88
Metastatic Colorectal Carcinoma Metastatic Colorectal Carcinoma What’s New? What’s New? Dr. Barbara Melosky
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
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
Conflict of InterestConflict of Interest
• I have received honorariums from • I have received honorariums from • Roche
• Sanofi-Aventis
• Roche
• Sanofi-Aventis
• Amgen• Amgen
Metastatic Colorectal CancerMetastatic Colorectal Cancer
Completely UnresectableResectable Completely UnresectableResectable Potentially Resectable Potentially Resectable
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
Metastatic Colorectal CancerMetastatic Colorectal Cancer
Completely UnresectableCompletely Unresectable
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
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
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
5FU – the Drug of Choice for over 30 Y !Years!
Nature, March 30, 1957
First LineFirst Line
FOLFOX or FOLFIRI?FOLFOX or FOLFIRI?
Why the bevacizumab?Why the bevacizumab?
VEGF
AngiogenesisAngiogenesis
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
Safety of bevacizumabSafety of bevacizumab
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
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
Treatment to Progression?Treatment to Progression?
Optimox 1Optimox 1Optimox 1Optimox 1
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).
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
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
Acute NeuropathyAcute Neuropathy+
TTXHg2+oxaliplatin
EXTRATTXHg
MembraneMembrane
Na+
ATP ATPINTRA
Ca2+
oxalate
CaDach-Pt
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
Oxaliplatin Neurotoxicity
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
What about prevention of the neuropathy?
What about prevention of the neuropathy?neuropathy?neuropathy?
The Calcium and Magnesium StoryThe Calcium and Magnesium Story
ConceptConceptConceptConcept
HoweverHoweverHowever….However….
Independent Radiological Review
Independent Radiological Reviewe ee e
Elderly/ PS poorElderly/ PS poor
Single Agent CapecitabineSingle Agent Capecitabine
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
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
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
Second Line?Second Line?
What ever you didn’t use first lineWhat ever you didn’t use first line
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
What’s New? What’s New?
Continuous Inhibition of VEGFContinuous Inhibition of VEGF
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)
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
AfliberceptAfliberceptAfliberceptAflibercept
• Blocks all human VEGF-A isoforms, VEGF-B and placental growth factor (PlGF)²
Aflibercept
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
Overall Survival, ITT PopulationOverall Survival, ITT Population
Tabernero et al. Eur J Cancer. 2011;47(2): Abstract 6LBA
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
Third LIneThird LIne
Kras Wild Type: EGFR Inhibitors Kras Mutation: … Clinical Trial
Kras Wild Type: EGFR Inhibitors Kras Mutation: … Clinical Trial
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
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
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
NomenclatureNomenclature
No mutation in Kras=Wild type Kras=
No mutation in Kras=Wild type Kras=yp
Treatment with EGFR MOAyp
Treatment with EGFR MOA
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
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
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
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
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
What about Preventing the Rash?What about Preventing the Rash?
Prophylactic MinocyclineProphylactic Minocycline
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
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
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
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.
What is new?What is new?
RegorafinibRegorafinib
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
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
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
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
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
O 2012
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
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
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
