Better Regimens & Predictive Markers

For Advanced Esophagogastric Cancer?

Peter C. Enzinger , M.D.Dana-Farber Cancer Institute/Harvard Medical School

Disclosures

Speaker / Consultant / Honoraria (prior to 6.09):

Sanofi – Aventis

Roche

Posters DiscussedKishimoto et al. Does Paclitaxel or Irinotecan improve a Japanese

Standard – S1?-----------------------------------------------------------------Shah et al. Is “Docetaxel, Cisplatin + mod de Gramont” better than

DCF?

Al-Batran et al.Is “Docetaxel + mFOLFOX” better than DCF?-----------------------------------------------------------------

Atmaca et al. What do we do with a new prognostic molecular factor?

JapanCan we improve S1?

Evolution of S1 Therapy in Gastric CA

FLAGS**

Cisplatin + S1

Cisplatin + 5-FU

29% 8.6 mos

32% 7.9 mos

P = NS

SPIRITS*

S1

Cisplatin + S1

*Koizumi. Lancet Oncol 2008**Ajani. J Clin Oncol 2010

31% 11 mos

54% 13 mos

P = 0.04Japan

“West”

RR: OS:Less toxic

Random Phase II: S1+ CPT or S1 + Pacli

•Arm B: 3 weeks / course

Day1

80 mg/m2/day x 2 wks, p.o.

Paclitaxel(50 mg/m2, iv)

S-1 1-week rest

•Arm A: 5 weeks / course

Day8 Day14 Day21

Day1

80 mg/m2/day x 3 wks, p.o.

CPT-11(80 mg/m2, iv)

S-1 2-weeks rest

Day15 Day21 Day35

•Unresectable, measurable advanced or recurrent gastric cancer

•No prior chemotherapy except adjuvant CTX

H0: 30% RR vs. HA: 50% RRpower 80%; 2-sided α 5%

Phase III:START

0 200 400 600 800 1000 12000

20

40

60

80

100

Time

Su

rviv

al r

ate

S-1+CPT

S-1+paclitaxel

S-1+CPT

S-1+paclitaxel

(%)

(days)

Progression-Free Survival Overall Survival

S-1+CPT

S-1+paclitaxel

S-1+CPT

S-1+paclitaxel

0 200 400 600 800 1000 1200 14000

20

40

60

80

100

Surv

ival

rat

e

(%)

(days)

HR=1.18; p=0.42 HR=0.99; p=0.96

Regimen Response PFS OS

S1 alone*/# 28-31% 4.2 mos 11.0-11.4 mos

S1 + Pacli 31% 4.6 mos 12.0 mos

S1 + Doce** 88% 6.5 mos 12.0 mos

S1 + CPT 33% 5.7 mos 12.5 mos

S1 + CPT*** 42% N/A 12.8 mos (IRIS)

S1 + CDDP* 54% 6.0 mos 13.0 mos*Koizumi. Lancet Oncol 2008#Boku. Lancet Oncol 2009**Ikeda. Proc ASCO 2009***Imamura. Proc ASCO 2008

ConclusionsThe authors conclude that neither S1+ paclitaxel or S1 +

irinotecan should be developed further – I agree!

S1 seems to be happiest by itself … or perhaps with cisplatin.

Where are the biologics – there seem to be no combinations with S1?

“West”Can we improve DCF?

DCF: What do you do with an active regimen that causes 82% G3-4 ANC and 81% G3-4 non-heme toxicity?

Dose and Schedule

Author Regimen Site Pts. RR ANC Non-heme OS

Van Cutsem.

J Clin Oncol ‘06

DCF

original

Gastric 221 37% 82% Stomatitis

21%

9.2mo.

Park. Am J Clin Oncol’05

Low dose D + C F

Gastric 47 40% 68% Stomatitis 21%

9.7mo.

Lorenzen. Ann Oncol 2007

DC q 2wks

+ AIO

GEJ

Gastric

60 47% 22% Diarrhea

20%

15.1mo

Overman. Cancer 2010

Weekly

DCF

retrospective

Esoph

Gastric

95 34% 4% Hospital

23%

8.9mo

Tebbutt. Br J Cancer 2010

Weekly D

q 3 wk CF

Esoph

Gastric

50 47% 10% Diarrhea

22%

11.2mo

DCF: What do you do with an active regimen that causes 82% G3-4 ANC and 81% G3-4 non-heme toxicity?

Substitutions

Author Regimen Site Pts. RR ANC Non-heme OS

van Cutsem.

J Clin Oncol ‘06

DCF

original

Gastric 221 37% 82% Stomatitis

21%

9.2mo.

Shankaran.

GI Symp’09

Docetaxel

Oxali /5-FU

GEJ

Gastric

35 74% 18% Neuro

21%

10.3mo

Moehler.

ASCO’09

Docetaxel

Oxali/Cape

Gastric 25 36% 3% Diarrhea

23%

N/A

Sato.

ASCO’08

D C S1 Gastric 31 87% 52% N/V 27% 18.9mo.

Enzinger.

Ann Oncol ‘09

D C Cpt

weekly

Esoph

Gastric

56 54% 21% Diarrhea 26%

11.9mo.

Conclusions

DCF is too toxic – worst way of giving either cisplatin or fluorouracil

Smaller, more frequent doses or substitutions are better but which one? or both?

Randomized trials are needed to move this forward:

DCF: What do you do with an active regimen that causes 82% G3-4 ANC and 81% G3-4 non-heme toxicity?

Dose and Schedule Substitutions(Shah) (Al-Batran)

FLO (mFOLFOX)5-FU 2600 mg/m² Folinic acid 200 mg/m² Oxaliplatin 85 mg/m²Every two weeks

FLOTDocetaxel 50mg/m2

5-FU 2600 mg/m² Folinic acid 200 mg/m² Oxaliplatin 85 mg/m²Every two weeks

RANDOMIZATION

DCF (original)Docetaxel 75mg/m2 Cisplatin 75mg/m2

5-FU 750mg/m2/d CI x 5dEvery three weeks

mDCFDocetaxel 40mg/m2

Cisplatin 40 mg/m², day 3Leucovorin 400 mg/m²5-FU 400 IVP5-FU 1000 mg/m²/d CI x 2d Every two weeks

RANDOMIZATION

DCF: What do you do with an active regimen that causes 82% G3-4 ANC and 81% G3-4 non-heme toxicity?

Dose and Schedule Substitutions(mDCF) (FLOT)

Disease site GEJ, Gastric GEJ, Gastric

Stage inop, metastatic

inop, metast, loc adv, recurrent

Response Rate

52% 49% (incl loc adv)

6-month PFS

63% 60% (inop/metastatic)

Overall Survival

15.1 mo (9.7 – 20.4)

est. 17mo (incl loc adv)

Neutropenia 54% 52%

Nausea 0% 21%

Diarrhea 2% 9%

Neuropathy 2% 20%

Fatigue 10% 11%

ConclusionsHard to choose between the two; mDCF perhaps

less toxic but more complicated

mDCF arm is still in progress and must wait for 6 mo PFS primary endpoint

FLOT– higher RR and toxicity more suited for adjuvant comparison

Randomization against ECF would require large pt numbers for significant difference

Matrix Metalloproteinase-9mRNA expression

What do we do with a new prognostic molecular factor in esophagogastric ca?

Other Molecular Prognostic Markers

“Hundreds” of prognostic molecular markers for gastric cancer in the literature …

HER2/neu – prognostic and antibody is effective

VEGF – prognostic – AVAGAST on Monday

EGFR – prognostic REAL 3 and EXPAND

Impressive Results!

months

0

0,2

0,4

0,6

0,8

1

0 5 10 15 20 25 30

pro

babilit

y

<best cut-offbest cut-off

P=0,00765

p=0,0193

0

0,2

0,4

0,6

0,8

1

0 10 20 30 40OS months

Quartile 1Quartile 2Quartile 3Quartile 4

p=0,0193

0

0,2

0,4

0,6

0,8

1

0 10 20 30 40OS months

Quartile 1Quartile 2Quartile 3Quartile 4

Median OS: 5,5 mo vs. 11,9 mo1 yr Survival: 25% vs. 50%2 yr Survival: 0% vs. 26%

Validation Cohort Pooled OS by Quartile

MMP-9 effect only in highest quartile

Independant by multivariate analysis

Questions?Training & Validation Cohorts in “cisplatin-based” therapy – same results

in non-platinum regimens or Asian patients?

Are there agents that target MMP-9? - ATRA*? Epigallocatechine-3-gallate**?

If interacts with angiogenesis or EGFR pathway, what would be the effect in bevacizumab or anti-EFGR studies?

Should one change treatment based on MMP9 status? More aggressive for high? What about adjuvant?

*Dutta. Cell Adh Migr. 2010**Farabegoli. Biosci Rep. 2010

Next steps …

1st step is for another group to run a validation cohort (West and East Asia)

Ideal cohorts to test interaction with MMP-9 would be the AVAGAST, REAL 3, and EXPAND studies

Too early for treatment changes – everybody gets max tolerated chemo for metastatic dz and in the adjuvant setting anyway.

Thank You!