Adjuvant Therapy of Colon Cancer: Where are we now ?

Leonard Saltz, MD

Memorial Sloan Kettering Cancer Center

New York, NY

Why do we give adjuvant treatment?

Why do we give adjuvant treatment?

“Because its there.”

The Drug Development Paradigm• Identify a new active agent in refractory

disease.• Combine that active agent with standard

agent(s) in refractory disease.• Take new active combination to front line

phase III metastatic trial.• Move new front line metastatic therapy into

adjuvant trials to try to increase the cure rate.

• But…..

Maybe this paradigm is wrong.

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00 33 66 99 1212 1515 1818 2121

MonthsMonths

Pro

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bil

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Survival: Second Line IrinotecanCunningham et al. Lancet 352:1413, 1998.

p=0.0001*p=0.0001*

CPT-11CPT-11

BSCBSC

*log-rank test*log-rank test

Phase III Irinotecan/5FU/LV in Metastatic Colorectal Cancer

(from Saltz et al,NEJM, 2000) 5FU/LV

Irinotecan 5FU/LV

Response rate 28 % 51 %

PFS 4.0 m 7.3 m

Grade 3-4 diarrhea 13 % 23%

Grade 4 neutropenia 43 % 24%

Grade 3 neuropathy 0% 0%

Median Survival 12.6 m 14.8 m (P=.04)

PFS = progression-free survival

Infusional 5FU/LV +/- Irinotecan Overall Survival (Douillard et al)

0.0

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0.3

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0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24 30

Months

Pro

bab

ility

CPT-11/5-FU/LV (N=198)

5-FU/LV (N=187)

p=0.03*

Censored

* log-rank test* log-rank test

C89803: IFL vs. FL (Stage III)Failure-Free Survival by Arm

0 1 2 3 4

Years from Study Entry

0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n F

ail

ure

-Fre

e

p=0.89

(All Patients)

5-FU/LVCPT-11/5-FU/LV

C89803: IFL vs. FL (Stage III)Overall Survival by Arm

0 1 2 3 4

Years from Study Entry

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0.8

1.0

Pro

po

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urv

ivin

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(All Patients)

5-FU/LVCPT-11/5-FU/LV

p=0.81

Bolus vs Biweekly Infusional 5FU/LVin Metastatic CRC

De Gramont et al. JCO Feb 1 1997: 808-815

p=.067 62 wks 57 wksSurvival

p=.0004 11% 24%Gr3/4 tox

p=.0012 28 wks 22 wksPFS

p=.0004 33 % 14 %RR

Infusion N=217

Bolus N=216

FNCLCC ACCORD-02/FFCD 9802, ASCO 2005

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1.0

0Pr

ob

ab

ility

0 1 2 3 4 5 6Years

LV5FU2 LV5FU2+IRITreatment

HR=1.19: 95%CI[0.90 - 1.59]

p=0.22

Disease-Free Survival

3-year DFS: 60% vs. 51%

FNCLCC ACCORD-02/FFCD 9802, ASCO 2005

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0Pr

ob

ab

ility

0 1 2 3 4 5 6Years

LV5FU2 LV5FU2+IRITreatment

HR=1.06: 95%CI[0.79 - 1.42]

p=0.68

Disease-Free Survival adjusted for T Stage and N+

3-year DFS: 59% vs. 53%

Phase III Oxaliplatin/5FU/LV in Metastatic Colorectal Cancer

(from DeGramont. J Clin Oncol 18:2938, 2000)

5FU/LV 5FU/LV/Oxali

Response rate 22 % 51 %

PFS 6.2 m 9.0 m

Grade 3-4 diarrhea 5 % 12%

Grade 4 neutropenia 2 % 12%

Grade 3 neuropathy 0% 18.2%

Median Survival 14.7 m 16.2 m (P=.12)

PFS = progression-free survival

MOSAIC: Stage II + IIIDisease-free Survival

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Months

Events

FOLFOX4 279/1123 (24.8%)

LV5FU2 345/1123 (30.7%)

HR [95% CI]: 0.77 [0.65 – 0.90]

DF

S p

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Data cut-off: January 16, 2005

MOSAIC: Disease-free Survival Stage II and Stage III Patients

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FOLFOX4 – Stage IILV5FU2 – Stage IIFOLFOX4 – Stage IIILV5FU2 – Stage IIIHR [95% CI]:

0.82 [0.60 – 1.13] Stage II0.75 [0.62 – 0.89] Stage III

Months

DF

S p

rob

abil

ity

666 12 18 24 30 36 42 48 54 60Data cut-off: January 16, 2005

Disease-free Survival in Stage III Patients: N1 & N2

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0.9

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FOLFOX4 – N1LV5FU2 – N1

FOLFOX4 – N2 LV5FU2 – N2

Months

DF

S p

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abil

ity

666 12 18 24 30 36 42 48 54 60Data cut-off: January 16, 2005

7.2%

11.5%

HR: 0.76

HR: 0.72

FU B RestLV 500

FU 500 Rest

LV 500

OHP 8585 2hr2hr

500

Week 1 2 3 4 5 6 7 8

R

NSABP C-07

2hr

x3

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0.6

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0.9

1

0 1 2 3 4

Ev # 3yr DFSFLOX 272 76.5%FULV 332 71.6%

p < 0.004HR: 0.79 [0.67 – 0.93]

21 % risk reduction

NSABP C-07 Trial (FLOX vs. FULV) 3 year Disease-Free Survival

Possible Conclusions

• Maybe our drug development paradigm is wrong?

• Corollary: How tumor cells survive therapy in the adjuvant (minimal disease) setting may differ from how they survive in the bulky metastatic setting.

• Therefore: what works in the metastatic setting may not work in the adjuvant setting and vice versa.

Does FLOX = FOLFOX ??

Oxaliplatin + Bolus vs. Infusion 5FU in Metastatic CRC: The TREE Studies

TREE-1 #pts RR*mFOLFOX6 41 47% bFOL 39 32% (p=.049)

TREE-2mFOLFOX6/bev 71 62%bFOL/bev 70 43% (p=.029)

*Responses unconfirmed

H Hochster: Presented at GI symposium Jan 05

Cross-Study ComparisonEfficacyFOLFOX 4

(MOSAIC)

FLOX

(C-07)

3 Year DFS 78 % 77 %

% improvement over 5FU/LV

5 % 5 %

Hazard Ratio 0.77 0.79

Cross-Study ComparisonToxicityFOLFOX 4

(MOSAIC)

FLOX

(C-07)

Gr 3-4 Neutropenia

41%

(2% neut. fever)

4%

Gr 3-4

Diarrhea

11% 38%

All Cause Mortality

0.5% 1%

Planned Oxaliplatin Usage

FOLFOX 4

(MOSAIC)

FLOX

(C-07)

# office visits for treatment

24

(12 for mFOLFOX 6)

18

# oxali doses 12 9

Oxali cost (ASP+6%)

1.8 m2

$39,552 $29,664

Do we need 12 doses of oxaliplatin when using FOLFOX?

9 ??

6 ??

Do we need 500 mg/m2 of LV?

QUASAR TRIAL

Is Disease Free Survival the true Endpoint?

FOLFOX4

LV5FU2

HR [95% CI]: 0.91 [0.75 – 1.11]

MOSAIC: Overall Survival1.0

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Months

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Data cut-off: January 16, 2005

RANDOMI

Z ATION FOLFIRIFOLFIRI

FOLFOXFOLFOX

FOLFOX/ FOLFIRI

Phase III Stage III Adjuvant Intergroup N0147

Accrual ~ 250

RANDOMI

Z ATION FOLFIRIFOLFIRI

FOLFOXFOLFOX

FOLFOX/ FOLFIRI

Phase III Stage III Adjuvant N0147

+/-Cetuxima

b

RANDOMI

Z ATION

FOLFOX + Cetuximab

FOLFOX + Cetuximab

FOLFOXFOLFOX

Phase III Stage III Adjuvant (N0147)Possible Modification:

RANDOMI

Z ATION

FOLFOX + Bev

FOLFOX + Bev

FOLFOXFOLFOX

NSABP C-08

Phase III Trial, Stage II and IIIColon Cancer

RANDOMI

Z ATION

FOLFOX + Bev

FOLFOX + Bev

FOLFOXFOLFOX

NSABP C-08

Phase III Trial, Stage II and IIIColon Cancer

6 months bev

alone

→

Average Selling Price (ASP) + 6%(Patient assumption: 75 kg, 1.8 m2 patient, two weeks Rx)

• 5FU 500 mg/m2 $ 7• Leucovorin 500 mg/m2 $ 47• Xeloda 2000 mg/m2/d $ 1065• Camptosar 180 mg/m2 $ 2135• Eloxatin 85 mg/m2 $ 3296

• Avastin 5 mg/kg $ 2283• Erbitux 250 mg/m2 $ 4964

Adjuvant Therapy of Colon Cancer

Estimated Cost Per Patient (ASP + 6%)

5FU/LV (HD)

5FU/LV (LD)

FLOX

FOLFOX

FOLFOX/cetuximab

FOLFOX/bev 6 m

FOLFOX/bev 12 m

$954

$162

$30,618

$40,506

$100,074

$67,902

$95,298

Estimated Cost Per Year if 55,000 Patients Treated (ASP + 6%)

5FU/LV (HD)

5FU/LV (LD)

FLOX

FOLFOX

FOLFOX/cetuximab

FOLFOX/Bev 6 m

FOLFOX/Bev 12 m

$55,000,000

$9,000,000

$1,680,000,000

$2,230,000,000

$5,500,000,000

$3,730,000,000

$5,240,000,000

Challenges

• Evaluate duration of therapy questions

• Select therapies rationally– Molecular markers– Genetics

• Assure availability of appropriate therapies to all patients

Conclusions

• Until we do the trial, we don’t know the answer.

• Negative trials are as helpful and informative as positive trials.

Conclusions

• Adjuvant treatment options for colon cancer patients are better than they were, but not as good as they need to be.

• Please offer clinical trials to your patients. Without your help and theirs, we can’t make the progress that we so desperately need.