f. maindrault-gbel, g. lledo, b. chibaudel, l. mineur, t. andr, m. bennamoun, m. mabro, p.artru, c....
DESCRIPTION
Rationale: OPTIMOX 1 Oxaliplatin Stop and Go Better tolerance Same efficacy results Tournigand, JCO 2006TRANSCRIPT
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.
RationaleChemotherapy-free intervals (CFI) have previously been studied in patients receiving 5FU- based therapy:Hejna et al (Br J Cancer (1998) have shown that patients can benefit from 5FU reintroduction after a CFI following 6 months of therapy.
Maughan et al (Lancet 2003) have show in a larger phase III that 3 months 5FU-based chemotherapy followed by CFI achieved the same survival than 5FU until progression.
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.
Plantade et al have shown in a retrospective study presented at ASCO 2006 that patients with MCRC an benefit from CFI, especially in first-line therapy.
Grade3-4 toxicity at each cycle
0
5
10
15
20
25
1 3 5 7 9 11 13 15 17 19 21 23
cycles
% p
atie
nts
FOLFOX4
FOLFOX7
RRAANNDDOOMMIISSAATTIIOONN
FOLFOX4 until progression
FOLFOX7 x 6 cysLV5FU2 x 12 cyFOLFOX7 x6 cy
A
B
Rationale: OPTIMOX 1
Oxaliplatin Stop and Go
Better tolerance
0 25 50 75 100 125 1500.00
0.25
0.50
0.75
1.00
FOLFOX4
FOLFOX7
weeks
prob
abili
ty
20.0 months
21.6 months
p = 0,68
Same efficacy results
Tournigand, JCO 2006
RRAANNDDOOMMIISSAATTIIOONN
maintenance therapy vs chemotherapy-free interval
mFOLFOX7 x 6 cy sLV5FU2 until baseline progressionmFOLFOX7 reintroduction
mFOLFOX7 x 6 cy No maintenance until baseline progressionmFOLFOX7 reintroduction
OPTIMOX 2 Study design
A
B
OPTIMOX2 : chemotherapy-free interval
OPTIMOX1 : maintenance therapy
A
FOLFOX7 x 6 cy
A A A A A
FOLFOX7 x 6sLV5FU2
Baseline progression
FOLFOX7 x 6 cy
A A A A
FOLFOX7 x 6Chemotherapy-free interval
Baseline progression
LV 400 5-FU 3000
mFOLFOX7
Oxali 100H0 H2 H24 H48
LV 400 5-FU 3000
sLV5FU2
H0 H2 H24 H48
5FUb 400
Cycles every 14 days, dose mg/m²
CHEMOTHERAPY
OPTIMOX 1
OPTIMOX 2
A
A
Baseline Progression
t
T size
FOLFOX FOLFOX
Progression Baseline progression
Progressionat reintroduction
Chemotherapy-free Interval
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
Primary objective was duration of disease control, no formal hypothesis were done between the two arms
Statistics
Duration of Disease Control
t
T size
FOLFOX FOLFOX
PFS 1
Progression Baseline progression
PFS 2
Progressionat reintroduction
DDC = PFS 1 + PFS 2 (if no PD)
ASCO 2001, 146a
Patients Characteristics
Arm AOPTIMOX1
N = 100
Arm BOPTIMOX2
N = 102
Median age, years (range) 67 (35 - 81) 67 (32 - 80)
Male/Female 60% / 40% 59% / 41%
WHO PS 0 / 1-2 58% / 42% 59% / 41%
LDH N / > ULN / Missing 35% / 48% / 17% 30% / 45% / 25%
Colon/Rectum/Both 63% /36% / 1% 69% /26% / 5%
Prior adjuvant CT/RT (oxali) 17% (0%) 18% (2%)
Synchronous metastasis 25% 27%
Nb metastatic sites 1/ 2/Uk
46% / 51% / 3% 52% / 47% / 1%
202 patients enrolled from 12 centers
Response was evaluated at 4 and 6 cycles then every 2 months.
OPTIMOX 2 Responses
OPTIMOX1 OPTIMOX2
CR 3% 3%
PR 58% 58%
PR+CR 61% 61%Stable 27% 32%
Prog 11% 6%
NE 0% 1%Too early 11 patients 12 patients
OPTIMOX1
PD 10
no Prog. 40> 6 mths 20 (surg. 7)
>12 mths 10 (surg.5)
OPTIMOX 2 Status of the study
A
B
Median follow-up 70 weeks
Prog on maintenance 49
Reintro. 31
Line 2 18
Dead 26
Dead 35
OPTIMOX2
PD 5
no Prog. 30> 6 mths 15 (surg. 6)
>12 mths 7 (surg.5)
Prog on CFI 64
Reintro. 52
Line 2 12
OPTIMOX1N = 100
OPTIMOX2 N = 102
Nb of cycles with oxaliplatin 649 783
Nb of cycles with and without oxaliplatin
1218 783
Median nb of cycles with oxaliplatin (range)
6(1-18)
6(1-18)
Median nb of cycles with or without oxaliplatin (range)
12(1-32)
6(1-18)
OPTIMOX 2 Number of Cycles
+21%
-36 %
Response was evaluated at 4 and 6 cycles then every 2 months.
OPTIMOX 2 Responses Reintroduction 1
OPTIMOX1 OPTIMOX2N 30 45CR 0 (0%) 0 (0%)PR 4 (13%) 14 (31%)Stable 13 (43%) 11 (24%)Prog 12 (40%) 18 (40%)NE 1 (3%) 2 (5%)Too early 1 patient 6 patients
Neuropathy
Grade 1 9.7 % 2 32.2 % 3 3.2%
Grade 1 21.7 % 2 30.4 % 3 8.7 %
Grade 1 4.4 % 2 19.1 % 3 4.4 %
Grade 1 27.0 % 2 16.2 % 3 13.5 %
Optimox 1 Optimox 2
After the first reintroduction
2 months after FOLFOX
Grade 1 69.9 % 2 17.2 % 3 0%
Grade 1 71.7 % 2 17.3 % 3 0%
During C1-C6
Toxicity Grade 3-4 (%) per Patient
OPTIMOX 1 OPTIMOX 2
C1-C6 maintenance R1 C1-C6 R1
Neutropenia 17.2 6.6 3.4 11.9 6.8
Anemia 1 0 0 0 1
Thrombopenia 6.4 1.7 0 3.2 2.2
Mucitis 1 3.3 0 1 2.2
Vomiting 2.1 0 0 4.3 4.4
Diarrhea 2.1 0 0 4.3 2.2
HFS 0 3.3 0 0 0
Progression-free Survival
0 10 20 30 40 50 60 70 80 90 1000.00
0.25
0.50
0.75
1.00
optimox1 median 38 weeks
optimox2 median 30 weeks
weeks
prob
abili
ty p=.009
Progression-free Survival
8.7 months
6.9 months
Duration of Disease Control
0 10 20 30 40 50 60 70 80 90 1000.00
0.25
0.50
0.75
1.00
optimox1 median 56 weeks
optimox2 median 51 weeks
weeks
prob
abili
ty
p=.41
Duration of Disease Control
12.9 months
11.7 months
Chemotherapy-free IntervalChemotherapy-free Interval
0 10 20 30 400.00
0.25
0.50
0.75
1.00
optimox 2 n=92 median 20 weeks
weeks
prob
abili
ty
4.6 months
CFI according to Initial ResponseChemotherapy-free intervals
0 25 500.00
0.25
0.50
0.75
1.00
CR+PR N=55 median CFI 5.1 months
SD N=29 median CFI 3.9 months
weeks
prob
abili
ty
5.1 months
3.9 months
CFI according to Pc factorsChemotherapy-free Interval
0 10 20 30 400.00
0.25
0.50
0.75
1.00
Good Prog. n=30 med. 35 weeks
Poor Prog. n=57 med. 20 weeks
p=.005
weeks
prob
abili
ty
8.0 months
4.6 months
PS 2LDH ↑Alk Ph >3ULN> 1 site
PFS of Reintroduction
3.7 months
4.1 months
Progression-free Survival
0 10 20 30 400.00
0.25
0.50
0.75
1.00
optimox1 n=31 median 16 weeks
optimox2 n=51 median 18 weeks
p=.74
weeks
prob
abili
ty
Conclusions (1)Maintenance therapy improves PFS but not DDC
Median duration of chemotherapy-free interval is 20 weeks (4.6 months), 35 weeks (8 months) in patients without adverse prognostic factors
Results in the OPTIMOX 1 arm are comparable to the previous study except DDC, 12.9 vs 10.6 months, which can be explained by a higher reintroduction rate, > 60% vs 40%.
Response rate after reintroduction of FOLFOX could be higher in patients who did not receive maintenance therapy
Conclusions (2)
A break in therapy can be proposed in patients who achieved a response or a stable disease with first-line FOLFOX therapy, especially those without adverse prognostic factors
The next GERCOR study, DREAM, will evaluate maintenance therapy with targeted drugs alone.
Acknowlegments:
• Dr Lledo Gérard – Lyon
• Pr de Gramont Aimery – Paris
• Dr Mineur Laurent – Avignon
• Pr André Thierry – Paris
• Dr Bennamoun Mustapha –
Montfermeil
• Dr Mabro May – Suresnes
• Dr Carola Elisabeth – Senlis
• Dr Flesch Michel- Dijon
• Dr Ganem Gérard – Le Mans
• Dr Colin Philippe – Reims
• Dr Auby Dominique - Libourne
For the GERCOR :
• Benoist Chibaudel
• Valentine Songeur
• Nourredine Ait Rahmoune
• Nora Zeghib
• Gaelle le Guludec
• Katia Neveu
• Laurence Renaud