What is the reference cytotoxic regimen in

advanced gastric cancer?

Florian Lordick

Klinikum BraunschweigGermany

Chemotherapy in Advanced Gastric Cancer – What do we know? (I)

Wagner et al. J Clin Oncol 2006; 24: 2903-9

• Chemotherapy prolongs survival• Chemotherapy improves symptom control• Combinations are more active than monotherapy

• Elderly (>70 years age) benefit equallyTrumper et al. Eur J Cancer 2006; 42: 827-34

Established standard:Platinum-fluoropyrimidine-combination

Established standard:Platinum-fluoropyrimidine-combination

• Oxaliplatin can substitute for cisplatin

• Oral fluoropyrimidines can substitute for i.v. 5-FU

• A 3rd drug makes CTx more effective but more toxic

Al-Batran et al. J Clin Oncol 2008; 26: 1435-1442Cunningham et al. N Engl J Med 2008; 358: 36-46

Cunningham et al. N Engl J Med 2008; 358: 36-46

Kang et al. Ann Oncol 2009; 20: 666-673

Van Cutsem et al. J Clin Oncol 2006; 24: 4991-7Wagner et al. J Clin Oncol 2006; 24: 2903-9

Ajani J et al. J Clin Oncol 2010; 28: 1547-1553

Chemotherapy in Advanced Gastric Cancer – What do we know? (I)

Oxaliplatin

Oxaliplatin in Gastric Cancer

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

R

A

N

D

O

M

R

A

N

D

O

M

E EpirubicinC CisplatinF Fluorouracil

E EpirubicinC CisplatinX Xeloda (Capecitabine)

E EpirubicinO OxaliplatinF Fluorouracil

E EpirubicinO OxaliplatinX Xeloda (Capecitabine)

N=964

Real-2-Study (UK)

Oxaliplatin in Gastric Cancer

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

Real-2-Study

Oxaliplatin in Gastric Cancer

R

A

N

D

O

M

R

A

N

D

O

M

P Cisplatin L LeucovorinF 5-Fluorouracil

O Oxaliplatin L Leucovorin F 5-Fluorouracil

N=220

AIO-Study (Germany)

Al-Batran SE et al. J Clin Oncol 2008;26:1435-1442

AIO-study: FLO versus FLP

Al-Batran SE et al. J Clin Oncol 2008;26:1435-1442

PFS: p = 0.077 OS: p = 0.506

Overall population

AIO-study: FLO versus FLP

Al-Batran SE et al. J Clin Oncol 2008;26:1435-1442

PFS: p = 0.029 OS: p = n. s.

Elderly (patients > 65 years)

Oxaliplatin can substitute for cisplatin in gastric cancer!

Potential advantages inthe elderly and frail population

Oral fluoropyrimidines

Capecitabine in Gastric Cancer

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

R

A

N

D

O

M

R

A

N

D

O

M

E EpirubicinC CisplatinF Fluorouracil

E EpirubicinC CisplatinX Xeloda (Capecitabine)

E EpirubicinO OxaliplatinF Fluorouracil

E EpirubicinO OxaliplatinX Xeloda (Capecitabine)

N=964

Real-2-Study (UK)

Capecitabine in Gastric Cancer

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

Real-2-Study

Capecitabine in Gastric Cancer

R

A

N

D

O

M

R

A

N

D

O

M

F 5-FluorouracilP Cisplatin

N=316

ML17032-Study (Korea)

X Xeloda (Capecitabine)P Cisplatin

Kang YK et al. Ann Oncol 2009; 20: 666-673

Primary endpoint: overall survival(non-inferiority)

ML17032-Study: XP versus FP

Kang YK et al. Ann Oncol 2009; 20: 666-673

Progression-free survival5.6 vs. 5.0 mon p<0.001

(non-inferior)

Survival10.5 vs. 9.3 mon p=0.008

(non-inferior)

Response rate46% vs. 32% p=0.02

S-1/cisplatin versus 5-FU/cisplatin

S-1 25mg/m2 2x/d d1-21

Cisplatin 75mg/m2 d1q4w

S-1 25mg/m2 2x/d d1-21

Cisplatin 75mg/m2 d1q4w

R

A

N

D

O

M

R

A

N

D

O

M5-FU 1000mg/m2 d1-5

Cisplatin 100mg/m2 d1q4w

5-FU 1000mg/m2 d1-5

Cisplatin 100mg/m2 d1q4w

Primary endpoint: overall survival(superiority)

N=1053

FLAGS-Study (multinational Western World)

Ajani J et al. J Clin Oncol 2010; 28: 1547-1553

S-1/cisplatin versus 5-FU/cisplatin

In a Non-Asian patient population S-1 was not superior to 5-FU

Ajani J et al. J Clin Oncol 2010; 28: 1547-1553

S-1/cisplatin versus 5-FU/cisplatin

Ajani J et al. J Clin Oncol 2010; 28: 1547-1553

S-1/cisplatin 5-FU/cisplatin

Neutropenia G3/4 32.3% 63.4%

Complicated neuropenia 5.0% 14.4%

Stomatitis 1.3% 13.6%

Toxic Death 2.5% 4.9%

Toxicity in favor of S-1/cisplatin

Oral fluoropyrimidines can substitute for i.v. 5-FU in gastric cancer!

Less severe toxicity for S-1/cisplatin

Doublets or triplets?

And which is the relevant third drug?

Cisplatinum

Wagner et al. J Clin Oncol 2006; 24: 2903-9

HR = 0.83 (95% CI 0,76 – 0,91) in favor of cisplatinum

Anthracyclines

Wagner et al. J Clin Oncol 2006; 24: 2903-9

HR = 0.77 (95% CI 0,62 – 0,95) in favor of anthracyclines

AnthracyclinesECF versus EOX

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

HR = 0.80 (95% CI, 0.66 to 0.97; P=0.02)

Real-2-Study (UK)

Docetaxel

Docetaxel 75mg/m2 d1

Cisplatin 75mg/m2 d1

5-FU 750mg/m2 d1-5q3w

Docetaxel 75mg/m2 d1

Cisplatin 75mg/m2 d1

5-FU 750mg/m2 d1-5q3w

R

A

N

D

O

M

R

A

N

D

O

MCisplatin 100mg/m2 d1

5-FU 1000mg/m2 d1-5q4w

Cisplatin 100mg/m2 d1

5-FU 1000mg/m2 d1-5q4w

Primary endpoint: time to progression (TTP)

Van Cutsem et al. J Clin Oncol 2006; 24: 4991-7

Stage IV

n=445

Tax-325-Study (multinational)

Van Cutsem et al. J Clin Oncol 2006; 24: 4991-7

Time to progression5.6 vs. 3.7 months p<0.01

Survival9.2 vs. 8.6 months p=0.02

Response rate37% vs. 25% p=0.01

Kaplan-Meier curve: time to progression

Docetaxel as 3rd Drug TAX-325

DCF Toxicity

Hematologic toxicity in DCF

Neutropenia grade 3/4 82%Febrile neutropenia 30%

Van Cutsem et al. J Clin Oncol 2006; 24: 4991-7

Alternative docetaxel-based regimen(AIO studies)

Lorenzen et al. Ann Oncol 2007; 18: 1673-9

GastroTax-1 regimen

Docetaxel 40mg/m2 + cisplatin 40mg/m2 2-weekly5-FU 2000mg/m2 – folinic acid 200mg/m2 weekly

Response rate 46.6%Time to progression (metastatic) 8.1 monthsSurvival (metastatic) 15.1 months

Al-Batran et al. Ann Oncol 2008; 19:1882-87

FLOT regimen

Docetaxel 50mg/m2 + modified FOLFOX 2-weekly

Response rate 53%Time to progression 5.3 monthsSurvival 11.3 months

Alternative docetaxel-based regimen(MSKCC)

Shah et al. ASO 2010; abstract 4014

Fra

ctio

n S

urvi

ving

Months

15.1 mo12.6 mo

Modified DCF

Classic DCF

Median follow up 10.3 mo

Modified DCF vs. classic DCF + G-CSF (rand. Ph. II)

The future of triplets in gastric cancer:Sequential treatment?

Arm A(120 pat.)

R

2:1

Arm B(80 pat.)

Induction6 cycles FLOT(3 months)

CR, PR, SD

FLOT Progression

De-escalationS-1

AIO – YMO – Maintain Study (proposal)

Triplets are more effective than doublets!

But…

Side effects are an issue!Patients‘ preferences matter!

Watch out for overlapping side effects and interactions, when combining with biologics

3 + 1 = X…when the unpredictable comes true

Arm A: EOX

Arm B: EOX-Panitumumab

R

• EOX (Arm A):– Epirubicin 50mg/m2 IV D1– Oxaliplatin 130mg/m2 IV D1– Capecitabine 1250mg/m2/day PO

in two divided doses D1-21

• mEOX-P (Arm B)1:

– Epirubicin 50mg/m2 IV D1– Oxaliplatin 100mg/m2 IV D1– Capecitabine 1000mg/m2/day PO

in two divided doses D1-21– Panitumumab 9mg/kg IV D1

Wardell et al. ASO 2012; abstract LBA 4000

REAL-3 study

3 + 1 = X…when the unpredictable comes true

Wardell et al. ASO 2012; abstract LBA 4000

349275EOC238278EOC-P

Number at risk

0

20

40

60

80

100

0 12 24 36

Months from Randomisation

Pro

bab

ility

of

Su

rviv

al (

%)

EOXEOX-P

Median OS(95% CI)

% alive at 1 year(95% CI)

11.3m (9.6 – 13.0) 46% (38% - 54%)

8.8m (7.7 – 9.8) 33% (26% - 41%)

HR 1.37, p = 0.013

HR 1.37 (95% CI: 1.07 – 1.76)

6 18 30

Reference regimens for advanced gastric cancer in 2012

Triplets

Indication: Severe tumor symptomsPatient preference (most active tx)Intact organ functions

Regimens: EOX (epirubicine, oxaliplatin, cape.)mod. DCF (docetaxel, cisplatin, 5FU)FLOT (docetaxel + mod. FOLFOX)

Doublets

Indication: Patient preference for less toxicityImpaired organ functionsCombination with biologics

Regimens: Capecitebine-cisplatinS-1-cisplatinFOLFOX-like / CapOx (elderly)

Reference regimens for advanced gastric cancer in 2012

Doublet or Triplet?

2 : 0

or

3 : 0

Let‘s win the match!