Oxaliplatin/5-FU/LV in Adjuvant Colon Cancer: Updated Efficacy Results of the Mosaic Trial, Including Survival, with a Median Follow-up of 6 Years Aimery

Oxaliplatin/5-FU/LV in Adjuvant Colon Cancer: Updated Efficacy Results of the Mosaic Trial,

Including Survival, with a Median Follow-up of 6 Years

Aimery de Gramont, Corrado Boni, Matilde Navarro, Josep Tabernero, Tamas Hickish, Clare Topham, Andrea Bonetti, Philip Clingan, Christelle Lorenzato, Thierry André, and

MOSAIC investigators

Aimery de Gramont

MOSAIC: Study Design

Primary end-point: disease-free survivalSecondary end-points: safety, overall survival

n=2246

Enrollment:Oct 1998–Jan 2001 (146 centres; 20 countries)

• Completely resected colon cancer

• Stage II, 40%; Stage III, 60%

• Age 18–75 years

• KPS ≥60

• No prior chemotherapy

RLV5FU2

FOLFOX4(LV5FU2 + oxaliplatin 85 mg/m²)

(n=1123)

(n=1123)

LV5FU2, Leucovorin 200 mg/m2 iv over 2 hours followed by 5-fluorouracil 400 mg/m2 bolus and 5-fluorouracil 600 mg/m2 iv over 22 hours on Days 1 and 2, every 14 days; FOLFOX4, LV5FU2 + oxaliplatin 85 mg/m2 iv over 2 hours on Day 1

Cut-off Dates for Efficacy Analyses

2003 3-year DFS: primary endpoint 1

2006 5-year DFS: final update (No further updates on relapses)

2007 Overall Survival: 6-year, final analysis

1. André, et al. N Engl J Med 2004;350:2343–2351

Primary End-Point: Disease-Free Survival

• “DFS allows to make more quickly a decision regarding the efficacy of a new treatment

• Clinical trials can be completed more quickly• Drug development time can be shortened• Better therapy can be made available to patients

more quickly• DFS can be considered as an endpoint of its

own merit in decreasing the high cost, quality-of life impact and debilitating consequence of recurrent disease”

1. Sargent, et al. J Clin Oncol 2005;23:8664–8670

3 Year DFS vs 5 Year OS

0,5

0,55

0,6

0,65

0,7

0,75

0,8

0,5 0,55 0,6 0,65 0,7 0,75 0,8

5 Year OS

3 Ye

arD

FS

r=0,88

Sargent, et al. J Clin Oncol 2005;23:8664–8670

3 years

(April 20031)

5 years

(June 2006)

FOLFOX4 LV5FU2 FOLFOX4 LV5FU2

Median follow-up, months 37.9 37.8 73.5 73.4

Events (%) 21.1 26.1 27.1 32.1

DFS (%) 78.2 72.9 73.3 67.4

HR

[95% CI]

0.77

[0.65–0.91]

0.80

[0.68–0.93]

p-value 0.002 0.003

1. Andre, et al. N Engl J Med 2004;350:2343–2351

Disease-free Survival

Events = Relapse + Second Primary Colon Cancer + Death any cause

Disease-free Survival: ITT

Data cut-off: June 2006Disease-free survival (months)

FOLFOX4LV5FU2

Prob

abili

ty

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

0 6 12 18 24 6030 36 42 48 54

Events

FOLFOX4 304/1123 (27.1%)

LV5FU2 360/1123 (32.1%)

HR [95% CI]: 0.80 [0.68–0.93]

5.9%

p=0.003

Disease-free Survival: Stage II and Stage III Patients

Data cut-off: June 2006

HR [95% CI] p-value

Stage II 0.84 [0.62–1.14] 0.258

Stage III 0.78 [0.65–0.93] 0.005

FOLFOX4 stage IILV5FU2 stage IIFOLFOX4 stage IIILV5FU2 stage III

Months

Prob

abili

ty

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

0 6 12 18 24 6030 36 42 48 54 66 72

3.8%

7.5%

p=0.258

p=0.005

Disease-free Survival: High-risk Stage II Patients

Disease-free survival (months)

FOLFOX4 n=286LV5FU2 n=290

Prob

abili

ty

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

0 6 12 18 24 6030 36 42 48 54 66 72

3-year 5-year

FOLFOX4 85.4% 82.1%

LV5FU2 80.4% 74.9%

HR [95% CI]: 0.74 [0.52–1.06]

High-risk stage II- defined as at least one of the following: T4, tumor perforation, bowel obstruction, poorly differentiated tumor, venous invasion , <10 lymph nodes examined; Data cut-off: June 2006

7.2%

Exploratory analysis

Summary: Disease-free SurvivalFinal Update

5-year DFS %

HR [95% CI] p-value FOLFOX4 LV5FU2

ITT (overall population) 73.3 67.4 0.80

[0.68–0.93]

0.003

Stage III 66.4 58.9 0.78

[0.65–0.93]

0.005

Stage II 83.7 79.9 0.84

[0.62–1.14]

0.258

High-risk stage II n=576 82.1 74.9 0.74

[0.52–1.06]

—

Low-risk stage II n=323 86.3 89.1 1.22

[0.66–2.26]

—


Secondary End-Point: Safety

NCI-CTC grade 3 (% patients) FOLFOX4 LV5FU2Neutropenia 41.0 (Gr 4, 12.2) 4.7Neutropenia with fever or infection

1.8 0.2

Diarrhea 10.8 6.7Stomatitis 2.7 2.2Vomiting 5.9 1.4Allergy 3.0 0.2Alopecia (grade 2) 5.0 5.0Neuropathy (grade 3) 12.4 0.0All cause mortality 0.5 0.5

Toxicity per Patient (on Treatment)

1. André, et al. N Engl J Med 2004;350:2343–2351

Long-term Safety

(% patients)

FOLFOX

5.3LV5FU2

5.7

0

10

20

30

40

50

60

DuringTx

6months

1-year 2-year 3-year 4-year

Grade 1Grade 2Grade 3

Data cut-off: January 2007

Second cancer

Peripheral Sensory Neuropathy

Evaluable patients n=811Grade 0 84.3%Grade 1 12.0%Grade 2 2.8%Grade 3 0.7%

Secondary End-Point: Overall Survival

FOLFOX4(n=1123)

LV5FU2(n=1123)

Number of deaths (%) 243 (21.6) 279 (24.8)Cause of death:

Adverse eventRelapseOtherMissing data

6 (0.5)189 (16.8)

44 (3.9)4 (0.4)

6 (0.5)230 (21.6)

27 (2.4)3 (0.3)

Probability of surviving (%): 3 years5 years6 years

88.281.378.6

86.679.176.0

Patients alive with recurrence (%) 69 (6.1) 88 (7.8)

Hazard ratio [95% CI] 0.85 [0.72–1.01]p-value 0.057


Overall Survival: ITT

Data cut-off: January 2007 Overall survival (months)

FOLFOX4LV5FU2

Prob

abili

ty

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

0 6 12 18 24 6030 36 42 48 54 66 9672 78 84 90

Events

FOLFOX4 243/1123 (21.6%)

LV5FU2 279/1123 (24.8%)

HR [95% CI]: 0.85 [0.72–1.01]

2.6%

p=0.057

Overall Survival: Stage II and Stage III


FOLFOX4 stage IILV5FU2 stage IIFOLFOX4 stage IIILV5FU2 stage III

Overall survival (months)

Prob

abili

ty

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

0 6 12 18 24 6030 36 42 48 54 66 9672 78 84 90

HR [95% CI]

Stage II 1.00 [0.71–1.42]

Stage III 0.80 [0.66–0.98]

0.1%

4.4%

p=0.996

p=0.029

Summary: Overall Survival

Probability of surviving

at 6 years, %

HR [95% CI] p-value FOLFOX4 LV5FU2

ITT (overall population) 78.6 76.0 0.85

[0.72–1.01]

0.057

Stage III 73.0 68.6 0.80

[0.66–0.98]

0.029

Stage II 86.9 86.8 1.00

[0.71–1.42]

0.996


0.5 0.7 0.9 1.1 1.3 1.5

Hazard Ratio

1

Stage III

High risk Stage II

Stage II

Stage III

High risk Stage II

Stage II

Overall survival (OS)

Disease-free survival (DFS)

Hazard ratios for DFS and OS by sub groupFavours FOLFOX4 Favours LV5FU2

Deaths other than Colon Cancer


FOLFOX4 LV5FU2Total numberOther cancers

GI cancersUrologic cancers

Lung cancersBreast-Gynecologic

HematologicalOther cancers

4821 (44%)

454323

3011 (37%)

202223

Cardio-vascular 18 (37%) 11 (37%)Pneumopathy 3 2OtherUnknown

24

33



FOLFOX4 LV5FU2

Number of patients with relapse 258 334

Any chemotherapy (%) 189 (73.3) 257 (76.9)

Oxaliplatin-based regimen* (%) 22 (8.5) 97 (29.0)

Irinotecan-based regimen* (%) 116 (45.0) 109 (32.6)

Other, including biologics (%) 37 (14.3) 45 (13.5)


Treatment for Recurrence

* first-line

Time from Relapse to Death: ITT

Time from relapse to death (months)

Prob

abili

ty

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

FOLFOX4 n= 258 median 21 monthsLV5FU2 n=334 median 24 months

0 6 12 18 24 6030 36 42 48 54 66 8472 78

Patients alive with relapse (%)

FOLFOX4 69 (6.1)

LV5FU2 88 (7.8)


Conclusions

For FOLFOX4 vs LV5FU2:• The DFS benefit at 3 years was maintained at 5

years• Trend showing improved DFS in ‘high-risk’ stage

II patients• Significant OS benefit in stage III patients • No increase in the rate of secondary cancers• Continued recovery from sensory neuropathy

AcknowledgmentsDr’s Abad A, Achille E, Agostara B, Albertsson M, Ales JE, Andersen OKD, André T, Anton A, Aranda E, Basser R, Beauduin M, Benavides M, Berger C, Bessel EM, Boaziz C, Bonetti A, Boni C, Boutan-Laroze A, Bridgewater J, Bruntsch U, Bumma C, Canon JL, Carlsson G, Carmichael J, Carola E, Carrato A, Cassidy J, Catane R, Cervantes A, Chauvenet L, Clarke S, Clingan P, Colin P, Colucci G, Cortes-Funes H, Craft P, Creemers GJ, Cumin I, Cunningham D, Dahl O, Davidson N, de Braud F, de Gramont A, Della-Fiorentina S, Demol J, Depisch D, Díaz-Rubio E, Dorval E, Erdkamp FLG, Facchini T, Fahlke C, Falk S, Figer A, Fillet G, Flesch M, Fountzilas G, Ganem G, Georgoulias V, Gervasio H, Glynne-Jones R, Green M, Guérin-Meyer V, Hansen J, Hawkins R, Heike M, Heikkilä R, Hendler D, Herben MG, Hickish T, Höhler T, Honhon B, Humblet Y, Isacson R, Izso J, James R, Janinis J, Janssen M, Kahan Z, Kalofonos H, Karina M, Kerger J, Landi B, Ledermann J, Lepoutre L, Lim R, Lledo G, Maartense E, Madoe V, Maigre M, Marcuello E, Marques F,Marti P, Massuti B, Mathijs R, Maughan T, Megyery E, Mejer J, Meurisse MP, Miccio-Belaiche A, Mignot L, Mineur L, Mitchell P, Monfardini S, Monfort L, Morvan F, Mousseau M, Muron T, Myint S, Nabico R, Navarro M, Noirclerc M, Nowacki M, Nylen U, Papamichael D, Pavlidis N, Piazza E, Pinotti G, Pinter T, Polus M, Raoul Y, Ridwelski K, Rinaldi Y, Rivera F, Rosenthal M, Roth A, Samantas E, Samuel L, Sanches E, Scheithauer W, Schrijvers D, Seymour M, Shani A, Simoens M, Singer J, Skosgaard T, Slancar M, Sleebom HP, Slevin M, Smit JM, Sörensen JB, Soyer P, Steger G, Steward W, Stuart NSA, Szanto J, Szucs M, Tabernero J, Topham C, Toumieux J, Tubiana-Mathieu N, Underhill C, van Deijk WA, van den Bossche L, van Eygen K, van Laethem JL, van Veelen H, Vandebroek J, Vilain C, Vindevoghel A, Wasan H, Westman G, Wilson C, Zaniboni A

Documents

Oxaliplatin/5-FU/LV in Adjuvant Colon Cancer: Updated Efficacy Results of the Mosaic Trial, Including Survival, with a Median Follow-up of 6 Years Aimery