Metastatic Gastric Cancer

John L. Marshall, MD

Lombardi Cancer Center

Georgetown University

Washington DC

• 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

Gastric cancer: a global disease

www.cancer.govKamangar F et al. J Clin Oncol 2006;24:2137–50

20 / 100 000

<10 / 100 000 10 - 20 / 100 000

Incidence (males)

Neo-adjuvant and adjuvant therapy for gastric cancer: different

strategies

Post-operative Post-operative

ChemoradiotherapyChemoradiotherapy

(trend to perioperative CT(trend to perioperative CT

in academic centers)in academic centers)

Peri-operative Peri-operative

ChemotherapyChemotherapy

(ECF- 5FU/cisplatin)(ECF- 5FU/cisplatin)

Post-operative Post-operative

ChemotherapyChemotherapy

(5FU/Xeloda or combination)(5FU/Xeloda or combination)

Postoperative CT

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

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)

Esophagogastric Cancer: Siewart Classification

From Siewart, J Surg Onc 2005,

v. 90: 139

Role of Docetaxel: V 325 Phase III

RANDOMIZE

Stratification Factors:

Liver Involvement

Prior Gastrectomy

Measurable vs

Evaluable Disease

Weight Loss (>5%) inPrior 3 Months

Centers

Adequate hydration and anti-emetics required, No Prophylactic Growth FactorsResponse assessment every 8 weeks independent of treatment schedule

Cisplatin 100 mg/m2/IV over 1-3 hrs

Cycles repeated every 4 weeks

Docetaxel 75 mg/m2 IV over 1 hr

Cisplatin 75 mg/m2 IV over 1-3 hrsboth on Day 1 only

5-FU 750 mg/m2/day by CIV over5 days Days 1-5

Cycles repeated every 3 weeks

5-FU 1000 mg/m2/day by CIV over5 days Days 1-5

Results: TAX 325

DCF (227) CF (230)

36.7% ORR (P=0.02) 25.4%

5.6 months Med. TTP (p=0.0004)

3.7 months

9.2 months Med. Survival

(HR=1.29, p=0.02)

8.6 months

40.2% 1-yr. Survival 31.6%

18.4% 2-yr. Survival 8.8%

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 %

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?

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)

REAL-2

2x2 design (ECF, EOF, ECX, EOX)

Cycles repeated every 21 days

– Epirubicin 50 mg/m2 IV D#1

– Cisplatin 60 mg/m2 IV D#1 or Oxaliplatin 130 mg/m2 IV D#1

– 5-Fluorouracil 200 mg/m2/d IVCI or Capecitabine 625 mg/m2 PO BID

Cunningham, NEJM 2008, v358, p. 42

Cunningham, NEJM 2008, v 358, p. 41

Cunningham, NEJM 2008, v358, p 44

CALGB 80403 / ECOG E1206: Schema

Stratification:ECOG 0-1 vs 2ADC vs. SCC

ARM A: (ECF + cetuximab); 1 cycle = 21 days

Cetuximab 400 250mg/m2 IV, weeklyEpirubicin 50 mg/m2 IV, day 1Cisplatin 60mg/m2 IV, day 1Fluorouracil 200mg/m2/day, days 1-21

ARM B: (IC + cetuximab); 1 cycle = 21 days

Cetuximab 400 250mg/m2 IV, weeklyCisplatin 30 mg/m2 IV, days 1 and 8Irinotecan 65 mg/m2 IV, days 1 and 8

ARM C: (FOLFOX + cetuximab); 1 cycle = 14 days

Cetuximab 400 250mg/m2 IV, weeklyOxaliplatin 85 mg/m2 IV, day 1Leucovorin 400 mg/m2, day 1Fluorouracil 400 mg/m2 IV bolus, day 1Fluorouracil 2400 mg/m2 IV over 46hrs (days 1-2)

CALGB 80403/ECOG 1206: Response

ECF-C N=64

IC-C N=68

FOLFOX-C N=69

Response CR 0 1 ( 1%) 2 ( 3%)

PR 37 (58%) 30 (44%) 35 (51%)

SD 15 (23%) 23 (34%) 19 (28%)

PD 4 ( 6%) 10 (15%) 8 (12%)

Not eval / unknown 5 / 3 (8% /5%) 2 / 2 (3% /3%) 3 / 2 (4% /3%) Objective Response Rate*

(CR+PR)/total 57.8 45.6 53.6

(90% C.I.) 46.8 68.3 35.2 56.3 43.1 64.0

p vs. H0<0.25 <.0001 <.0001 <.0001 Response duration (mos) median 6.1 5.3 5.7

range 0.5 - 22.7 0.5 - 20.1 2.4 - 18.2

*RECIST - confirmed; restaging every 6 weeks

0 5 10 15 20 25

Months from Study Entry

0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n S

urv

ivin

g ECF-C (n=67)IC-C (n=71)FOLFOX-C (n=72)

CALGB 80403/ECOG 1206: Overall Survival by Arm

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

HER2 and trastuzumab mechanism of action

HER2 receptortrastuzumab

Trastuzumab

Inhibits HER2-mediated signalling in HER2-positive tumors

Prevents HER2 activation by blocking extracellular domain cleavage

Activates antibody-dependent cellular cytotoxicity

The Rules for EGFR Targeting

Breast- HER2 overexpression

Colon- KRAS

Lung- ATP binding site mutations

Gastric- Do we actually know?

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

HER2 testing – 2 main methods

1. Immunohistochemistry (IHC)

– Shows how much of the HER2 protein is present in the tumour sample

HER2-negative HER2-positive

HER2 testing – 2 main methods

2. Fluorescence in-situ hybridization (FISH)

– Measures the amount of the HER2/neu gene in each cell

HER2-negative HER2-positive

ToGA trial design

HER2-positiveadvanced GC

(n=584)

5-FU or capecitabinea + cisplatin(n=290)

R

aChosen at investigator’s discretion GEJ, gastroesophageal junction

5-FU or capecitabinea + cisplatin

+ trastuzumab(n=294) Stratification factors

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

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

1Bang et al; Abstract 4556, ASCO 2009

3807 patients screened1

810 HER2-positive (22.1%)

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

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)− α-level = 0.05, 80% power− required sample size: 584 patients randomized 1:1

Analyses− 1st pre-planned interim analysis after 230 events (50%)− 2nd interim analysis after 345 events (75%) considered final by

Independent Data Monitoring Committee

Main patient selection criteria

Exclusion criteria

• Previous adjuvant chemotherapy within 6 months • Chemotherapy for advanced disease• Congestive heart failure or baseline LVEF <50%• Creatinine clearance <60 mL/min

Exclusion criteria

• Previous adjuvant chemotherapy within 6 months • Chemotherapy for advanced disease• Congestive heart failure or baseline LVEF <50%• Creatinine clearance <60 mL/min

IHC, immunohistochemistry; FISH, fluorescence in situ hybridization; LVEF, left ventricular ejection fraction

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

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

Patient demographics and baseline characteristics

Characteristic F+Cn=290

F+C + trastuzumabn=294

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

74.2a

8.7a

17.1a

76.8b

8.9b

14.3b

Prior gastrectomy 21.4 24.1

Highest recruitment was from Korea, Japan, China and Russia F, fluoropyrimidine; C, cisplatin an=287; bn=293

Primary end point: OS

Time (months)

294290

277266

246223

209185

173143

147117

11390

9064

7147

5632

4324

3016

2114

137

126

65

40

10

00

No. at risk

11.1 13.8

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

Event

FC + TFC

Events

167182

HR

0.74

95% CI

0.60, 0.91

p value

0.0046

MedianOS

13.811.1

T, trastuzumab

Secondary end point: PFS

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Event

294290

258238

201182

14199

9562

6033

4117

287

215

133

93

82

62

61

61

40

20

00

5.5 6.7

No. at risk

0.00.10.20.30.40.50.60.70.80.91.0

Time (months)

FC + TFC

Events

226235

HR

0.71

95% CI

0.59, 0.85

p value

0.0002

MedianPFS

6.75.5

Secondary end point: tumor response rate

2.4%5.4%

32.1%

41.8%

34.5%

47.3%

Intent to treat

ORR= CR + PRCR, complete response; PR, partial response

p=0.0599

p=0.0145

F+C + trastuzumab

F+C

p=0.0017Patients (%)Patients (%)

CRCR PRPR ORRORR

113

OS in IHC2+/FISH+ or IHC3+ (exploratory analysis)

1.0

0.8

0.6

0.4

0.2

0.0

363432302826242220181614121086420

Time (months)

11.8 16.0

FC + T

FC

Events

120136

HR

0.65

95% CI

0.51, 0.83

MedianOS

16.011.8

Event

0.1

0.3

0.5

0.7

0.9

218 198

40

53

124

2011

228 218

196 170

170 141

142 112

12296

10075

8453

6539

5128

10

00

No. at risk

3920

2813

Safety: non-hematological AEs

AE, %

F+Cn=290

F+C + trastuzumabn=294

All Grade 3/4 All Grade 3/4

NauseaVomitingFatigueDiarrheaConstipationAstheniaStomatitisWeight decreaseAbdominal pain

634628283218151414

782423221

675035372619242316

7649

<14

<121

AEs occurring in >10% of patients

Safety: cardiac AEs

aMeasured at baseline and every 12 weeks; MI, myocardial infarction

Cardiac event, n (%) F+C(n=290)

F+C + trastuzumab (n=294)

All Grade 3/4 All Grade 3/4

Cardiac AEs, total 18 (6) 9 (3) 17 (6) 4 (1)

Cardiac failure 2 (<1) 2 (<1) 1 (<1) 1 (<1)

Asymptomatic LVEF dropsa

<50% <50% and by 10%

2 (1.1)2 (1.1)

14 (5.9)11 (4.6)

Cardiac AEs leading to death 2 (<1)Cardiac arrest;

cardio-respiratory arrest

2 (<1)Acute MI; angina unstable and

cardiac failure

Cardiac AEs related to treatment 2 (<1) 2 (<1)

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; p=0.0046) 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

AVAGAST: A Randomized Double-Blind Placebo- Controlled Phase III Study

Starting dose of bev/placebo: 30 minutes, subsequent doses: 15 minutes

Capecitabine*/Cisplatin (XP)

+ Placebo q3w

Capecitabine*/Cisplatin (XP)

+ Bevacizumab q3w

Locally advanced or metastatic gastric cancer

R

*5-FU also allowed if cape contraindicated

Cape 1000 mg/m2 oral bid, d1–14, 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

Stratification factors:

1. Geographic region

2. Fluoropirimidine backbone

3. Disease status

Patient Characteristics (I)

Number of patients N=774 (%)XP + Placebo

N=387XP + Bev

N=387

Gender Male 258 (67) 257 (66)

Age, years Median (range) 59 (22–82) 58 (22–81)

ECOG PS 0–1≥2

367 (95)20 (5)

365 (94)22* (6)

Region AsiaEuropePan-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 advancedMetastatic

9 (2)378 (98)

20 (5)367 (95)

*1 additional patient had an ECOG PS of 4

Patient Characteristics (II)

Number of patients N=774 (%)XP + Placebo

N=387XP + Bev

N=387

Primary siteStomachGEJ

338 (87)49 (13)

333 (86)54 (14)

Histologic typeIntestinalDiffuseMixed

135 (35)206 (53)26 (7)

155 (40)176 (46)35 (9)

Disease measurability

MeasurableEvaluable

297 (77)90 (23)

311 (80)76 (20)

Metastatic sites, n01≥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)

Overall Survival

387387

343355

271291

204232

146178

98104

1519

XP + PlaceboXP + Bev

Number at risk

5450

00

XP + Placebo

XP + Bev

HR = 0.87

95% CI 0.73–1.03

p = 0.1002

Survival rate

3 9 15 18 21 240

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

6 12

Study month

10.1

12.1

Progression-Free Survival

387387

279306

145201

86123

5571

3238

33

1511

00

XP + PlaceboXP + Bev

Number at risk

XP + Placebo

XP + Bev

HR = 0.80

95% CI 0.68–0.93

p = 0.0037

Progression-free survival rate

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

3 9 15 18 21 240 6 12

5.3

6.7

Study month

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