individualizing therapy for metastatic colorectal cancer
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Individualizing Therapy for Metastatic Colorectal Cancer. ASCO Educational Session. Session 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 - PowerPoint PPT PresentationTRANSCRIPT
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