Minimal versus Intense Upfront Systemic Therapy in Metastatic Colorectal Cancer Paulo M. Hoff, MD, FACP Hospital Sirio Libanes Sao Paulo, Brazil Centro

Minimal versus Intense Upfront Systemic Therapy in Metastatic

Colorectal Cancer

Paulo M. Hoff, MD, FACPHospital Sirio Libanes

Sao Paulo, Brazil

Centro de Oncologia

Medical Oncology Treatment Objectives in CRC

• To cure patients:

– Adjuvant chemotherapy

– Convert inoperable into operable disease

• To palliate symptoms:

– Reduce tumor volume

• To prolong survival

– Control disease growth

5 – Fluorouracil: 1957

NH

HN

O

O

F

5-FU

50 years later, fluoropyrimidines remain the backbone of colorectal cancer treatment.

Treatment Options for Advanced Colorectal Cancer in 2006

• Six different classes of drugs available:– Fluoropyrimidines

• 5-FU, FUDR, Capecitabine, UFT, S-1

– Platins • Oxaliplatin

– Topoisomerase I inhibitors • Irinotecan

– Direct TS inhibitors• Raltitrexed

– Anti-VEGF • Bevacizumab

– Anti-EGFR • Cetuximab, Panitumumab

Irinotecan Combination Trials

IFL* IFL* (n=231)(n=231)

5-FU/LV(n=226)

RRAANNDDOOMMII

Z Z EE IrinotecanIrinotecan

(n=226)(n=226)

Saltz et al. Saltz et al. N Engl J MedN Engl J Med. 2000;343:905-914. 2000;343:905-914

Metastatic Colorectal

Cancer

Saltz et al. Saltz et al. N Engl J MedN Engl J Med. 2000;343:905-914.. 2000;343:905-914.

Irinotecan Combination Trials: Efficacy

Irinotecan + 5-FU/LV 5-FU/LV P Value

RR (confirmed, %) 39% 21% <.001*

PFS (median, mo) 7.0 4.3 .004

OS (median, mo) 14.8 12.6 .04

Oxaliplatin as Second-Line Treatment for CRC

Rothenberg et al. Rothenberg et al. J Clin OncolJ Clin Oncol. 2003;21:2059-2069.. 2003;21:2059-2069.

LV5FU2(n=151)

Oxaliplatin(n=156)

R

A

N

D

O

M

I

Z

E

FOLFOX4(n=152)


Cancer S/P IFL

Oxaliplatin as Second-Line Treatment for CRC

LV5FU2 FOLFOX4 Oxaliplatin P Value

RR 0% 9.9% 1.3%

<.0001

TTP 2.7 mo 4.6 mo 1.6 mo <.0001

Overall Survival

8.7 mo 9.8 mo 8.1 mo .07

Rothenberg et al. Rothenberg et al. J Clin OncolJ Clin Oncol.. 2003;21:2059-2069. 2003;21:2059-2069.

N9741: Modified Schema

IFLIFL(n=264)(n=264)

IROX(n=264)

FOLFOX4FOLFOX4(n=267)(n=267)

Goldberg et al. Goldberg et al. J Clin OncolJ Clin Oncol. 2004;22:23-30.. 2004;22:23-30.

R

A

N

D

O

M

I

Z

E


Cancer

N9741: Efficacy Results

IFL(N=264)

FOLFOX(N=267)

IROX(N=264)

RR (CR + PR) 31% 45% 34%

Median TTP (Months)

6.9 8.7 6.5

Median OS

(Months) 14.8 19.5 17

Goldberg et al. Goldberg et al. J Clin OncolJ Clin Oncol. 2004;22:23-30.. 2004;22:23-30.

N9741: Second Line Treatment

Saltz FOLFOX-4 WassermanCPT-11 Oxaliplatin CPT-11

5-FU/LV 5-FU/LV OxaliplatinN=235 N=235 N=237

Any 59% 67% 63%

CPT-11 22% 52% 28%

Oxaliplatin 17% 6% 6%

5-FU 35% 33% 45%

Other 28% 20% 27%

FOLFOX6(n=111)

FOLFIRI With FOLFOX6 Sequencing Trial in CRC

Tournigand et al. Tournigand et al. J Clin Oncol.J Clin Oncol. 2004;22:229-237. 2004;22:229-237.

FOLFIRI(n=109)

R

A

N

D

O

M

I

Z

E

FOLFIRI(n=69)

FOLFOX6(n=81)Until

progression

Untilprogression

Untilprogression

Untilprogression

RR, % 56 15 54 4

PFS, mo 8.5 4.2 8.0 2.5

OS, mo 21.5 20.6

FOLFIRI FOLFOX6 FOLFOX6 FOLFIRI n = 109 n = 81 n = 111 n = 69

Tournigand C et al. J Clin Oncol 2004;22:229-237

FOLFIRI With FOLFOX6 Sequencing Trial in CRC

Availability of All Cytotoxic Agents and Survival

Grothey A and Sargent D. J Clin Oncol. 2005;23:9441-9442.

Patients With 3 Drugs (%)

0

Med

ian

OS

(m

on

ths)

10 20 30 40 50 60 70 80

13

14

15

16

17

18

19

20

2122

12

5-FU/IRI vs FOLFOXIRI: Falcone et al

N = 244

FOLFOXIRI

5-FU/Iri5-FU/IriDouillardDouillard

Falcone ASCO 2007Falcone ASCO 2007

R

A

N

D

O

M

I

Z

E

Metastatic Colorectal Cancer

Efficacy

5-FU/IRI

N=122

FOLFOXIRI

N=122

P-value

Response rate (%)

41% 66% ?

PFS (mos) 6.9

(BICC = 8.3)

9.9 0.0009

OS (mos) 16.7

(BICC = 23)

23.6 0.042

Falcone ASCO 2007

Availability of All Cytotoxic Agents and Survival

Courtesy of Dr. Goldberg, adapted from Grothey A and Sargent D. J Clin Oncol. 2005;23:9441-9442.

Patients With 3 Drugs (%)

0

Med

ian

OS

(m

on

ths)

10 20 30 40 50 60 70 80

13

14

15

16

17

18

19

20

2122

12

*FOLFOXIRI

FU/IRI(42 pts)

FOLFOXIRI(39 pts)

R0 12%*(5 pts)

36%*(14 pts)

* p=0.017

Post-ChemoRx Resections(patients with liver mts only)

Falcone ASCO 2007

Phase III Trial With Bevacizumab Therapy in First-Line MCRC

Bolus IFL + BV(n = 403)

5-FU/LV + BV(n = 110)

Bolus IFL + placebo(n = 412)

RR

AA

NN

DD

OO

MM

II

ZZ

EE

Untreated

MCRC

Hurwitz H, et al. N Engl J Med 2004;350:2235–42

Phase III Trial of Bevacizumab in First-Line MCRC

IFL + Placebo (n=411)

IFL + Bevacizumab

(n=402) P Value

ORR (%)

CR

PR

35

2.2

32.5

45

3.7

41.2

0.0036


Median PFS (months)IFL + placebo: 6.2 (95% CI: 5.6–7.7)IFL + Bevacizumab: 10.6 (95% CI: 9.0–1.0)HR=0.54 (95% CI: 0.45–0.66) p<0.001

Pro

bab

ilit

y o

f b

ein

g p

rog

ress

ion

-fre

e 1.0

0.8

0.6

0.4

0.2

00 10 20 30

PFS (months)

6.2 10.6

IFL + Bevacizumab

IFL + placebo

Phase III trial : PFS


Median survival (months)IFL + placebo: 15.6 (95% CI: 14.3–17.0) vsIFL + Bevacizumab: 20.3 (95% CI: 18.5–24.2)HR=0.66 (95% CI: 0.54–0.81) p<0.001

Pro

bab

ilit

y o

f su

rviv

al

1.0

0.8

0.6

0.4

0.2

00 10 20 30 40

Survival (months)

IFL + Bevacizumab

IFL + placebo

15.6 20.3


Phase III trial : Survival

FOLFIRI(n=144)

RmIFL

(n=141)

XELIRI(n=145)

Feb 2003 – April 2004

Initial design

n=430

FOLFIRI+Bev.

mIFL+Bev.

(n=60)

(n=57)

May 2004 – Dec 2004n=117

Primary endpoint: PFS

Trial of Bevacizumab plus FOLFIRI/mIFL (BICC-C): design

Protocol amended due

to approval of bevacizumab

Amended design

R

* Celecoxib data not shownFuchs et al, ASCO 2007

BICC Efficacy in 430 Patients

mIFL CapeIRI FOLFIRI P-value

Response rate (%)

43.3 38.6 47.2 N.S.

PFS (mos) 6.0 5.7 8.2 0.01

OS (mos) 17.6 18.9 23.1 N.S.

Fuchs et al, ASCO 2007

Adverse EventGrade 3-4

FOLFIRIn = 137

(%)

m-IFLn = 137

(%)

CapeIRI n = 141

(%)

Nausea 8.8 7.3 18.4

Vomiting 8.8 7.3 15.6

Diarrhea 13.9 19 47.5

Dehydration 5.8 7.3 19.1

Neutropenia 43.1 40.9 31.9

Febrile neutropenia 3.6 12.4 7.1

Hand-foot syndrome 0 0 9.9

60-day mortality 3.6 5.1 3.5

Period 1: Grade 3-4 AEs


Period 2: Efficacy

mIFL + Bev

N=60

FOLFIRI + Bev

N=57

P-value

Response rate (%)

? ? ?

PFS (mos) 8.3 11.2 0.28

OS (mos) 19.2 Not reached 0.01


Progression Free SurvivalP

rop

ort

ion

of

Su

bje

cts

Wh

o

Did

No

t P

rog

ress

Regimen PFS (Mos) P Value

FOLFIRI + BEV 11.2 --

mIFL + BEV

8.3 0.28

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 10 20 30

Time to Progression (months)

FOLFIRI + Bevacizumab

mIFL + Bevacizumab


Overall Survival

Survival Time (months)

RegimenMedian OS (Months) 1 Year P Value

FOLFIRI+ BEV Not Reached 87% --

mIFL + BEV 19.2 61% 0.01

Pro

po

rtio

n o

f S

ub

ject

s W

ho

Su

rviv

ed

FOLFIRI + Bevacizumab

mIFL + Bevacizumab

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 10 20 4030


E3200: Phase III Trial of Bevacizumab in Second-Line Metastatic CRC

FOLFOX4

BV monotherap

y

FOLFOX4 + BV

Previously IFL

Treated Metastati

c CRC(n=880)

Giantonio, ASCO 2005

E3200: Efficacy

4.8P < 0.0001 vs. BV

3.0%9.2%21.8%P < 0.0001 vs.

FOLFOX

RR

2.77.2P < 0.0001 vs.

FOLFOX

PFS (months)

10.2

230

Bevacizumab

10.8

12.9P = 0.0018 vs.

FOLFOX

OS

(months)

271271

FOLFOX4FOLFOX4 + bevacizumab

Giantonio BJ et al. ASCO 2005

Phase III Trial of Bevacizumab With Oxaliplatin-Based Therapy in CRC

Primary end point:

PFS

Previously untreated MCRC

(N=1600)

XELOX

FOLFOX4

+ Placebo

+ Placebo

+ Bevacizumab(7.5 mg/kg, q3w)

+ Bevacizumab(5 mg/kg, q2w)

Saltz L, et al. ASCO 2007

Efficacy

XELOX/FOLFOX

N=701

XELOX/FOLFOX + bev

N=699

P-value

Response rate (%) 49% 47% 0.99

PFS (mos) 8.0 9.4 0.0023

OS (mos) 19.9 21.3 0.076

Saltz L, et al. GI ASCO 2007

Overall survival

HR=0.89 (97.5% CI 0.76–1.03)

p=0.0769

XELOX / FOLFOX-4 + bevacizumab n=699 (420 events)

XELOX / FOLFOX-4 + placebo n=701 (455 events)

1.0

0.8

0.6

0.4

0.2

0

Months

Su

rviv

al e

stim

ate

0 6 12 18 24 30 36

19.9 21.3

Saltz L, et al. ASCO 2007

Cetuximab in Colorectal Cancer “Bond Trial”

Irinotecan pre-treated EGF-R positive Metastatic CRC

Cetuximab and Irinotecan218 patients

Cetuximab 111 patients

* 577 patients screened 329 patients included in a 2:1 randomization

PD

Cunningham et al. NEJM 2004;351:337-345

Cetuximab Combination Therapy “BOND” Trial

IRI/Cx Cx Assessment (n=218) (n=111) P-value

Response Rate 22.9% 10.8% 0.007

TTP 4.1 mo. 1.5 mo.<0.001 (Median)

Survival (Median) 8.6 mo. 6.9 mo. 0.48

Cunningham et al. NEJM 2004;351:337-345

Cetuximab may circumvent irinotecan resistance

Correlation Between Response Rate and Prior Treatment

SubgroupsCombination

n/N (%)Monotherapy

n/N (%)

Prior regimens

1 7/41 (17.1) 5/27 (18.5)

2 20/79 (25.3) 5/41 (12.2)

≥3 23/98 (23.5) 2/43 (4.7)

Prior oxaliplatin

yes 30/135 (22.2) 6/71 (8.5)

no 20/83 (24.1) 6/40 (15.0)

The BOND II Trial

RANDOMI

Z E

Bevacizumab+

Cetuximab

Bevacizumab+

Cetuximab+

Irinotecan

CRC patients who progressed

on irinotecan(any line)

Saltz et al, ASCO 2005

The BOND II Trial

• Best response on study

– CBI (n= 41) PR = 37%

– CB (n=40) PR = 20%

• Median time to tumor progression:

– Cetux/Bev/IRI 7.9 months

– Cetux/Bev 5.6 months

Saltz et al, ASCO 2005

CALGB 80405 Intergroup Trial

mFOLFOX6or

FOLFIRI

Bevacizumab

Cetuximab

Bevacizumab + Cetuximab

R

A

N

D

O

M

I

Z

E

Panitumumab Phase III Trial in First Line Metastatic CRC: PACCE

RRAANNDDOOMMII

Z Z E E

FOLFOX or FOLFIRI+

Bevacizumab+

Panitumumab

FOLFOX or FOLFIRI+

Bevacizumab

Previously untreated CRC

patientsN=1000

PACCE: Panitumumab Advanced Colorectal Cancer Evaluation

Press release reported lack of benefit in experimental arm

First Line Trials: Caveats for Survival as Endpoint

Randomization

Drug A

Drug A + B

Crossover to B not encouraged

Classic

Randomization

Drug A

Drug A + B

Crossover to B mandatory

Practical

The FOCUS Trail

Drug A until it fails… …then B until it fails“staged single

agents”A

Drug A until it fails……then add drug B until both fail

“staged

combination”B

Drugs A + B together until both fail“1st-line

combination”C

A: FU until it fails, then change to Ir

“3rd drug” salvage

OxCap

OxCap

IrCap

OxCap

IrCap

B(ir): FU until it fails, then add Ir

B(ox): FU until it fails, then add Ox

C(ir): FU+Ir from the start, until it fails

C(ox): FU+Ox from the start, until it fails

700

350

350

350

350

2100patients

Focus Design

Seymour et al ASCO 2005

Overall survival

Plan First 2 drugs schedule Median OS

A FU then Ir 13.9

B(ir)

B(ox)

FU then FU/Ir

FU then FU/Ox

14.8

15.2

C(ir)

C(ox)

1st-line FU/Ir

1st-line FU/Ox

16.3

15.2

Seymour et al ASCO 2005

FOCUS Summary

• Use of sequential chemotherapy, with deferred use

of combinations, appears as effective as using the

combination upfront; HOWEVER…

• Sequential single agents appears to be inferior than

single agent followed by an appropriate combination

• Questions remain regarding exposure to all agents

• Not all agents should be used alone

CAIRO: Trial Profile

Arm A Arm B

Randomize

capecitabineN=397

capecitabine +oxaliplatin

N=143 (36%)

irinotecanN=251 (62%)

capecitabine +oxaliplatin

N=213 (53%)

capecitabine +irinotecan

N=398

1st line

2nd line

3rd line

Courtesy of Punt et al, ASCO 2007

Median Overall Survival

Combination treatment 17.4 months (15.2-19.2)

----------- Sequential treatment 16.3 months (14.3-18.2)

p = 0.33

Courtesy of Punt et al, ASCO 2007

Who, What, How Definitions

• Intense therapy:

– Implies early use of more complex combinations

– Is not the same as piling all active drugs together

• Minimal therapy:

– Seeks to minimize toxicity and perhaps cost

– It is not the same as sequential monotherapy

– It is not minimalist therapy

Who, What, How

• Who should get upfront intense therapy?

– Depends on what you call intense therapy!

– Patients who may become resectable with a good

response

– Patients whose quality of life may improve with a

tumor response

– Patients who are unlikely to get second and third

line treatment regimens (e.g., aggressive tumors)

Who, What, How

• Who should get upfront minimal therapy?

– Reserved for patients with little hope for a

curative surgery

– Patients who have relatively indolent disease, and

who can expect to receive additional lines of

therapy

– Patients with good quality of life who are not

interested in trading it for improvements in the

therapy’s efficacy

Chemotherapy for CRCSummary

• Doublets are more active than single agents, and

triplets may be even better

• Use of combinations of agents, in some sequence,

results in better response rates, resection rates, time

to progression, and overall survival

• However, the agents do not all need to be used

upfront

• Judicious use of combination therapy, in an

appropriate sequence, is indicated for most patients

How Should We Use the Available Drugs

• Good activity by itself– 5-FU/LV– Capecitabine– UFT– Irinotecan– Raltitrexed

• Better used in combination– Oxaliplatin

• FOLFOX / XELOX• IROX

– Bevacizumab• 5-FU • Oxaliplatin• Irinotecan• Cetuximab

– Cetuximab• Irinotecan• FOLFOX / XELOX

– Panitumumab?

The Building Block Strategy

5-FU + LV

5-FU + Oxaliplatin

Irinotecan + Cetuximab

Capecitabine

Irin

ote

can

5-F

U +

B

ev

aciz

um

ab

Capecitabine + OxaliplatinPanitumumab

Conclusion

• Treatment objectives are often different

• Patients are different

• Tumor biology and behavior is variable1

• Why should the treatment be the same ?

• We desperately need studies to learn how to match

the correct treatment with the appropriate patient

1O’Connell et al Abst. 4009, ASCO 2007

Documents

Minimal versus Intense Upfront Systemic Therapy in Metastatic Colorectal Cancer Paulo M. Hoff, MD, FACP Hospital Sirio Libanes Sao Paulo, Brazil Centro