Individualizing Therapy for Metastatic Colorectal CancerIndividualizing Therapy for

Metastatic Colorectal Cancer

ASCO Educational SessionASCO Educational Session

Session AgendaSession Agenda

• Axel Grothey

• How to optimize the sequence and duration of treatment for metastatic colorectal cancer?

• Heinz-Josef Lenz

• Established biomarkers guiding treatment decisions in colorectal cancer

• Lee Ellis

• Promising future biomarkers for colorectal cancer

• Axel Grothey

• How to optimize the sequence and duration of treatment for metastatic colorectal cancer?

• Heinz-Josef Lenz

• Established biomarkers guiding treatment decisions in colorectal cancer

• Lee Ellis

• Promising future biomarkers for colorectal cancer

How to

opti

mize the

sequence

and

duration

of treat

ment for

metastatic

colorectal

cancer?

How to

opti

mize the

sequence

and

duration

of treat

ment for

metastatic

colorectal

cancer?

Axel Grothey

Professor of Oncology

Mayo Clinic Rochester

Axel Grothey

Professor of Oncology

Mayo Clinic Rochester

DisclosuresDisclosures

• Consulting activities (honoraria went to the Mayo Foundation)

• Amgen• Bayer• Pfizer• Roche/Genentech• Sanofi-Aventis

• Consulting activities (honoraria went to the Mayo Foundation)

• Amgen• Bayer• Pfizer• Roche/Genentech• Sanofi-Aventis

Personalized Medicine- Decision Tools -

Personalized Medicine- Decision Tools -

• New: Molecular Biomarkers• Patient-based (Pharmacogenomics)• Tumor-based

• Old: Clinical parameters• Patient-based

• Age, PS, co-morbidities, experience with prior therapies, financial implications…

• Tumor-based• Stage, differentiation, number and sites of

metastases…⇒ Goal oriented approach to therapy

• New: Molecular Biomarkers• Patient-based (Pharmacogenomics)• Tumor-based

• Old: Clinical parameters• Patient-based

• Age, PS, co-morbidities, experience with prior therapies, financial implications…

• Tumor-based• Stage, differentiation, number and sites of

metastases…⇒ Goal oriented approach to therapy

Advances in the Treatment of Stage IV CRCAdvances in the Treatment of Stage IV CRC

1980 1985 1990 1995 2000 2005

5-FUIrinotecan

CapecitabineOxaliplatin

CetuximabBevacizumab

Best supportive care (BSC)

median overall survival

Panitumumab

Concept of “All-3-Drugs” - Update 200511 Phase III Trials, 5768 Patients

Concept of “All-3-Drugs” - Update 200511 Phase III Trials, 5768 Patients

OS (mos) = 13.2 + (%3drugs x 0.1), R^2 = 0.85Grothey & Sargent, JCO 2005

0 10 20 30 40 50 60 70 80

Infusional 5-FU/LV + irinotecanInfusional 5-FU/LV + oxaliplatinBolus 5-FU/LV + irinotecanIrinotecan + oxaliplatinBolus 5-FU/LV

LV5FU2

22

21

20

19

18

17

16

15

14

13

12

Med

ian

OS

(m

o)

Patients with 3 drugs (%)

P =.0001

First-Line Therapy

Different Philosophies…Different Philosophies…

Piling up

Sequencing

FOLFOXIRIPACCE

FOCUSCAIRO

Phase III Trial of FOLFOXIRI vs FOLFIRI as First-Line Therapy of Advanced Colorectal Cancer

Phase III Trial of FOLFOXIRI vs FOLFIRI as First-Line Therapy of Advanced Colorectal Cancer

FOLFIRIN=122

FOLFOXIRIN=122 P-value

RR* (%) 34 60 <0.0001

CR+PR+SD* (%) 68 81

R0 resection (%) (all patients) 6 15 0.033

R0 resection (%) (liver limited) 12 36 0.017

PFS (mos) 6.9 9.8 0.0006

OS (mos) 16.7† 22.6 0.032

* externally reviewed; †67% 2nd line FOLFOX Falcone et al., JCO 2007

CAIRO: Trial DesignCAIRO: Trial Design

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

Koopman et al., Lancet 2007

CAIRO: Overall SurvivalCAIRO: Overall Survival

Koopman et al., Lancet 2007

Median OS17.4 vs 16.3 mos

Take-Home Messages CAIRO/FOCUSTake-Home Messages CAIRO/FOCUS

• CAIRO (and FOCUS) validate the importance of post- first-line therapies for overall survival

• But the OS survival is shorter than what we like to see nowadays

• Likelihood of patients to receive all active agents is higher with combination therapy upfront

• FOLFOXIRI (OS 22.6 mos) vs CAIRO/FOCUS approach

• What about potentially resectable metastases?• How do targeted agents fit in here?

Start with single agent and subsequent sequential therapy can be an option in select patients, but should NOT be the standard of care

• CAIRO (and FOCUS) validate the importance of post- first-line therapies for overall survival

• But the OS survival is shorter than what we like to see nowadays

• Likelihood of patients to receive all active agents is higher with combination therapy upfront

• FOLFOXIRI (OS 22.6 mos) vs CAIRO/FOCUS approach

• What about potentially resectable metastases?• How do targeted agents fit in here?

Start with single agent and subsequent sequential therapy can be an option in select patients, but should NOT be the standard of care

Tournigand-Trial (N=220)Tournigand-Trial (N=220)

Tournigand et al., JCO 2004

N pts

FOLFOX(1st line

111

FOLFIRI2nd line)

69

FOLFIRI(1st line

109

FOLFOX2nd line)

81

RR 54% 4% 56% 15%

Liver resection

21% 9%

PFS (mos) 8.1 2.5 8.5 4.2

OS (mos) 20.6 21.5

2nd line:62%

2nd line:74%

Concept of “All-3-Drugs” - Update 200511 Phase III Trials, 5768 Patients

Concept of “All-3-Drugs” - Update 200511 Phase III Trials, 5768 Patients

OS (mos) = 13.2 + (%3drugs x 0.1), R^2 = 0.85Grothey & Sargent, JCO 2005

0 10 20 30 40 50 60 70 80

Infusional 5-FU/LV + irinotecanInfusional 5-FU/LV + oxaliplatinBolus 5-FU/LV + irinotecanIrinotecan + oxaliplatinBolus 5-FU/LV

LV5FU2

FOLFOXIRI

CAIRO

22

21

20

19

18

17

16

15

14

13

12

Med

ian

OS

(m

o)

Patients with 3 drugs (%)

P =.0001

First-Line Therapy

2007

Evolution in CRC Treatment ParadigmEvolution in CRC Treatment Paradigm

• Old paradigm

• Distinct lines of non–cross-resistant therapy initiated at each disease progression

• New paradigm: continuum of care

• Comprehensive, strategic, long-term, and individualized disease management

• Exposure to all active agents and modalities

• Maximal OS and QOL by minimizing toxicity and unnecessary treatment

• No more distinct “lines of therapy”

• Old paradigm

• Distinct lines of non–cross-resistant therapy initiated at each disease progression

• New paradigm: continuum of care

• Comprehensive, strategic, long-term, and individualized disease management

• Exposure to all active agents and modalities

• Maximal OS and QOL by minimizing toxicity and unnecessary treatment

• No more distinct “lines of therapy”

Goldberg. Oncologist. 2007;12:38; Grothey. ASCO 2007 Educational Book.

Murine AbMurine Ab““momab”momab”

ChimericChimericMouseMouse--HumanHuman Ab Ab

““ximab”ximab”

Humanized AbHumanized Ab““zumab”zumab”

FcFc

FabFab

Human AbHuman Ab““mumab”mumab”

Biologic Agents in Colorectal Cancer = Monoclonal Antibodies

Biologic Agents in Colorectal Cancer = Monoclonal Antibodies

(17-1A)(17-1A) CetuximabCetuximab BevacizumabBevacizumab

PanitumumabPanitumumabEGFR

VEGF

Phase III Trial IFL +/- Bevacizumab in MCRC: Efficacy

Phase III Trial IFL +/- Bevacizumab in MCRC: Efficacy

IFL+ Placebo (n=411)

IFL+ Bevacizumab(n=402) P Value

Median survival (mo) 15.6 20.3 0.00004

PFS (mo) 6.2 10.6 <0.00001

ORR (%)

CR

PR

35

2.2

32.5

45

3.7

41.2

0.0036

Duration of resp. (mo) 7.1 10.4 0.0014

Hurwitz et al. N Engl J Med 2004

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 5 10 15 20 25 30

BICC-C Trial Period 1: Progression Free Survival

BICC-C Trial Period 1: Progression Free Survival

Months

Pro

po

rtio

n o

f P

rog

ress

ion

Fre

e S

urv

ival

RegimenMedian PFS

(Months)HR

(95% CI) P Value

FOLFIRI 7.6 -- --

mIFL 5.9 1.55(1.2, 2.0)

0.0009

CapeIRI 5.8 1.47(1.1, 1.9)

0.0049

FOLFIRI

mIFL

CapeIRI

Primary endpoint!Fuchs et al., JCO 2007

BICC-C: SummaryBICC-C: Summary

Period 1, no BEV Period 2, + BEV

Efficacy FOLFIRIN=144

mIFLN=141

CapIriN=145

FOLFIRIN=57

mIFLN=60

RR (%) 46.6 41.9 38 57.9 53.3

PFS (mo) 7.6 5.9 5.8 11.2 8.3

OS 23.1 17.6 18.9 28.0 19.2

G 3/4 (%)

Diarrhea 14 19 48 11 12

Dehydr. 6 7 19 5 2

MI/stroke 0.7 4.4 0 1.8 0

60d mort. 3.4 5.1 3.5 1.8 6.8

Fuchs et al., JCO 2007, JCO 2008

XELOX + placebo N=350

FOLFOX4 + placebo N=351

XELOX + bevacizumab

N=350

FOLFOX4 + bevacizumab

N=350

XELOX N=317

FOLFOX4 N=317

Initial 2-arm open-label study

(N=634)

Protocol amended to 2x2 placebo-controled design after bevacizumab

phase III data1 became available (N=1401)

RecruitmentJune 2003 – May 2004

RecruitmentFeb 2004 – Feb 2005

XELOX vs FOLFOX +/- Bevacizumab Roche NO16966 study design

XELOX vs FOLFOX +/- Bevacizumab Roche NO16966 study design

1Hurwitz H, et al. Proc ASCO 2003;22 (Abstract 3646) Cassidy et al., JCO 2008

PFS chemotherapy + bevacizumab superiority: primary objective metPFS chemotherapy + bevacizumab superiority: primary objective met

0 5 10 15 20 25

Months

PF

S e

stim

ate

HR = 0.83 [97.5% CI 0.72–0.95] (ITT)p = 0.0023

9.48.0

1.0

0.8

0.6

0.4

0.2

0

FOLFOX+placebo/XELOX+placebo N=701; 547 events FOLFOX+bevacizumab/XELOX+bevacizumab N=699; 513 events

Saltz et al., JCO 2008

PFS chemotherapy + bevacizumab superiority: XELOX and FOLFOX subgroups

PFS chemotherapy + bevacizumab superiority: XELOX and FOLFOX subgroups

XELOX subgroupHR = 0.77 [97.5% CI 0.63–0.94] (ITT)

p = 0.0026

9.37.4

1.0

0.8

0.6

0.4

0.2

00 5 10 15 20 25

Months

PF

S e

stim

ate

XELOX+placebo N=350; 270 events

XELOX+bevacizumab N=350; 258 eventsFOLFOX subgroup

HR = 0.89 [97.5% CI 0.73–1.08] (ITT)p = 0.1871

9.48.6

FOLFOX+placebo N=351; 277 events

FOLFOX+bevacizumab N=349; 255 events

1.0

0.8

0.6

0.4

0.2

00 5 10 15 20 25

Months

Saltz et al., JCO 2008

Why did BEV not increase PFS when added to FOLFOX in

NO16966?

Why did BEV not increase PFS when added to FOLFOX in

NO16966?

• No synergistic/additive effect with FOLFOX?

• No, see E3200 (second-line)

• Ceiling effect of first-line chemotherapy?

• Perhaps…

• Failure to OPTIMOXize?

• Very likely!

• No synergistic/additive effect with FOLFOX?

• No, see E3200 (second-line)

• Ceiling effect of first-line chemotherapy?

• Perhaps…

• Failure to OPTIMOXize?

• Very likely!

Treatment-Free IntervalsTreatment-Free Intervals

• Rationale

• Decrease intensity of therapy

• Reduce toxicity

• Prevent discontinuation of therapy

• Preserve ability to administer later therapy

• Maximize time on treatment

• Increase QOL

• Recognize drug toxicities

• Proactively determine therapeutic strategy

• Assess acute and cumulative toxicity

• Develop strategies to avoid or minimize toxicity

• Rationale

• Decrease intensity of therapy

• Reduce toxicity

• Prevent discontinuation of therapy

• Preserve ability to administer later therapy

• Maximize time on treatment

• Increase QOL

• Recognize drug toxicities

• Proactively determine therapeutic strategy

• Assess acute and cumulative toxicity

• Develop strategies to avoid or minimize toxicity

Chemo-HolidaysChemo-Holidays

• Types of treatment breaks

• Treatment break with maintenance regimen

• OPTIMOX-1

• CONcePT

• Complete Chemotherapy-free intervals (CFI)

• OPTIMOX-2

• When to interrupt therapy

• After pre-planned number of cycles

• When toxicity reaches a certain grade

• Stop 1 drug or all?

• Types of treatment breaks

• Treatment break with maintenance regimen

• OPTIMOX-1

• CONcePT

• Complete Chemotherapy-free intervals (CFI)

• OPTIMOX-2

• When to interrupt therapy

• After pre-planned number of cycles

• When toxicity reaches a certain grade

• Stop 1 drug or all?

Goldberg. Oncologist. 2007;12:38; Grothey. ASCO 2007 Educational Book.

Stop and Go concept - OPTIMOX1Stop and Go concept - OPTIMOX1

Tournigand et al, JCO 2006

6x FOLFOX7- 12x sLV5FU2 - 6x FOLFOX7

FOLFOX4

620 pts

R

Cum. Oxali 780 1560

Primary endpoint

FOLFOX4 FOLFOX7

RR (%) 58.5 58.3

PFS (mos) 9.0 8.7

DDC (mos) 9.0 10.6

OS (mos) 19.3 21.3

G3/4 sNT (%) 17.9 13.3

OPTIMOX 1: neurotoxicity FOLFOX4 vs 7

OPTIMOX 1: neurotoxicity FOLFOX4 vs 7

Grade 3 neurotoxicity

0

5

10

15

20

25

1 3 5 7 9 11 13 15 17 19 21 23

Cycles

Pe

rce

nta

ge

of

pa

tie

nts

FOLFOX4

FOLFOX7

Tournigand et al, JCO 2006

OPTIMOX StudiesOPTIMOX Studies

OPTIMOX-1

FOLFOX 4 until TF

FOLFOX 7 FOLFOX 7

sLV5FU2

OPTIMOX-2

mFOLFOX 7 mFOLFOX 7

sLV5FU2

mFOLFOX 7 mFOLFOX 7

CFIMaindrault-Goebel et al, ASCO 2006

OPTIMOX2: Progression-free Survival

0 10 20 30 40 50 60 70 80 90 1000.0

0.2

0.4

0.6

0.8

1.0

36 weeks

29 weeks

Maintenance

CFI

P =0.08

Maindrault-Goebel et al, ASCO 2007weeks

Lesson from OPTIMOX2: If PFS is the primary endpoint of your trial,don’t stop treatment before progression!

NO16966 Study Drug Exposure – Median Months of Treatment

NO16966 Study Drug Exposure – Median Months of Treatment

FOLFOX+Placebo

(N=336)

FOLFOX+Bev

(N=341)

XELOX+Placebo

(N=339)

XELOX+Bev

(N=353)

Oxaliplatin 6.0 6.0 5.5 5.8

Fluoropyrimidine 6.3 6.7 5.6 6.3

Placebo or Bev 6.3 6.0 5.5 6.0

* Per protocol, patients discontinuing oxaliplatin could continue with a fluoropyrimidine + placebo or bevacizumab. Patients could also remain on a fluoropyrimidine alone or placebo or bevacizumab alone but not oxaliplatin alone

Saltz et al., ASCO GI 2007

NO16966 PFS Subgroup Analyses:On-Treatment Population

NO16966 PFS Subgroup Analyses:On-Treatment Population

Saltz et al., ASCO GI 2007

HR = 0.61 [97.5% CI 0.48–0.78]P ≤ .0001

HR = 0.65 [97.5% CI 0.50–0.84]P = .0002

XELOX + placeboFOLFOX4 +

placeboXELOX + Bev

FOLFOX-4 + BevVS VS

XELOX Group FOLFOX Group

Su

rviv

al

1.0

0.8

0.6

0.4

0.2

00 100 200 300 400 500

Study day

1.0

0.8

0.6

0.4

0.2

00 100 200 300 400 500

Su

rviv

al

Study day

10.6 m8.4 m9.5 m7.0 m

CONcePT study: IO armCONcePT study: IO arm

2400

x 8

Cumulative oxaliplatin

680 mg/m2

Months

42400

x 8

8680 mg/m2

2400

200855

2005

200855

x 8 1360 mg/m2 12

etc.

LVOXBEV

5-FU

Grothey et al, ASCO 2008

CONcePT: ResultsCONcePT: Results

P=0.002

CO

IO

Censored data.

0 2 4 6 8 10 12 14 16

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Months

TTF

Pro

po

rtio

n o

f P

atie

nts

4.2 5.6

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 2 4 6 8 10 12 14 16

PFS

Months

7.3 12

P=0.044

Pro

po

rtio

n o

f P

ati

en

ts

Grothey et al, ASCO 2008

Should Bevacizumab Be Continued Beyond Progression?

Should Bevacizumab Be Continued Beyond Progression?

BBP(n=642)

No BBP(n=531)

No Post-PD Treatment

(n=253)

Evaluablepatients(n=1953)

1st Progression(n=1445)

BRiTE Registry - Patients with Bevacizumab Beyond Progression (BBP)

BRiTE:Total N=1953 1445 pts with 1st PD 932 deaths (1/21/07 cut-off) Median follow-up 19.6 mo

Grothey et al. JCO 2008

Physician decision - no randomization

BRiTE: Patient Outcome Based on Treatment Post 1st PD

BRiTE: Patient Outcome Based on Treatment Post 1st PD

BBP(n=642)

No BBP(n=531)

No Post-PD Treatment

(n=253)

# of deaths (%)

168(66%)

306(58%)

260(41%)

Median OS (mo) 12.6 19.9 31.8

1yr OS rate (%) 52.5 77.3 87.7

OS after 1st PD (mo) 3.6 9.5 19.2

Grothey et al. JCO 2008

SWOG/NCCTG S600/iBET- Revised -

SWOG/NCCTG S600/iBET- Revised -

(FOLFOX orXELOX orOPTIMOX)

+ BEV

(FOLF) IRI + BEV

(FOLF) IRI + C225

RKRAS wt

N = 620Primary EP: PFS (HR 1.3, 5 -> 6.5 mos for BEV arm)Secondary EP: OS (HR 1.3, 12 -> 15.6 mos in BEV arm)

AIO 0504Multinational European Trial

AIO 0504Multinational European Trial

Any-OX+ BEV

Any-IRI+ BEV

Any-IRI+ BEV

Any-IRI Any-OXAny-OX+ BEV

R R

N = 820Primary EP: OS

Optimized Medical Therapy of Advanced CRC

Optimized Medical Therapy of Advanced CRC

1. Identify the goal of therapy• RR only matters for

• conversion therapy of liver metastases or• if patient is symptomatic from his tumor

burden• For most patients gain of time and

maintaining QOL is more important

2. Treat to progression (and perhaps beyond?)• Be mindful about toxicities, stop oxaliplatin

before neurotoxicity develops• Some select patients can have CFI

1. Identify the goal of therapy• RR only matters for

• conversion therapy of liver metastases or• if patient is symptomatic from his tumor

burden• For most patients gain of time and

maintaining QOL is more important

2. Treat to progression (and perhaps beyond?)• Be mindful about toxicities, stop oxaliplatin

before neurotoxicity develops• Some select patients can have CFI

Optimized Medical Therapy of Advanced CRC

Optimized Medical Therapy of Advanced CRC

3. Expose patients to all potentially active agents• These agents are the oncologist’s tools to

keep patients alive• Use fluoropyrimidine-based combinations as

default backbone, reserve sequential single agent therapy for select patients

4. Reutilize chemotherapeutic agents (in different combinations?) in the course of the therapy• Continuum of care vs distinct lines of therapy

5. Keep in mind that personalized medicine in colorectal cancer did not start with KRAS

3. Expose patients to all potentially active agents• These agents are the oncologist’s tools to

keep patients alive• Use fluoropyrimidine-based combinations as

default backbone, reserve sequential single agent therapy for select patients

4. Reutilize chemotherapeutic agents (in different combinations?) in the course of the therapy• Continuum of care vs distinct lines of therapy

5. Keep in mind that personalized medicine in colorectal cancer did not start with KRAS