Werner ScheithauerProfessor of Internal Medicine,

Cancer Center at the Vienna University Hospital, Austria

Capecitabine: the new standard chemotherapy in advanced

gastric cancer?

Werner Scheithauer University Hospital

Vienna, Austria

Second most common cause of cancer mortalityWorldwide: 934, 000 new cases and 700, 000 deaths/year

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 to 20/100,000

Gastric cancerincidence

17%

15% 68%

10–15%

25–30% 30–35%

25–30%

Japan1

Resectable

Locally advanced

Metastatic

Western countries2

Resectable

Locally advanced

Metastatic

Unstaged

1http://www.ncc.go.jp/en/ncch/annrep/20002sanofi-aventis Internal Epidemiology Data

Stage at diagnosis

Non-measurable lesions

Variable study inclusion criteria

Heterogeneous patient populations

Inadequate number of patients

Response rate rather than survival

Palliative chemotherapy for advanced gastric cancer (AGC)

Chemotherapy improves survival in metastatic gastric cancer (MGC)

Med

ian

OS

(m

on

ths)

FAMTX1

(n=30)BSC1

(n=10)FEMTX2

(n=21)BSC2

(n=20)ELF3

(n=31)BSC3

(n=30)CLF4

(n=51)BSC4

(n=52)

1Murad AM, et al. Cancer 1993;72:37–41; 2Pyrhonen S, et al. Br J Cancer 1995;71:587–91; 3Glimelius B, et al. Ann Oncol

1997;8:163–8; 4Scheithauer W, et al. Second International Conference on Biology, Prevention and Treatment of GI

Malignancy, Koln, Germany, 1995;68 (Abstract)

12

10

8

6

4

2

0

Chemotherapy

Best supportive care (BSC)

OS = overall survival; 5-FU = 5-fluorouracilFAMTX = 5-FU, doxorubicin, methotrexateFEMTX = 5-FU, epirubicin, methotrexateELF = etoposide, leucovorin, 5-FUCLF = cisplatin, leucovorin, 5-FU

FAM = 5-FU, doxorubicin, mitomycin CFP = 5-FU, cisplatin; ECF = epirubicin, cisplatin, 5-FU

BSC1

5-FU monotherapy2,3

FAM2,4

FAMTX5–7

FP2,3,6 and ECF5,8,9

4 months

7 months

6–7 months

6–7 months

7–9 months

Median OS

1Wagner AO, et al. Cochrane Database Syst Rev 2005;2:CD004064; 2Kim NK, et al. Cancer 1993;71:3813–183Ohtsu A, et al. J Clin Oncol 2003;21:54–9; 4Wils JA, et al. J Clin Oncol 1991;9:827–31

5Waters JS, et al. Br J Cancer 1999;80:269–72; 6Vanhoefer U, et al. J Clin Oncol 2000;18:2648–57 7Cocconi G, et al. Ann Oncol 2003;14:1258–63; 8Ross P, et al. J Clin Oncol 2002;20:1996–2004

9Webb A, et al. J Clin Oncol 1997;15:261–7

Survival has improvedwith conventional regimens

Chemotherapy in patients with MGC Conventional regimens prolong survival and achieve acceptable

response rates

BUT . . .

Median OS still <12 months

Complete response rate is low

Response duration is short

Inconvenient drug administration

Regimens may be toxic

No standard treatment

– all options have similar survival outcomes and safety profiles

– FP/ECF most common reference therapy in Europe

There is a clear need for new active treatments

New treatment options for AGC aim to improve survival

Epirubicin Cisplatin Fluorouracil

New treatment options for AGC aim to improve survival

Paclitaxel Irinotecan Docetaxel

Epirubicin? Oxaliplatin Capecitabine, S-1

Capecitabine: the new standard chemotherapy in AGC?

FP5-FU c.i. 800mg/m2 day 15

cisplatin 80mg/m2 day 1 every 3 weeks

XPCapecitabine 1, 000mg/m2 b.i.d. day 114cisplatin 80mg/m2 day 1 every 3 weeks

AGC and/orMGC

(n=316)

n=156

n=160

RANDO MISATION

Primary endpoint: non-inferiority in PFS

Can XP improve PFS versus FP?International phase III study in MGC (ML17032)

Kang Y-K, et al. Ann Oncol2006;17(Suppl. 6):vi19 (Abstract O-003)

PFS = progression-free survival; b.i.d. = twice dailyc.i. = continuous infusion

Why should XP be moreeffective than FP?

FP is a reference regimen for AGC

Capecitabine monotherapy is effective and well tolerated in AGC1–4

– ORR: 19–34%; SD: 30–56%

– median TTP: 2.8–4.8 months

– median OS: 8.1–10.0 months

XP was effective and well tolerated in phase II study5

– ORR: 55%; SD: 16.7%

– median TTP: 5.8 months

– median OS: 10.1 months 1Hong YS, et al. Ann Oncol 2004;15:1344–72Leon-Rodriguez E, et al. Ann Oncol2002;13(Suppl. 5):191 (Abstract 708)

3Sakamoto J, et al. Anticancer Drugs 2006;17:231–64Koizumi W, et al. Oncology 2003;64:232–6

5Kim TW, et al. Ann Oncol 2002;13:1893–8

ORR = overall response rateSD = stable diseaseTTP = time to progression

Primary endpoint met:XP improves PFS versus FP (HR=0.81)

Per protocol HR = hazard ratio; CI = confidence interval

Est

imat

ed p

rob

abil

ity

HR=0.81 (95% CI: 0.63–1.04)Compared to HR upper limit 1.25, p=0.0008

0 2 4 6 8 10 12 14 16 18 20 22 24 26Months

1.0

0.8

0.6

0.4

0.2

0

XP (n=139)

FP (n=137)

5.65.0

Kang Y-K, et al. Ann Oncol 2006;17(Suppl. 6):vi19 (Abstract O-003)

PFS: robust results in subgroups

Kang Y-K, et al. Ann Oncol 2006;17(Suppl. 6):vi19 (Abstract O-003)

PP population

Prior chemotherapy

No prior chemotherapy

Male

Female

65 years

>65 years

KPS <80%

KPS 80%

1 metastatic site

2 metastatic sites

276

28

248

185

91

238

38

30

246

98

178

HR (95% CI)

Favours XP Favours FP

0.2 0.6 1.0 1.4 1.8 2.2 2.6

KPS = Karnofsky performance status

Est

imat

ed p

rob

abil

ity

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

Months

1.0

0.8

0.6

0.4

0.2

0

HR=0.85 (95% CI: 0.64–1.13)Compared to HR upper limit 1.25, p=0.0076

10.59.3

XP (n=139)

FP (n=137)

XP versus FP also showsnon-inferiority in OS (HR=0.85)

Kang Y-K, et al. Ann Oncol 2006;17(Suppl. 6):vi19 (Abstract O-003)Per protocol

Superior response ratewith XP versus FP

RECIST confirmed response (%)

XP(n=160)

FP(n=156) p value

ORR95% CI

41(33–49)

29(22–37)

0.033

CR 2 3 0.720

PR 39 26 0.022

SD 37 42 0.421

PD 10 18 0.051Intent-to-treat (ITT), investigators’ assessment

Kang Y-K, et al. Ann Oncol2006;17(Suppl. 6):vi19 (Abstract O-003)

RECIST = Response Evaluation Criteria in Solid TumoursCR = complete responsePR = partial responsePD = progressive disease

Similar incidence of grade 3/4 adverse events: XP versus FP

Grade 3/4 adverse events (AEs)

Neutropenia

Nausea/

vomiti

ng

Stom

atitis

Diarrhoea

Febrile

neutropenia

LeucopeniaHFS

Kang Y-K, et al. Ann Oncol 2006;17(Suppl. 6):vi19 (Abstract O-003)

Pat

ien

ts (

%)

XP (n=156)

FP (n=155)

60

50

40

30

20

10

0

HFS = hand-foot syndrome

XP: a potential new standardchemotherapy in AGC

As effective as FP

Improved tolerability

Avoids inconvenience and complicationsassociated with infused 5-FU

Multicentre phase III REAL-2 trial:can capecitabine improve OS versus 5-FU?

Locally advanced or metastatic oesophagogastric cancer (n=1,002)

R A N D O M I S A T I O N

EpirubicinCisplatin Fluorouracil

EpirubicinOxaliplatinFluorouracil

EpirubicinCisplatinCapecitabine

EpirubicinOxaliplatin Capecitabine

Epirubicin 50mg/m2 day 1

Cisplatin 60mg/m2 vs oxaliplatin 130mg/m2 day 1

5-FU 200mg/m2 c.i. daily vs capecitabine 500–625mg/m2 b.i.d. p.o. daily

For 24 weeks: eight cycles every 3 weeks

Cunningham D, et al. N Engl J Med 2008;358:36–46p.o. = orally

Regimen nORR(%)

TTP(months)

OS(months) Reference

FOLFOX 49 45 6.2 8.6 Louvet et al. 2002

FU(inf)/Ox 55 56 5.2 10.0 Chao et al. 2004

FUFOX 48 54 6.5 11.4 Dyster et al. 2005

FOLFOX4 61 38 7.1 11.2 DeVita et al. 2005

FLO 41 43 5.6 9.6 Al-Batran et al. 2005

Why should EOC be moreeffective than ECF?

Capecitabine is effective and well tolerated in AGC XP has become a new reference regimen for AGC Oxaliplatin has shown promising activity in phase II trials

EOC = epirubicin, oxaliplatin, capecitabineFOLFOX = 5-FU, leucovorin, oxaliplatin; FU(inf)/Ox = 5-FU infusion, oxaliplatinFUFOX = 5-FU, oxaliplatin; FLO = 5-FU, leucovorin, oxaliplatin

REAL-2: can capecitabine replace 5-FU, can oxaliplatin replace cisplatin?

In combination treatments of oesophagogastric cancer

– can capecitabine replace 5-FU?

– can oxaliplatin replace cisplatin?

Primary endpoint of non-inferiority in OS for capecitabine versus 5-FU, oxaliplatin versus cisplatin (PP population)

– based on ECF 1-year survival of 35%, 1,000 patients(250 per arm) needed to show non-inferiority (80% power, one-sided =0.05)

– upper limit of HR for experimental arms compared with standard arms should be <1.23

– secondary endpoint: superiority in OS among the four regimens (intent-to-treat)

Cunningham D, et al. N Engl J Med 2008;358:36–46

HR=0.86 (95% CI: 0.80–0.99)

REAL-2: primary endpoint met – non-inferior OS with capecitabine versus 5-FU

Per protocol

Est

imat

ed p

rob

abil

ity

Capecitabine combinations (n=480)

5-FU combinations (n=484)

1.0

0.8

0.6

0.4

0.2

00 12 24 36 48 60 72

10.99.6

Months

Cunningham D, et al. N Engl J Med 2008;358:36–46

Similar OS with oxaliplatinversus cisplatin

HR=0.92 (95% CI: 0.8–1.1)

Oxaliplatin combinations (n=474)

Cisplatin combinations (n=490)

10.410.0

0 12 24 36 48 60 72Months

Est

imat

ed p

rob

abil

ity

1.0

0.8

0.6

0.4

0.2

0

Cunningham D, et al. N Engl J Med 2008;358:36–46Per protocol

Superior OS with EOC versus ECF

Intent-to-treat

HR=0.80 (95% CI: 0.66–0.97)Log-rank p=0.02

Median OS

(months)

ECF (n=249) 9.9

EOC (n=239) 11.2

0 12 24 36 48 60 72Months

Est

imat

ed p

rob

abil

ity

1.0

0.8

0.6

0.4

0.2

0

Cunningham D, et al. N Engl J Med 2008;358:36–46

Grade 3 / 4 AEs

Neutropenia

Nausea/

vomiti

ng

Stom

atitis

Diarrhoea

Febrile

neutropenia

Throm

boembolic

events

Cunningham D, et al. N Engl J Med 2008;358:36–46Starling N, et al. Proc ASCO GI 2007 (Abstract 74)

Pat

ien

ts (

%)

*p<0.05compared with ECF

Capecitabine-based regimensare well tolerated

ECF (n=236)

ECC (n=241)

EOF (n=235)

EOC (n=239)

60

50

40

30

20

10

0

*

* *

* ** *

HFS

ORR(%)

PFS*(months)

OS* (months)

ECC1 46 6.7 9.9ECF1 41 6.2 9.9EOC1 48 7.0 11.2EOF1 42 6.5 9.3

XP2 41 5.6 10.4FP2 29 5.0 8.9

REAL-2 versus ML17032: consistent efficacy with capecitabine regimens

Response evaluated every 3 months in REAL-2,1 every 1.5 months in ML170322

In REAL-2,1 maximum treatment duration: 6 months

1Cunningham D, et al. N Engl J Med 2008;358:36–462Kang Y-K, et al. Ann Oncol 2006;17(Suppl. 6):vi19 (Abstract O-003)* * Intent-to-treat

Capecitabine plus platinum-based chemotherapy approved in Europe

1Murad AM, et al. Cancer 1993;72:37–41 2Vanhoefer U, et al. J Clin Oncol 2000;18:2648–57; 3Van Cutsem E, et al. J Clin Oncol 2006;24:4991–7 4Dank M, et al. J Clin Oncol 2005;23(Suppl. 16S):403s (Abstract 4003);

5Cunningham D, et al. N Engl J Med 2008;358:36–46; 6Kang Y-K, et al. Ann Oncol 2006;17(Suppl. 6):vi19 (Abstract O-003)

Months

BSC1

FAMTX2

FP3

IF4

EOF5

DCF3

ECF5

XP6

ECx5

EOx5

0 2 4 6 8 10 12

IF = irinotecan + 5-FU

Putting the evidenceinto practice: case study

45-year-old male; ECOG PS: 0

Chief complaint: epigastric pain

No dysphagia or weight loss

Gastroscopy: largeulceroinfiltrative lesionencircling the antral lumen

Biopsy: tubularadenocarcinoma, M/D

ECOG = Eastern Cooperative Oncology Group; PS = performance status

Abdomen and pelvis computed tomography (CT)

Patient received EOC chemotherapy

Before treatment

After cycle 2: PR 01 October 2004

22 August 2004

After cycle 4: ++PR

After cycle 8: CR?

07 February 2005

10 November 2004

Upper limit of normal

August 04

Septem

ber 04

October 0

4

November 0

4

December 0

4

January 05

February

05

CE

A (

ng

/mL

)

Carcinoembryonic antigen (CEA) levels

18

16

14

12

10

8

6

4

2

0

Patient received EOC chemotherapy

Before treatment After cycle 7

Biopsy: no cancer

Patient was in remission for9 months without chemotherapy

Chemotherapy stopped in February 2005

Patient followed-up every 3 months

– abdomen and pelvis CT

– gastrofiberscopy (GFS)

– CEA

CT scans 22 September 2006revealed disease progression

Patient receivedsecond-line chemotherapy

Re-induction of EOC

– four cycles: SD (for 4 months)

Irinotecan 150mg/m2 day 1, 14 plus mitomycin C 8mg/m2 day 1 every 4 weeks1,2

– four cycles: SD (for 2 months)

Docetaxel 75mg/m2 every 3 weeks3

– three cycles: PD

1Giuliani F, et al. Am J Clin Oncol 2005;28:581–52Bamias A, et al. J Chemother 2003;15:275–81

3Lee JL, et al. Cancer Chemother Pharmacol 2008;61:631–7

CEA: 20.9ng/mL

4 December 2007: patient with PD,alive no longer receiving treatment

What other capecitabine-basedoptions are available?

EfficacyDCX1

(n=40)DCF2

(n=227)

ORR (%)95% CI

6852–83

3730–43

TTP/PFS (months) 7.8 5.6

OS (months) 16.9 9.2

1Kang Y-K, et al. J Clin Oncol 2004;22(Suppl. 14S):329s (Abstract 4066)2Van Cutsem E, et al. J Clin Oncol 2006;24:4991–7

Integrating docetaxel in the treatmentof AGC: high efficacy with capecitabine

Trial Setting n

Advanced disease

XP or FP ± trastuzumab (TOGA) HER2+ AGC 374

Capecitabine + cisplatin ± bevacizumab MGC 760

ECX FOLFIRI vs FOLFIRI ECX AGC/MGC 416

ECX ± panitumumab (REAL-3) AOGC 660

Operable disease

Perioperative ECX ± bevacizumab (STO-3) Adjuvant 1,100

XELOX vs observation (CLASSIC) Adjuvant 1,024

Capecitabine: the backbone of future standards in gastric cancer

HER2 = human epidermal growth factor receptor 2; AOGC = advanced oesophagogastric cancerXELOX = capecitabine + oxaliplatin

Capecitabine is effective and well tolerated

– can replace 5-FU in current treatment regimensfor AGC

Further data will support the use of capecitabine in this indication

Capecitabine is an effective, safe and convenient oral therapy for gastric cancer

Conclusions