU or capecitabinea cisplatin (n290)
3807 patients screened1 810 HER2-positive
(22.1)
HER2-positiveadvanced GC (n584)
R
5-FU or capecitabinea cisplatin
trastuzumab (n294)

• Stratification factors
• advanced vs metastatic
• GC vs GEJ
• measurable vs non-measurable
• ECOG PS 0-1 vs 2
• capecitabine vs 5-FU

aChosen at investigators discretion GEJ,
gastroesophageal junction
1Bang et al Abstract 4556, ASCO 2009
26
Treatment regimens

• Capecitabine1000 mg/m2 bid d1-14 q3w x 6
• 5-Fluorouracil 800 mg/m2/day continuous iv
  infusion d1-5 q3w x 6
• Cisplatin 80 mg/m2 q3w x 6
• Trastuzumab 8 mg/kg loading dose followed by 6
  mg/kg q3w until PD

27
ToGA trial end points

• Primary end point
• overall survival
• Secondary end points
• PFS, TTP, ORR, Clinical Benefit Rate, Duration of
  Response, QoL, safety, pain intensity,
  analgesic consumption, weight change,
  pharmacokinetics
• Sample size assumptions
• median OS improvement from 10 to 13 months (HR
  0.77)
• a-level 0.05, 80 power
• required sample size 584 patients randomized 11
• Analyses
• 1st pre-planned interim analysis after 230 events
  (50)
• 2nd interim analysis after 345 events (75)
  considered final by Independent Data Monitoring
  Committee

28
Main patient selection criteria

• Inclusion criteria
• Adenocarcinoma of stomach or GEJ
• Inoperable locally advanced and/or metastatic
  disease
• Measurable (RECIST), or non-measurable evaluable
  disease
• HER2-positive tumor (centrally assessed)
• IHC 3 and/or FISH
• Adequate organ function and ECOG performance
  status 2
• Written informed consent

• Exclusion criteria
• Previous adjuvant chemotherapy within 6 months
• Chemotherapy for advanced disease
• Congestive heart failure or baseline LVEF lt50
• Creatinine clearance lt60 mL/min

IHC, immunohistochemistry FISH, fluorescence in
situ hybridization LVEF, left ventricular
ejection fraction
29
Patient demographics and baseline characteristics
Characteristic FCn290 FC trastuzumabn294
Sex, Male / Female 75 / 25 77 / 23
Age, median (range) years 59.0 (21-82) 61.0 (23-83)
Weight, median (range) kg 60.3 (28-105) 61.5 (35-110)
Region, n ()AsiaC/S AmericaEuropeOther 166 (56)26 (9)95 (32)9 (3) 158 (53)27 (9)99 (33)14 (5)
Type of GC (central assessment)IntestinalDiffuseMixed 74.2a8.7a17.1a 76.8b8.9b14.3b
Prior gastrectomy 21.4 24.1
Highest recruitment was from Korea, Japan, China
and Russia F, fluoropyrimidine C, cisplatin
an287 bn293
30
Primary end point OS
MedianOS 13.811.1
1.0
Event
Events 167182
HR 0.74
95 CI 0.60, 0.91
p value 0.0046
0.9
FC T
0.8
FC
0.7
0.6
0.5
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
T, trastuzumab
31
Secondary end point PFS
MedianPFS 6.75.5
Event
1.0
Events 226235
HR 0.71
95 CI 0.59, 0.85
p value 0.0002
0.9
FC T
0.8
FC
0.7
0.6
0.5
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
32
Secondary end point tumor response rate
Intent to treat
p0.0017
FC trastuzumab
Patients ()
p0.0145
FC
47.3
41.8
34.5
32.1
p0.0599
5.4
2.4
CR
PR
ORR
ORR CR PRCR, complete response PR, partial
response
33
OS in IHC2/FISH or IHC3 (exploratory analysis)
MedianOS 16.011.8
1.0
Event
Events 120136
HR 0.65
95 CI 0.51, 0.83
0.9
FC T
0.8
0.7
FC
0.6
0.5
0.4
0.3
0.2
11.8
16.0
0.1
0.0
36
34
32
30
28
26
24
22
20
18
16
14
12
10
8
6
4
2
0
Time (months)
No. at risk
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
1 0
0 0
39 20
28 13
34
Safety non-hematological AEs
AE, FCn290 FCn290 FC trastuzumabn294 FC trastuzumabn294
AE, All Grade 3/4 All Grade 3/4
Nausea Vomiting Fatigue Diarrhea Constipation Asthenia Stomatitis Weight decrease Abdominal pain 63 46 28 28 32 18 15 14 14 7 8 2 4 2 3 2 2 1 67 50 35 37 26 19 24 23 16 7 6 4 9 lt1 4 lt1 2 1
AEs occurring in gt10 of patients
35
Safety cardiac AEs
Cardiac event, n () FC(n290) FC(n290) FC trastuzumab (n294) FC trastuzumab (n294)
Cardiac event, n () All Grade 3/4 All Grade 3/4
Cardiac AEs, total 18 (6) 9 (3) 17 (6) 4 (1)
Cardiac failure 2 (lt1) 2 (lt1) 1 (lt1) 1 (lt1)
Asymptomatic LVEF dropsa
lt50 lt50 and by ?10 2 (1.1)2 (1.1) 2 (1.1)2 (1.1) 14 (5.9)11 (4.6) 14 (5.9)11 (4.6)
Cardiac AEs leading to death 2 (lt1)Cardiac arrest cardio-respiratory arrest 2 (lt1)Cardiac arrest cardio-respiratory arrest 2 (lt1)Acute MI angina unstable and cardiac failure 2 (lt1)Acute MI angina unstable and cardiac failure
Cardiac AEs related to treatment 2 (lt1) 2 (lt1) 2 (lt1) 2 (lt1)
aMeasured at baseline and every 12 weeks MI,
myocardial infarction
36
Summary

• ToGA met the primary end point
• trastuzumab reduces the risk of death by 26 when
  combined with a reference chemotherapy (HR 0.74)
• prolongs the median survival by nearly 3 months
  (11.1 to 13.8 months p0.0046) in patients with
  HER2-positive advanced GC
• All secondary efficacy parameters (PFS, TTP, ORR,
  CBR, DoR) were also significantly improved
• Addition of trastuzumab to chemotherapy was well
  tolerated there was no difference in overall
  safety profile, including cardiac AEs, between
  treatment arms

37
AVAGAST A Randomized Double-Blind Placebo-
Controlled Phase III Study
Capecitabine/Cisplatin (XP) Placebo q3w
Locally advanced or metastatic gastric cancer
R
Capecitabine/Cisplatin (XP) Bevacizumab q3w
Stratification factors 1. Geographic region 2.
Fluoropirimidine backbone 3. Disease status
5-FU also allowed if cape contraindicated Cape
1000 mg/m2 oral bid, d114, 1-week rest Cisplatin
80 mg/m2 d1 Bevacizumab 7.5 mg/kg d1 Maximum of
6 cycles of cisplatin Cape and bevacizumab/placebo
until PD
Starting dose of bev/placebo 30 minutes,
subsequent doses 15 minutes
38
Patient Characteristics (I)
Number of patients N774 () Number of patients N774 () XP Placebo N387 XP Bev N387
Gender Male 258 (67) 257 (66)
Age, years Median (range) 59 (2282) 58 (2281)
ECOG PS 01 2 367 (95) 20 (5) 365 (94) 22 (6)
Region Asia Europe Pan-America 188 (49)124 (32)75 (19) 188 (49)125 (32)74 (19)
Fluoropyrimidine Capecitabine5-FU 365 (94)22 (6) 364 (94)23 (6)
Disease status Locally advanced Metastatic 9 (2) 378 (98) 20 (5) 367 (95)
1 additional patient had an ECOG PS of 4
39
Patient Characteristics (II)
Number of patients N774 () Number of patients N774 () XP Placebo N387 XP Bev N387
Primary site Stomach GEJ 338 (87) 49 (13) 333 (86) 54 (14)
Histologic type Intestinal Diffuse Mixed 135 (35) 206 (53) 26 (7) 155 (40) 176 (46) 35 (9)
Disease measurability Measurable Evaluable 297 (77) 90 (23) (80) 76 (20)
Metastatic sites, n 0 1 2 8 (2) 131 (34) 247 (64) 8 (2) 131 (34) 247 (64)
Prior gastrectomy Yes 107 (28) 110 (28)
Liver metastasis Yes 126 (33) 130 (34)
40
Overall Survival
Number at risk
387 387
343 355
271 291
204 232
146 178
98 104
15 19
XP Placebo XP Bev
54 50
0 0
41
Progression-Free Survival
Number at risk
387 387
279 306
145 201
86 123
55 71
32 38
3 3
15 11
0 0
XP Placebo XP Bev
42
Conclusion and Questions

• FOLFOX or XELOX- a new standard?
• Established role of Herceptin
• New role of Avastin?
• PFS , OS not
• Should we use Avastin beyond progression