F. Maindrault-Gœbel, G. LLedo, B. Chibaudel, L. Mineur, T. André, M. Bennamoun, M. Mabro,

P.Artru, C. Louvet, A. de Gramont

OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with

metastatic colorectal cancer (MRC). A GERCOR study.

Rationale

New combination therapies have improved survival but also increased toxicity, especially the cumulative toxicities like the oxaliplatin sensory neuropathy. The need to preserve the quality of life is the clinical rationale to evaluate CFI.

Chemotherapy-free intervals (CFI) have previously been studied in patients receiving 5FU- based therapy (Hejna et al. Br J Cancer 1998, Maughan et al. Lancet 2003).

The goal of the OPTIMOX2 study is to further evaluate the oxaliplatin stop and go strategy and the role of maintenance therapy.

RRAANNDDOOMMIISSAATTIIOONN

RRAANNDDOOMMIISSAATTIIOONN

maintenance therapy vs chemotherapy-free intervalwith oxaliplatin stop and go

mFOLFOX7 x 6 cy sLV5FU2 before « baseline » progressionFOLFOX7 reintroduction

mFOLFOX7 x 6 cy No maintenance until progressionFOLFOX7 reintroduction

OPTIMOX 2 Study design

A

B

OPTIMOX2 : chemotherapy-free interval

OPTIMOX1 : maintenance therapy

Only 6 pts in both arms had FOLFOX reintroduction more than 30 days after the first progression

LV 400 5-FU 3000

mFOLFOX7

Oxali 100

H0 H2 H24 H48

LV 400 5-FU 3000

sLV5FU2

H0 H2 H24 H48

5FUb 400

Cycles every 14 days, dose mg/m²

CHEMOTHERAPY

6 cycles(Both arms)

Maintenance until progression(OPTIMOX1)

Histologically proven colorectal cancer

Unresectable metastases

Mesurable or evaluable metastasis

No prior CT except adjuvant CT if ended 6 months before study entry

18 - 80 years

alk. ph.<5 UNL , platelets> 100 109, creatinin <3 UNL

WHO PS 2

No peripheral sensory neuropathy

Inclusion criteria

Randomisation using minimization technique

Stratification by

• center, PS (0-1 vs 2),

• number of sites (1 vs > 1),

• age (18 - 50 vs 51-75 vs 76 - 80),

• Alk Ph. ( 3x UNL vs 3 - 5 ULN),

• adjuvant chemo or not

Initial sample size was 600, downgraded to 200 when bevacizumab was approved in France; no formal hypothesis were done between the two arms but sample size was enough to detect a 20% difference in 2-year survival (30 vs 50%).

Statistics

Duration of Disease Control

t

T size

FOLFOX FOLFOX

PFS 1

Progression

PFS 2

Progressionat reintroduction

DDC = PFS 1 + PFS 2 (if no PD)

Patients Characteristics

Arm AOPTIMOX1

N = 99

Arm BOPTIMOX2

N = 103

Median age, years [range] 67 [35 – 80] 67 [31 – 80]

Male/Female 61% / 39% 58% / 42%

WHO PS 0 / 1-2 58% / 42% 58% / 42%

LDH N / > ULN / Missing 35% / 48% / 17% 42% / 36% / 22%

Colon/Rectum/Both 63% /36% / 1% 69% / 25% / 6%

Prior adjuvant CT/RT (oxali) 21% (0%) 18% (3%)

Synchronous metastasis 76 % 77 %

Nb metastatic sites 1/ 2

46% / 54% 52% / 48%

202 patients enrolled from 12 centers

OPTIMOX2 results

Arm AOPTIMOX1

N = 99

Arm BOPTIMOX2

N = 103

Surgery R0-R1

R0

14%

12%

19.4%

17.5%

Maintenance

median cycles

69%

8

Chemotherapy-free interval

CFI > 12 weeks

Interval maintenance –

reintro

Interval progression-reintro

18%

9.5 weeks

7 days

57.2%

20 weeks

7 days

OPTIMOX2 results

Arm AOPTIMOX1

N = 99

Arm BOPTIMOX2

N = 103

Oxaliplatin reintroduction % (1/>1)

52/9 60/16.5

Reason for not reintroducing :

Toxicity

Surgery

Prog. disease or death

no Prog

Other

Irinotecan second line

Death

9

6

20

6

7

53%

47%

10

14

10

0

7

52.4%

57.3%

Response was evaluated at 4 and 6 cycles then every 2 months.

OPTIMOX 2 Responses

OPTIMOX1 OPTIMOX2

CR 2% 4%

PR 58% 55%

PR+CR 60% 59%

Stable 32% 36%

Prog 7% 4%

NE 0% 1%

OPTIMOX 2 Responses Reintroduction 1

OPTIMOX1 OPTIMOX2

N 52 62

CR 0 (0%) 0 (0%)

PR 11 (21%) 15 (25%)

Stable 18 (35%) 16 (26%)

Prog 22 (42%) 29 (47%)

NE

Too early

0 (0%)

1(2%)

1 (1%)

1(1%)

Grade 3-4 Toxicity per Patient (%)

OPTIMOX 1 OPTIMOX 2

C1-C6 maintenance R1 C1-C6 R1

570 cy 662 cy 591 cy

Neutropenia 19 6 12 12 12

Anemia 1 0 0 0 2

Thrombopenia 12 1 6 4 2

Mucitis 3 2 0 2 2

Vomiting 6 0 0 4 3

Diarrhea 7 0 0 4 2

HFS 0 3 0 0 0

Neuropathy

Grade 1 8 % 2 21.2 % 3 2 %

Grade 1 29.4 % 2 35.3 % 3 5.9 %

Grade 1 6.8 % 2 15.5 % 3 3.9 %

Grade 1 36.8 % 2 19.2 % 3 7 %

Optimox 1 Optimox 2

After the first reintroduction

2 months after FOLFOX

Grade 1 70.7 % 2 18.1 % 3 0 %

Grade 1 70.8 % 2 16.5 % 3 0 %

During C1-C6

Progression-free SurvivalProgression-free survival

0 10 20 30 40 50 60 70 80 90 1000.0

0.2

0.4

0.6

0.8

1.0

OPTIMOX1 median 36 weeks

OPTIMOX2 median 29 weeks

weeks

Pro

ba

bili

ty

p=0.08

Duration of Disease ControlDuration of Disease Control

0 10 20 30 40 50 60 70 80 90 1000.0

0.2

0.4

0.6

0.8

1.0

OPTIMOX1 median 52 weeks

OPTIMOX2 median 39 weeks

p=0.39

weeks

Pro

ba

bili

ty

Chemotherapy-free IntervalChemotherapy-free interval

0 10 20 30 40 50 60 70 80 90 1000.0

0.2

0.4

0.6

0.8

1.0

OPTIMOX2 median 17 weeks

R0 surgery excluded

weeks

Pro

ba

bili

ty

CFI according to Pc factors

PS 2LDH ↑Alk Ph >3ULN> 2 sites

Chemotherapy-free interval

0 10 20 30 40 500.0

0.2

0.4

0.6

0.8

1.0

Good prognosis median 17.5 weeks

Poor prognosis median 17.0 weeks

p=0.38

weeks

Pro

ba

bili

ty

CFI according to Initial ResponseChemotherapy-free interval

0 10 20 30 40 500.0

0.2

0.4

0.6

0.8

1.0

Responders median 20 weeks

Stable disease median 13.5 weeks

p=0.31

weeks

Pro

ba

bili

ty

Overall SurvivalOverall Survival

0 10 20 30 40 500.0

0.2

0.4

0.6

0.8

1.0

OPTIMOX1 median 26 months

OPTIMOX2 median 19 months

p=0.0549

months

Pro

ba

bili

ty

Overall Survival in Patients with Good Prognosis

0 20 40 60 80 100 120 1400.00

0.25

0.50

0.75

1.00

OPTIMOX1

OPTIMOX2

p=0.17

N=45, Median NA

N=50, Median 28.7 months

weeks

pro

ba

bili

tyOS according to Pc factors

PS <2LDH NAlk Ph <3ULN< 3 sites

Overall Survival Good Prognostic

0 10 20 30 40 500.0

0.2

0.4

0.6

0.8

1.0OPTIMOX1 median NA months (n=45)

OPTIMOX2 median 29 months (n=50)

p=0.11

months

Pro

ba

bili

ty

OS according to Pc factors

PS 2LDH ↑Alk Ph >3ULN> 2 sites

Overall Survival Poor Prognostic

0 10 20 30 40 500.0

0.2

0.4

0.6

0.8

1.0

OPTIMOX1 median 17 months (n=54)

OPTIMOX2 median 15 months (n=53)

p=0.105

months

Pro

ba

bili

ty

PFS at ReintroductionPFS reintroduction

0 10 20 30 40 500.0

0.2

0.4

0.6

0.8

1.0

OPTIMOX1 median 18 weeks (n=52)

OPTIMOX2 median 17 weeks (n=62)

p=0.42

weeks

Pro

ba

bili

ty

Conclusions (1)

OPTIMOX 1 without targeted therapies in first-line therapy achieved a prolonged DDC and overall survival (median 26 months) with a good tolerance in patients with MCRC. Maintenance therapy followed by oxaliplatin reintroduction may improve PFS and OS, but not DDC.

Median duration of chemotherapy-free interval is 4 months in patients who did not have surgery. This CFI was comparable in patients with or without adverse prognostic factors

Response rate and PFS after reintroduction of FOLFOX was the same in patients who did or did not receive maintenance therapy

Conclusions (2)

Despite the advantages for the patients, a full break in therapy can not be recommended based on the results of this study.

A shorter break or intermittent chemotherapy (Labianca, ASCO 2006) deserve to be evaluated

The ongoing GERCOR study, DREAM, is evaluating maintenance therapy with targeted drugs alone.

Acknowlegments:

• Dr Gérard Lledo – Lyon

• Pr Aimery de Gramont– Paris

• Dr Laurent Mineur – Avignon

• Pr Thierry André – Paris

• Dr Mustapha Bennamoun –

Montfermeil

• Dr May Mabro – Suresnes

• Dr Elisabeth Carola – Senlis

• Dr Michel Flesch - Dijon

• Dr Gérard Ganem – Le Mans

• Dr Philippe Colin – Reims

• Dr Dominique Auby - Libourne

For the GERCOR :

• Dr Benoist Chibaudel

• Pr Christophe Louvet

• Nourredine Ait Rahmoune

• Nora Zeghib

• Gaelle le Guludec

• Katia Neveu

• Kristell Gélard

• Rachel Moukoko