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Metastatic Colorectal Carcinoma Metastatic Colorectal Carcinoma What’s New? What’s New? Dr. Barbara Melosky
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Page 1: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

Metastatic Colorectal CarcinomaMetastatic Colorectal Carcinomaetastat c Co o ecta Ca c o aWhat’s New?

etastat c Co o ecta Ca c o aWhat’s New?

Dr. Barbara Melosky

Page 2: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

ObjectivesObjectives

• Review any recent changes regarding t t t ti f CRC

• Review any recent changes regarding t t t ti f CRCtreatment options for mCRC

• Discuss the common and expected

treatment options for mCRC

• Discuss the common and expected toxicities of treatment

• Discuss new targeted therapies that will

toxicities of treatment

• Discuss new targeted therapies that willDiscuss new targeted therapies that will be seen in the clinic in the futureDiscuss new targeted therapies that will be seen in the clinic in the future

Page 3: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

Conflict of InterestConflict of Interest

• I have received honorariums from • I have received honorariums from • Roche

• Sanofi-Aventis

• Roche

• Sanofi-Aventis

• Amgen• Amgen

Page 4: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

Metastatic Colorectal CancerMetastatic Colorectal Cancer

Completely UnresectableResectable Completely UnresectableResectable Potentially Resectable Potentially Resectable

Page 5: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

mCRCmCRC

Resectable 15% Unresectable 85%Resectable 15% Unresectable 85%

PreoperativeTherapy First-Line

Ch thResectable

15 30%

Hepatectomy

py2-3 months Chemotherapy

2-3 months15-30%

“CONVERSION”(One-stage or

Two-stage)± PVE*

Second-Line Chemotherapy

Third-Line Chemotherapy

PostoperativeTherapy

Chemotherapy3-4 months

Kopetz S and Vauthey JN Lancet 2008

Page 6: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

Metastatic Colorectal CancerMetastatic Colorectal Cancer

Completely UnresectableCompletely Unresectable

Page 7: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

mCRCmCRC

Resectable 15% Unresectable 85%Resectable 15% Unresectable 85%

PreoperativeTherapy First-Line

Ch thResectable

15 30%

Hepatectomy

py2-3 months Chemotherapy

2-3 months15-30%

“CONVERSION”(One-stage or

Two-stage)± PVE*

Second-Line Chemotherapy

Third-Line Chemotherapy

PostoperativeTherapy

Chemotherapy3-4 months

Kopetz S and Vauthey JN Lancet 2008

Page 8: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

Lines of Therapy TodayLines of Therapy Today

• First Line• First Line• First Line• FOLFIRI + Bevacizumab• FOLFOX + Bevacizumab

• First Line• FOLFIRI + Bevacizumab• FOLFOX + BevacizumabFOLFOX Bevacizumab

• Optimox or Drug Holidays• Capecitabine

FOLFOX Bevacizumab• Optimox or Drug Holidays

• Capecitabine• Second Line

• FOLFOX or FOLFIRI• Second Line

• FOLFOX or FOLFIRI• No Bevacizumab is allowed

• Third Line• No Bevacizumab is allowed

• Third Line• Kras WT: Panitumumab or Cetuximab • Kras WT: Panitumumab or Cetuximab

Page 9: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

Treatment Options in mCRCTreatment Options in mCRC

• Monotherapy• Monotherapy• Monotherapy• RR 15-30% MS 11-14 months

• Monotherapy• RR 15-30% MS 11-14 months

• Combination therapy• RR 30-50% MS 15-21 months

• Combination therapy• RR 30-50% MS 15-21 months

• Sequential therapy incorporating different combination therapy and single agents

MS 20 26 th

• Sequential therapy incorporating different combination therapy and single agents

MS 20 26 th• MS 20-26 months• MS 20-26 months

Page 10: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

5FU – the Drug of Choice for over 30 Y !Years!

Nature, March 30, 1957

Page 11: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

First LineFirst Line

FOLFOX or FOLFIRI?FOLFOX or FOLFIRI?

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Why the bevacizumab?Why the bevacizumab?

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VEGF

AngiogenesisAngiogenesis

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IFL and Avastin: OSIFL and Avastin: OS

HR=0.66 (95% CI: 0.54–0.81) p<0 0011.0 p<0.0011.0

0.8

lity

0.6

IFL + Avastind pr

obab

il

0.4

0.2

IFL + placebo

Estim

ated

0.0

0 10 20 30 40

15.6 20.3

E

0 10 20 30 40Months

ITT population Hurwitz et al. NEJM 2004

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Safety of bevacizumabSafety of bevacizumab

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Bevacizumab Safety profileBevacizumab Safety profile• Most common

• Hypertension proteinuria fatigue• Most common

• Hypertension proteinuria fatigueHypertension, proteinuria, fatigue,

• Most Serious • GI f ti bl di ATE

Hypertension, proteinuria, fatigue,

• Most Serious • GI f ti bl di ATE• GI perforation, bleeding, ATE

• Special Interest

• GI perforation, bleeding, ATE

• Special Interest • Wound-healing, epistaxis, VTE, fistula• Wound-healing, epistaxis, VTE, fistula

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Overview of grade ≥3 adverse events of special interest in randomised trials inOverview of grade ≥3 adverse events of special interest in randomised trials in25

AVF2107g

special interest in randomised trials in mCRC

special interest in randomised trials in mCRC

1

2

15

20E3200

NO16966

%)

2

3

10

Patie

nts

(%

0

5

1. Hurwitz NEJM 2004; 2. Giantonio JCO 2007; 3. Saltz JCO 2008

Page 24: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

Treatment to Progression?Treatment to Progression?

Page 25: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

Optimox 1Optimox 1Optimox 1Optimox 1

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OPTIMOX Continous vs Stop and Go

OPTIMOX Continous vs Stop and GoContinous vs Stop and GoContinous vs Stop and Go

OPTIMOX

FOLFOX

OPTIMOXFOLFOX x6 cycles5FU/LV x 12 cycles600+

patients

5FU/LV x 12 cyclesFOLFOX

Andre T et al. Proc ASCO. 2003;23 (abstr 1016).

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OPTIMOXOPTIMOXFOLFOX

R6x FOLFOX- 12x sLV5FU2 - 6x FOLFOX

620 pts

R

620 pts

(%) Continuous Stop and Go RR 58.5 58.3 PFS 9.0 8.7 DDC 9.0 10.6 OS 19 3 21 2

Primary endpoint

Tournigand et al, JCO 2006

OS 19.3 21.2 G3/4 NTox 17.9 13.3

Page 28: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

OPTIMOX 1: neurotoxicityOPTIMOX 1: neurotoxicityOPTIMOX 1: neurotoxicityOPTIMOX 1: neurotoxicity

25 ContinousGrade 3 neurotoxicity

20

25 ContinousStop and Go

10

15

5

10

0

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

Tournigand et al, JCO 2006

Page 29: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

Acute NeuropathyAcute Neuropathy+

TTXHg2+oxaliplatin

EXTRATTXHg

MembraneMembrane

Na+

ATP ATPINTRA

Ca2+

oxalate

CaDach-Pt

Page 30: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

Acute NeuropathyAcute Neuropathy

• Transient• Transient• Cold-triggered paresthesia/dysesthesia• Frequent (85-95%)• Cold-triggered paresthesia/dysesthesia• Frequent (85-95%)q ( )• Not dose-limiting• Treatment: Prolong the infusion

q ( )• Not dose-limiting• Treatment: Prolong the infusion• Treatment: Prolong the infusion• Treatment: Prolong the infusion

Page 31: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

Oxaliplatin Neurotoxicity

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Chronic NeuropathyChronic Neuropathy

• Cumulative dose• Cumulative dose

• Frequency of grade 3: 15-20% • Frequency of grade 3: 15-20%

• Dose-limiting toxicity of Oxaliplatin• Dose-limiting toxicity of Oxaliplatin

• Treatment: Dose reduction • Treatment: Dose reduction

Page 33: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

What about prevention of the neuropathy?

What about prevention of the neuropathy?neuropathy?neuropathy?

The Calcium and Magnesium StoryThe Calcium and Magnesium Story

Page 34: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

ConceptConceptConceptConcept

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HoweverHoweverHowever….However….

Independent Radiological Review

Independent Radiological Reviewe ee e

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Elderly/ PS poorElderly/ PS poor

Single Agent CapecitabineSingle Agent Capecitabine

Page 42: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

Fluoropyrimidines in Metastatic Fluoropyrimidines in Metastatic DiseaseDisease

• Median survival: ~ 12 months• Median survival: ~ 12 months• Median survival: ~ 12 months• Infusional 5FU better than bolus• Capecitabine oral 5FU

• Median survival: ~ 12 months• Infusional 5FU better than bolus• Capecitabine oral 5FU

Regimen Response, %Bolus 5-FU 7-15Bolus 5 FU 7 15Infusional 5-FU 20-305-FU/LV

M R ll h d l 12 35• Mayo, Roswell schedules• de Gramont (LV5-FU2)• AIO (once weekly, 24-hour infusion)

12-3528-3325-44

Capecitabine 20-25

Page 43: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

Enzymatic activation of XelodaEnzymatic activation of Xeloda

Intestine Liver

Xeloda®

TumourXeloda®

CE

5´-DFCR 5´-DFCR

CyD

CE

5´-DFUR

CyD

5´-DFURThymidine

CyD

5-FU

Thymidinephosphorylase (TP)

5´-DFCR = 5´-deoxy-5-fluorocytidine; 5´-DFUR = 5´-deoxy-5-5 -DFCR = 5 -deoxy-5-fluorocytidine; 5 -DFUR = 5 -deoxy-5-fluorouridine;CyD = cytidine deaminase; CE = carboxylesterase

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Xeloda: Phase III-results in metastatic CRCXeloda: Phase III-results in metastatic CRC

Arms: no. % RR TTP/m Med.

Surv/ mPooled Data

Xeloda: 604 22.4* 4.7 13.1Data FU/LV: 603 13.2 4.8 13.1

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Second Line?Second Line?

What ever you didn’t use first lineWhat ever you didn’t use first line

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Concept of “All-3-Drugs” 11 Phase III Trials 5768 PatientsConcept of “All-3-Drugs” 11 Phase III Trials 5768 Patients11 Phase III Trials, 5768 Patients11 Phase III Trials, 5768 Patients

22

Infusional 5-FU/LV + irinotecan

212019(m

o)

First-Line Therapy

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

i i t

19181716ed

ian

OS

+ irinotecanIrinotecan + oxaliplatinBolus 5-FU/LV

16151413

Me

0 10 20 30 40 50 60 70 80

LV5FU2

FOLFOXIRI

1312

Grothey & Sargent, JCO 2005

CAIROPatients with 3 drugs (%)

2007

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What’s New? What’s New?

Continuous Inhibition of VEGFContinuous Inhibition of VEGF

Page 51: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

TML StudyASCO 2012Bevacizumab beyond progressionBevacizumab beyond progression

StandardR

Standard

Standardsecond-line

chemotherapy

ANDOStandard

first-line chemotherapy + bevacizumab Standard

Progression MISA

second-line chemotherapy + bevacizumab

TION

First-line Second-line

Primary endpoint = OS(n=820)

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OSOSOSOS1.0 CT (n=410)

BEV + CT (n=409)

ate

0.8

0 6

BEV + CT (n=409)

HR: 0.81 (95% CI: 0.69–0.94)p=0.0062 (log-rank test)

OS

estim

a 0.6

0.4

p 0.0062 (log rank test)

0.2

09.8 mo 11.2 mo

Time (months)

0 6 12 18 24 30 36 42 48

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AfliberceptAfliberceptAfliberceptAflibercept

• Blocks all human VEGF-A isoforms, VEGF-B and placental growth factor (PlGF)²

Aflibercept

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VELOURVELOURVELOURVELOURR Aflibercept 4 mg/kg IV, day 1

+ FOLFIRI

mCRC Previously Treated FOLFOX +/-

AND

+ FOLFIRI q2 weeks600600

Treated FOLFOX /Bevacizumab O

MI

600600ZE

Placebo IV, day 1+ FOLFIRIq2 weeks

600600

Tabernero et al. Eur J Cancer. 2011;47(2): Abstract 6LBA

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Overall Survival, ITT PopulationOverall Survival, ITT Population

Tabernero et al. Eur J Cancer. 2011;47(2): Abstract 6LBA

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Overall SurvivalOverall Survival

Placebo/ FOLFIRIM di ( )

Aflibercept/FOLFIRIM di ( )

P-value for interactionMedian (mos)

N = 614Median (mos)

N = 612

interaction

All Patients 12.1 13.5 All Patients

Prior BEVNo 12.4 13.9 0.7231

Y 11 7 12 5Yes 11.7 12.5

Tabernero et al. Eur J Cancer. 2011;47(2): Abstract 6LBA

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Third LIneThird LIne

Kras Wild Type: EGFR Inhibitors Kras Mutation: … Clinical Trial

Kras Wild Type: EGFR Inhibitors Kras Mutation: … Clinical Trial

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EGFR (Epidermal Growth Factor Receptor)mCRC

Cell Membrane

TK TK

P P

PI3 kinase Ras/RafSTATs

Akt P MAPK/ERKPTEN

P

Apoptosis

MAPK/ERK

Proliferation

AngiogenesisInvasion & metastasis

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EGFR (Epidermal Growth Factor Receptor)

PanitumumabCetuximab

Cell Membrane

TK TK

P P

PI3 kinase Ras/RafSTATs

Akt P MAPK/ERKPTEN

P

Apoptosis

MAPK/ERK

Proliferation

AngiogenesisInvasion & metastasis

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EGFR (Epidermal Growth Factor Receptor)

PanitumumabCetuximab

Cell Membrane

TK TK

P P

PI3 kinase Ras/RafSTATs

Akt P MAPK/ERKPTEN

P

Apoptosis

MAPK/ERK

Proliferation

AngiogenesisInvasion & metastasis

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NomenclatureNomenclature

No mutation in Kras=Wild type Kras=

No mutation in Kras=Wild type Kras=yp

Treatment with EGFR MOAyp

Treatment with EGFR MOA

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NCIC CTG CO.17NCIC CTG CO.17NCIC CTG CO.17NCIC CTG CO.17Failed all recommended therapiesFailed all recommended therapies

REG

RAN

Disease Disease Progression Progression

oror

GIS

NDOM

Cetuximab* + BSC

Unacceptable Unacceptable ToxicityToxicityT

ER

MI Z

BSC alone

R E

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NCIC CTG C0.17: Overall survival in NCIC CTG C0.17: Overall survival in KK--Ras WildRas Wild--Type patientsType patients

NCIC CTG C0.17: Overall survival in NCIC CTG C0.17: Overall survival in KK--Ras WildRas Wild--Type patientsType patientsKK Ras WildRas Wild Type patientsType patientsKK Ras WildRas Wild Type patientsType patients

1 Study armStudy arm MS (months)MS (months) 95% CI95% CI

Cetuximab + BSCCetuximab + BSC 9.59.5 7.7 7.7 –– 10.310.3

HR HR 0.550.55 95% CI (0.41,0.74) 95% CI (0.41,0.74)

0.8

ve

BSC aloneBSC alone 4.84.8 4.2 4.2 –– 5.55.5

Stratified Log rank pStratified Log rank p--value: value: <0.0001<0.0001

0 4

0.6

ropo

rtio

n Al

iv

0.2

0.4P

00 2 4 6 8 10 12 14 16 18

CetuximabBSC

0 2 4 6 8 10 12 14 16 18

Time from Randomisation (Months)

CetuximabBSC

117 108 95 81 52 34 20 9 6 2113 92 69 36 24 17 12 5 3 3

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Page 68: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

Mild Mild

• Grade 1 may not need treatment• Grade 1 may not need treatmenty

• Topical clindamycin 2%, with hydrocortisone 1% in lotion base

y

• Topical clindamycin 2%, with hydrocortisone 1% in lotion basehydrocortisone 1% in lotion base applied twice daily hydrocortisone 1% in lotion base applied twice daily

Page 69: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

ModerateModerate

• Minocycline 100 mg bid for 4 weeks• Minocycline 100 mg bid for 4 weeks• Minocycline 100 mg bid for 4 weeks

• Topical clindamycin 2% with hydrocortisone 1% in lotion base bid

• Minocycline 100 mg bid for 4 weeks

• Topical clindamycin 2% with hydrocortisone 1% in lotion base bid1% in lotion base bid

• Scalp lesions:Cli d i 2% T i i l id 0 1%

1% in lotion base bid

• Scalp lesions:Cli d i 2% T i i l id 0 1%• Clindamycin 2%, Triamcinolone acetonide 0.1% in equal parts of propylene glycol and water

• Clindamycin 2%, Triamcinolone acetonide 0.1% in equal parts of propylene glycol and water

Page 70: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

Grade 3Grade 3

• Stop drug therapy for 1 week and restart at lower• Stop drug therapy for 1 week and restart at lower• Stop drug therapy for 1 week and restart at lower dose

• Minocycline 100 mg bid for 4 weeks

• Stop drug therapy for 1 week and restart at lower dose

• Minocycline 100 mg bid for 4 weeksMinocycline 100 mg bid for 4 weeks

• Topical clindamycin 2% with hydrocortisone 1% in lotion base bid

Minocycline 100 mg bid for 4 weeks

• Topical clindamycin 2% with hydrocortisone 1% in lotion base bid

• Scalp lesions:• Clindamycin 2%, Triamcinolone acetonide 0.1% in equal

parts of propylene glycol and water

• Scalp lesions:• Clindamycin 2%, Triamcinolone acetonide 0.1% in equal

parts of propylene glycol and waterparts of propylene glycol and waterparts of propylene glycol and water

Page 71: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

What about Preventing the Rash?What about Preventing the Rash?

Prophylactic MinocyclineProphylactic Minocycline

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Page 73: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

Patient Assignments: Treatment Patient Assignments: Treatment

22ndnd LINE TREATMENTLINE TREATMENT

gArm and Randomization

gArm and Randomization

22ndnd LINE TREATMENTLINE TREATMENT

FOLFIRI Q2W +FOLFIRI Q2W + IRINOTECAN Q3W +IRINOTECAN Q3W +PANITUMUMAB THERAPY*PANITUMUMAB THERAPY* PANITUMUMAB THERAPYPANITUMUMAB THERAPY

n = 47n = 47n = 48n = 48

RANDOMIZATIONRANDOMIZATION

PREPRE--EMPTIVEEMPTIVE REACTIVEREACTIVEPREPRE EMPTIVEEMPTIVESKINSKIN

TREATMENTTREATMENT

REACTIVEREACTIVESKINSKIN

TREATMENTTREATMENT

Doxycycline 100 mg BIDDoxycycline 100 mg BID

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Page 75: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

STEPP Subsets: Summary of Efficacy By C t l R iCentral Review

ReactivePre-emptiveReactivePre-emptiveReactivePre-emptive

Mutant KRASWT KRASITT

6101217915ORR (%)

172126234748n

335644.7Median PFS (months)

6101217915ORR (%)

(months)

Do Not Copy or Distribute Amgen Canada 2008

Page 76: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

Overall Survival for Panitumumab Patients by G d f Ski T i it

Overall Survival for Panitumumab Patients by G d f Ski T i itGrade of Skin ToxicityGrade of Skin Toxicity

Page 77: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

Overall Survival by Worst Grade of RashNCIC CTG CO17

Overall Survival by Worst Grade of RashNCIC CTG CO17NCIC CTG CO17NCIC CTG CO17

100 Grade HR 95%CI p-value

80

ive

2+ vs 0 0.33 (0.22, 0.50) <0.0001

1 vs 0 0.61 (0.40, 0.93) 0.021

2+ vs 1 0.54 (0.41, 0.72) <0.0001

60

porti

on A

l

Grade nMedian Survival

0 32 2.6 mo

1 115 4.8 mo

20

40

Pro

p

2+ 136 8.4 mo

0

20

0 6 12 18

Grade 0 Grade 1 Grade 2+Survival (months)

0 6 12 18

Jonker DJ et al. N Engl J Med 2007;357:2040-8.

Page 78: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

What is new?What is new?

RegorafinibRegorafinib

Page 79: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

Mode of action of regorafenib (BAY 73-4506)g ( )

• Regorafenib inhibits multiple cell signaling kinases:cell-signaling kinases:– Angiogenic

• VEGFR1–3, TIE2– Stromal

• PDGFR-β, FGFR– Oncogenicg

• KIT, PDGFR, RET

• T1/2 in man: approx. 26-28 hrs– Two major metabolites (M2,

M5) are pharmacologically active

Wilhelm SM et al. Int J Cancer 2011

Page 80: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

CORRECTRAND

RAND

Regorafenib + BSC 160 mg orally once daily 3 weeks on, 1 week off

mCRC after standard therapy

OM I ZAT

OM I ZAT

2 : 1Primary

Endpoint: OS

T I ON

T I ON

Placebo + BSC 3 weeks on, 1 week off

Page 81: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

Overall response and disease control rates

Best response, % RegorafenibN=505

PlaceboN=255

Complete response 0 0

Partial response 1.0 0.4

Stable disease 43.8 14.9

Progressive disease 49.5 80.0

Disease control rate, %* 44.8 15.3, %

*DCR = PR + SD; p<0.000001

Page 82: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

Progression-free survival

1.00 R f ib Pl b

0.75unct

ion

Regorafenib Placebo

Median 1.9 mos 1.7 mos95% CI 1.9–2.1 1.7–1.7

0.50

strib

utio

n fu Hazard ratio: 0.49 (95% CI: 0.42–0.58)

1-sided p-value: <0.000001

0.25

urvi

val d

is

Placebo N=255Regorafenib N=505

0200100500 150 300250 350

Su

Days from randomization

Page 83: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

Overall survival

1.00

n

Median 6.4 mos 5.0 mos95% CI 5 9 7 3 4 4 5 8

Regorafenib Placebo

0.75

on fu

nctio

n 95% CI 5.9–7.3 4.4–5.8

Hazard ratio: 0.77 (95% CI: 0.64–0.94)1-sided p-value: 0.0052

0.50

dist

ribut

io

0.25

Sur

viva

l

Placebo N=255Regorafenib N=505

0200100500 150 300250 400350 450

Days from randomization

Regorafenib N 505

Days from randomization

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O 2012

Page 85: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

Lines of Therapy TodayLines of Therapy Today(Yesterday)(Yesterday)

• First Line• First Line• First Line• FOLFIRI + Bevacizumab• FOLFOX + Bevacizumab

• First Line• FOLFIRI + Bevacizumab• FOLFOX + BevacizumabFOLFOX Bevacizumab

• Optimox or Drug Holidays• Capecitabine

FOLFOX Bevacizumab• Optimox or Drug Holidays

• Capecitabine• Second Line

• FOLFOX or FOLFIRI• Second Line

• FOLFOX or FOLFIRI• No Bevacizumab is allowed

• Third Line• No Bevacizumab is allowed

• Third Line• Kras WT: Panitumumab or Cetuximab • Kras WT: Panitumumab or Cetuximab

Page 86: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

Lines of Therapy TomorrowLines of Therapy Tomorrow• First Line

• FOLFIRI + Bevacizumab• FOLFOX + Bevacizumab

• First Line• FOLFIRI + Bevacizumab• FOLFOX + BevacizumabFOLFOX Bevacizumab

• Optimox or Drug Holidays• Capecitabine

• Second Line

FOLFOX Bevacizumab• Optimox or Drug Holidays

• Capecitabine • Second Line• Second Line

• FOLFOX or FOLFIRI• + Bevacizumab is allowed• + Aflibercept (with FOLFIRI)

• Second Line• FOLFOX or FOLFIRI

• + Bevacizumab is allowed• + Aflibercept (with FOLFIRI)• + Aflibercept (with FOLFIRI)

• Third Line• Kras WT: Panitumumab or Cetuximab

• + Aflibercept (with FOLFIRI) • Third Line

• Kras WT: Panitumumab or Cetuximab • End of Line

• Regorafinib• End of Line

• Regorafinib

Page 87: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

Each month, the Canadian Oncology Societies produces live, interactive

Each month, the Canadian Oncology Societies produces live, interactive Soc et es p oduces e, te act e

educational webinars aimed at oncology professionals. Programs are archived on

the COS website www cos ca

Soc et es p oduces e, te act eeducational webinars aimed at oncology professionals. Programs are archived on

the COS website www cos cathe COS website www.cos.ca

Your input and suggestions would be

the COS website www.cos.ca

Your input and suggestions would be p ggwelcome.

For information: [email protected] or 1 877 990 9044

p ggwelcome.

For information: [email protected] or 1 877 990 90441 877 990 90441 877 990 9044

Page 88: Metastatetastat c Co o ecta Ca c o aic Colorectal Carcinoma · 2012. 10. 23. · Overview of grade ≥3 adverse events of special interest in randomised trials in 25 AVF2107g special

Thank youThank youThank youThank you

[email protected]@bccancer.bc.ca


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