“continuum of care” en cáncer de colon metastásico no curable mauricio lema medina md clínica...
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“Continuum of care” en cáncer de colon metastásico no curableMauricio Lema Medina MDClínica de Oncología Astorga – Clínica SOMA – MedicáncerMedellín, Colombia
QuimioterapiaA qué llegamos?
Page 3
Fluoropirimidines en mCRC
No cambio en la supervivencia mediana con diferentes esquemas
– Supervivencia mediana: ~ 12 meses
Regimen Respuesta, %5-FU en bolo 7-15
5-FU en infusión 20-30
5-FU/LV
Mayo, Roswell Park
de Gramont (LV5-FU2)
AIO (cada semana, 24-hour infusion)
12-35
28-33
25-44
Capecitabina 20-25
Grothey A, et al. J Clin Oncol. 2005;23:9441-9442.
www.clinicaloptions.com
Page 4
IFL(n=264)
RFOLFOX
(n=267)
IROX(n=264)
diseño
n=795
Primary endpoint: PFS
IFL vs FOLFOX vs IROX (N9741)
Bolo (IFL) vs infusión (FOLFOX)
Goldberg et al, JCO 2004Goldberg et al, JCO 2004
Page 5 N9741: Sanoff HK. J Clin Oncol 26:5721-5727.
Page 6
IFL FOLFOX IROX
n 264 267 264
RR (%) 31 45 35
PFS (m) 6.9 8.7 6.5
OS (m) 15 19.5 17.4
p 0.0001
N9741Resultados
Goldberg et al, JCO 2004Goldberg et al, JCO 2004
Page 7
FOLFIRI(n=144)
RmIFL
(n=141)
XELIRI(n=145)
Feb 2003 – April 2004
Initial design
n=430
Primary endpoint: PFS
Trial of Bevacizumab plus FOLFIRI/mIFL (BICC-C): design
* Celecoxib data not shown* Celecoxib data not shownFuchs et al, JCO 2008Fuchs et al, JCO 2008
Courtesy of: Paulo Hoff
BICC-C Study: FOLFIRI vs mIFL vs CapeIRI
Fuchs CS, et al. J Clin Oncol. 2007;25:4779-4786.
0 10 20 30
25
50
75
100
040
Months
Pro
gre
ssio
n F
ree
(%)
FOLFIRI vs mIFL: P = .004FOLFIRI vs Capelri: P = .015mIFL vs Capelri: P = .46
FOLFIRImIFLCapelri
FOLFIRI vs mIFL: P = .09FOLFIRI vs Capelri: P = .27mIFL vs Capelri: P = .93
0 10 20 30
25
50
75
100
040
Months
Aliv
e (%
) FOLFIRImIFLCapelri
50
Progression-Free Survival Overall Survival
Fuchs CS, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007;25(30):4779-4786. Reprinted with permission from the American Society of Clinical Oncology.
Access to Chemotherapy Improves Survival
Grothey A, et al. J Clin Oncol. 2005;23:9441-9442.
22
20
18
16
14
12
Med
ian
OS
(M
os)
0 20 40 60 80
Patients With 3 Drugs (%)
LV5FU2
Bolus 5-FU/LV
Infusional 5-FU/LV+ irinotecanInfusional 5-FU/LV+ oxaliplatinBolus 5-FU/LV+ irinotecanIrinotecan+ oxaliplatin
First-line therapy
Page 10
Efficacy: Sequence FOLFIRI/FOLFOX
No statistically significant differences in first- or second-line therapy RR or TTP and OS
Tournigand C, et al. J Clin Oncol. 2004;22:229-237.
ResultsArm A Arm B
FOLFIRI FOLFOX FOLFOX FOLFIRI
Patients, n 109 81 111 69
Confirmed RR, % 56 15 54 4
TTP, mos 8.5 4.2 8.0 2.5
Survival, mos 21.5 20.6
FOLFOXIRI vs FOLFIRI: Trial Design
Patients with unresectable, previously untreated metastatic colorectal cancer
(N = 244)
Falcone A, et al. ASCO 2006. Abstract 3513.
Primary endpoint: RRStratification: study center, PS (0/1-2), adjuvant chemotherapy
FOLFOXIRIIrinotecan 165 mg/m2 Day 1Oxaliplatin 85 mg/m2 Day 1LV 200 mg/m2 over 2 hours Day 15-FU 3200 mg/m2 48-hour infusion Days 2, 3Every 2 wks
(n = 122)
FOLFIRIIrinotecan 180 mg/m2 Day 1LV 100 mg/m2 over 2 hours Days 1, 25-FU 400 mg/m2 bolus, then 600 mg/m2 22-hour infusion Days 1, 2Every 2 wks
(n = 122)
FOLFOXIRI vs FOLFIRI: Efficacy and Tolerability
FOLFOXIRI, %(n = 122)
FOLFIRI, %(n = 122)
P Value
RR
Complete 7 6< .0001*
Partial 53 28
Stable disease 21 34 --
Median PFS, mos 9.8 6.9 .0006
Median OS, mos 22.8 16.7 .032
Grade 3/4 toxicity
Neutropenia 50 28 .0008
Neurotoxicity† 20 0 < .0001
Diarrhea 20 12 .08
Falcone A, et al. ASCO 2006. Abstract 3513.
*External review; 95% CI for overall response: 0.25-0.43 for FOLFIRI, 0.51-0.68 for FOLFOXIRI.†Includes grade 2 events.
Quimioterapia más Bevacizumab
Page 14
Adapted from Folkman. Cancer.Principles and practice of oncology 2005
VEGF es expresado durante toda la historia natural
bFGF = basic fibroblast growth factorTGF-1 = transforming growth factor -1PIGF = placenta growth factor PD-ECGF = platelet-derived endothelial cell growth factor
PIGFPD-ECGF
Pleiotrophin
bFGFTGF-1
bFGFTGF-1bFGF
Evolución tumoral
TGF-1 PIGF PIGFPD-ECGF
bFGFTGF-1
VEGF VEGF VEGF VEGF VEGF
www.clinicaloptions.com
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Bevacizumab (Avastin®): Mecanismo de Acción
PP
PP
VEGFBevacizumab
Page 16
VEGFBevacizumab
PP
PP
BLOQUEO de la activación del VEGFR
Bevacizumab (Avastin®): Mecanismo de Acción
Page 17
Phase III Trial With Bevacizumab Therapy in First-Line MCRC
Bolus IFL + BVBolus IFL + BV(n = 403)(n = 403)
5-FU/LV + BV5-FU/LV + BV(n = 110):(n = 110):
Closed due to lack of Closed due to lack of efficacyefficacy
Bolus IFL + placeboBolus IFL + placebo(n = 412)(n = 412)
Hurwitz. NEJM, 2004
RR
AA
NN
DD
OO
MM
II
ZZ
EE
UntreatedUntreatedMCRCMCRC
Courtesy of: Paulo Hoff
Page 18
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
Hurwitz H et al. N Engl J Med 2004;350:2335–42
Courtesy of: Paulo Hoff
Page 19
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
Hurwitz H et al. N Engl J Med 2004;350:2335–42
Phase III Trial: Survival
Courtesy of: Paulo Hoff
Page 20
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 shown* Celecoxib data not shownFuchs et al, JCO 2008Fuchs et al, JCO 2008
Courtesy of: Paulo Hoff
Page 21
Overall Survival
Survival Time (months)
RegimenMedian OS (months) 1 Year P Value
FOLFIRI+ BEV 28 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
Fuchs et al. JCO 2008Courtesy of: Paulo Hoff
Page 22
Phase III Trial of Bevacizumab + Panitumumab-CT With Bev-CT in CRC (PACCE)
Hecht JR, et al. JCO 2008
Page 23
Impact of bevacizumab on OS in mCRC: a population-based study
Renouf, et al. ASCO GI 2009
Patients with mCRC (n=1,417): 2003–2004 (pre-bevacizumab) versus 2006 (post-bevacizumab)
Proportion of patients receiving
Addition of bevacizumab to systemic chemotherapy significantly improved OS:
23.6 vs 18.6 months (p<0.001)
Irinotecan or oxaliplatin and 5-FU:
no change (p=0.68)
Anti-EGFR therapy:
no change (p=0.63)
Bevacizumabtherapy:
increased 5.9% vs 30.6%
(p<0.001)
Page 24
Est
ima
ted
pro
ba
bilit
y
1.0
0.8
0.6
0.4
0.2
00 6 12 18 24
Bevacizumab era (2006)30.6% received bevacizumab
Pre-bevacizumab (2003–2004)5.9% received bevacizumab p<0.001
OS (months)
Renouf, et al. ASCO GI 2009
30
Bevacizumab era (2006), n=448Pre-bevacizumab (2003–2004), n=969
Bevacizumab + standard chemotherapy significantly improved OS:
23.6 vs 18.6 months (p<0.001)
Impact of bevacizumab in mCRC: significantly improved OS
Page 25
Phase IV BRiTETherapy in First-Line MCRC
Bev + CTBev + CT
EE
NN
RR
OO
LL
LL
UntreatedUntreatedMCRCMCRC
Grothey, et al. JCO 2008
Page 26
Phase IV BRiTETherapy in First-Line MCRC
Bev + CTBev + CT
EE
NN
RR
OO
LL
LL
UntreatedUntreatedMCRCMCRC
Grothey, et al. JCO 2008
PFS FOLFIRI + Bev: 10.4 m (n=280)
PFS FOLFOX + Bev: 10 m (n=1092)
Page 27
BRiTE:* continuation of bevacizumab post-first progression significantly increases OS (time from initiation of first-line treatment to death)
Grothey, et al. ASCO 2007 (poster) Grothey, et al. JCO 2008*Non-randomised, observational trial
OS (months)
12.6 19.9 31.8
Post-progression bevacizumabHR=0.48 (95% CI: 0.41–0.57)
0 5 10 15 20 25 30 35
1.0
0.8
0.6
0.4
0.2
0
Est
ima
ted
pro
ba
bilit
y
p<0.001
Post-progression therapy
Bevacizumab post-PD (n=642)No bevacizumab post-PD (n=531)No treatment (n=253)
Quimioterapia más cetuximab
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Phase III MRC COIN
XELOX/OxMdG +XELOX/OxMdG +CetuximabCetuximab(n = 815)(n = 815)
XELOX/OxMdG +XELOX/OxMdG +CetuximabCetuximab(n = 815)(n = 815)
IntermitentIntermitent
XELOX/OxMdGXELOX/OxMdG(n = 815)(n = 815)
ESMO, 2009
RR
AA
NN
DD
OO
MM
II
ZZ
EE
UntreatedUntreatedMCRCMCRC
Page 30
COIN: K-ras WT OS
1.00
0.75
0.50
0.25
0
Survival probability
Time (months)0 6 12 18 24 30 36 42
No. at riskArm AArm B
367362
316306
250238
154149
8380
4442
1917
13
ITT analysisITT analysis Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)
Arm A (XELOX/FOLFOX)Arm B (XELOX/FOLFOX + cetuximab)
Arm A Arm B Diff.
Median OS, months
17.9 17.0 –0.92
2-year survival, %
36.1 34.4 -1.66
HR point estimate = 1.03895% CI 0.90–1.20
p=0.68
Page 31
1.00
0.75
0.50
0.25
0
Survival probability
COIN: K-ras WT PFS
ITT analysisITT analysis
No. at riskArm A Arm B
0
367361
245249
92103
4142
1822
119
66
10
Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)
Arm A (XELOX/FOLFOX)Arm B (XELOX/FOLFOX + cetuximab)
Arm A Arm B Diff.
Median PFS, months
8.6 8.6 +0.07
HR point estimate = 0.95995% CI 0.84–1.09
p=0.60
6 12 18 24 30 36 42
Page 32
COIN: No Significant Difference in OS, PFS Between Treatment Arms, Pt Subsets
Survival Outcome, Mos
Cetuximab + Chemotherapy
Chemotherapy HR (95% CI) P Value
Wild-type KRAS
Median OS 17.0 17.9 1.038 (0.90-1.20) .68
Median PFS 8.6 8.6 0.959 (0.84-1.09) .60
All wild-type patients
Median OS 19.9 20.1 1.019 (0.86-1.20) .86
Median PFS 9.2 8.8 0.922 (0.80-1.07) .36
Patients with mutated KRAS, NRAS, or BRAF
Median OS 12.7 14.4 1.004 (0.87-1.15) .96
Median PFS 6.3 6.6 1.079 (0.95-1.23) .33
Maughan TS, et al. ASCO 2010. Abstract 3502.
Page 33
ITT Survival: WT K-Ras (n=729)
XELOX/OxMdG XELOX/OxMdG +
Cetuximab
HR
(p value)
OS
(months)
17,9 17,0 1,038
(0,68)
2y OS (%) 36,1 34,4
PFS
(months)
8,6 8,6 0,95
(0,60)
ESMO, 2009
Page 34Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)
COIN: K-RAS and Response
All patients K-ras WT K-ras MT
FOLFOX/XELOX(n=815)
Cetuximab + FOLFOX/
XELOX(n=815)
FOLFOX/XELOX(n=367)
Cetuximab + FOLFOX/
XELOX(n=362)
FOLFOX/XELOX(n=268)
Cetuximab + FOLFOX/
XELOX(n=297)
Best overall response (%)
51 53 57 64 46 43
Odds ratio 1.08 (p=0.428) OR=1.35 (p=0.049) OR=0.88 (p=0.449)
Page 35
NORDIC VII: Cetuximab in First Line mCRC
Nordic FLOX (FU 500 mg/m2 + LV 60 mg/m2, d1,2 Q2W)
Nordic FLOX + CetuximabmCRC
Endpoint:• PFSRandomized patients: 571
R
Tveit KM, ESMO 2010
Nordic FLOX stop & go + Cetuximab
Page 36
NORDIC VII: Cetuximab in First Line mCRC
Nordic FLOX (FU 500 mg/m2 + LV 60 mg/m2, d1,2 Q2W)
Nordic FLOX + CetuximabmCRC
Endpoint:• PFSRandomized patients: 571
R
Tveit KM, ESMO 2010
Nordic FLOX stop & go + Cetuximab
Outcome FLOX F+Cet Stop&Go-Cet
PFS 7.9 8.3 7.3
RR 41% 49% 47%
OS 20.4 19.7 20.3
Page 37
TRIALS IN mCRC 1st Line treatmentK-Ras status WT
TRIAL PH PFS OS
CRYSTAL 3
FOLFIRIFOLFIRI+
CETUXIMABP FOLFIRI
FOLFIRI + CETUXIMAB
P
8.4 9.90.001
720 23.5 0.0094
OPUS 2FOLFOX
FOLFOX +CETUXIMAB
P FOLFOXFOLFOX +
CETUXIMABP
7.2 8.3 0.006 18.5 22.8 0.3854
COIN 3
XELOX/FOLFOX
XELOX/FOLFOX+CETUXIMAB
PXELOX/FOLFOX
XELOX/FOLFOX + CETUXIMAB
P
8.6 8.6 0.6 17.9 17 0.68
NORDIC 3FLOX
FLOX + CETUXIMAB
P FLOXFLOX +
CETUXIMABP
7.9 8.3 0.3 20.4 19.7 0.30
Page 38
EPIC: Cetuximab + Irinotecan after Fluoropyrimidine + Oxaliplatin failure
Cetuximab 400 mg/m2 initial dose cycle 1, wk 1, 250 mg/m2 weeklyIrinotecan 350 mg/m2 (n=648)
Irinotecan (n=650)
mCRC with progression after
1st line fluoropyirimidine and Oxaliplatin
(n=1298)
Primary endpoint:Overall survival
R
Sobrero AF. J Clin Oncol. 26: 2311-2319, 2008
Page 39
Cetuximab + Irinotecan vs Irinotecan in 2nd line - EPIC
Sobrero AF. J Clin Oncol. 26: 2311-2319, 2008
Page 40
Cetuximab versus BSC
BSC(285)
Cetuximab + BSC(287)
Jonker et al. NEJM 2007; 357: 2040
R
A
N
D
O
M
I
Z
E
Metastatic colorectal cancer with prior 5-FU, irinotecan and
oxaliplatin(572 pts)
Courtesy of: Paulo Hoff
Page 41
NCIC CTG C0.17: Overall Survival in K-ras Wild-Type Patients
HR 0.55 95% CI (0.41,0.74)
Log rank p-value: <0.0001
Study arm MS (months) 95% CI
Cetuximab + BSC 9.5 7.7 – 10.3
BSC alone 4.8 4.2 – 5.5
Karapetis C et al, New Engl J Med 2008
0
0.2
0.4
0.6
0.8
1
0 2 4 6 8 10 12 14 16 18
Time from Randomization (Months)
Pro
po
rtio
n A
live
CetuximabBSC
CetuximabBSC
117 108 95 81 52 34 20 9 6 2113 92 69 36 24 17 12 5 3 3
Courtesy of: Paulo Hoff
Continuum of care
OPTIMOX2: Study Design
Patients with metastatic colorectal cancer
(N = 202)
Maindrault-Goebel F, et al. ASCO 2006. Abstract 3504.
Until progressionOPTIMOX1 (n = 100)
OPTIMOX2 (n = 102)
Started before tumor progression reached baseline measurements
Chemotherapy- free interval*
mFOLFOX76 cycles
s5-FU/LV2mFOLFOX76 cycles
mFOLFOX76 cycles
mFOLFOX76 cycles
Primary endpoint: duration of disease control (DDC)
*Median duration: 20 weeks
OPTIMOX2: DDC and PFS
No difference observed in duration of disease control between study arms
Longer median PFS with OPTIMOX1 regimen
Maindrault-Goebel F, et al. ASCO 2006. Abstract 3504.
Results, mos OPTIMOX1 OPTIMOX2 P Value
DDC 12.9 11.7 .41
Median PFS 8.7 6.9 .009
Alternating vs Continuous FOLFIRI
Labianca R, et al. ASCO 2006. Abstract 3505.
Evaluation for PD 2 mos from randomization, then every 4 mos thereafterPrimary endpoint: OS
Patients with advanced colorectal cancer without prior chemotherapy in the advanced setting
(N = 331)No treatment2 mos
Continuous FOLFIRIEvery 2 wks for 6 mos(n = 168)
Alternating FOLFIRIEvery 2 wks, 2 mos(n = 163)
Alternating FOLFIRIEvery 2 wks, 2 mos
Alternating vs Continuous FOLFIRI in Advanced Colorectal Cancer (cont’d)
Labianca R, et al. ASCO 2006. Abstract 3505.
Alternating FOLFIRI not inferior to continuous FOLFIRI in terms of PFS and OS
– Median follow-up: 30 months
Results, mos A-FOLFIRI C-FOLFIRI HR (5% CI)
Median PFS 6.2 6.5 1.01 (0.78-1.27)
Median OS 16.9 17.6 1.03 (0.78-1.35)
XELOX + Bevacizumab(n = 239)
Bevacizumab(n = 241)
Patients withpreviously
untreated mCRC
(N = 480)
Maintenance cycles administered q3w:Oxaliplatin 130 mg/m2 IV on Day 1Capecitabine 1000 mg/m2 BID PO on Days 1-14Bevacizumab 7.5 mg/kg IV on Day 1
InductionTherapyXELOX +
Bevacizumab6 cycles
Disease progression,
severe toxicity, or consent
withdrawal
Tabernero J, et al. ASCO 2010. Abstract 3501.
MACRO: Maintenance Bev vs Continued Bev + XELOX in Patients With mCRC
MACRO: Duration of PFS Comparable Between Bev vs XELOX + Bev No significant difference between treatment arms in any efficacy outcome
Noninferiority of bevacizumab vs XELOX + bevacizumab cannot be confirmed
– The median PFS HR 95% CI (0.89-1.37) beyond the planned noninferiority limit of 1.32
Outcome Bevacizumab(n = 241)
XELOX/Bevacizumab
(n = 239)
HR(95% CI)
OR(95% CI)
Median PFS,* mos 9.7 10.4 1.11(0.89-1.37)
--
Median OS,* mos 21.7 23.4 1.04(0.81-1.32)
--
Confirmed objective response, %
49 46 -- 0.89(0.62-1.27)
*Median follow-up: 20.4-21.1 mos.
Tabernero J, et al. ASCO 2010. Abstract 3501.
Page 49
BRiTE:* continuation of bevacizumab post-first progression significantly increases OS (time from initiation of first-line treatment to death)
Grothey, et al. ASCO 2007 (poster) Grothey, et al. JCO 2008*Non-randomised, observational trial
OS (months)
12.6 19.9 31.8
Post-progression bevacizumabHR=0.48 (95% CI: 0.41–0.57)
0 5 10 15 20 25 30 35
1.0
0.8
0.6
0.4
0.2
0
Est
ima
ted
pro
ba
bilit
y
p<0.001
Post-progression therapy
Bevacizumab post-PD (n=642)No bevacizumab post-PD (n=531)No treatment (n=253)
Advanced/mCRC Patients Can Tolerate Intensive Therapy
Primera línea Segunda línea Tercera línea
FOLFOX ± bevacizumab CapeOx ± bevacizumab FOLFIRI + bevacizumab FOLFIRI ± cetuximab*
5-FU/leucovorin + bevacizumab
FOLFOXIRI (2B)
FOLFIRI Irinotecan
FOLFOX CapeOx
Irinotecan + cetuximab*†
FOLFOX CapeOx
Irinotecan → Irinotecan + cetuximab*†
Clinical trial BSC
*KRAS no mutado.
NCCN Clinical Practice Guidelines in Oncology. Colon Cancer. V1.2010.
Page 51
FOLFOX + Bevacizumab
6 meses
“Continuum of care”
Bevacizumab
Hasta progresión1o línea
FOLFIRI + Bevacizumab
6 meses
Fluoruracilo + Bevacizumab
Hasta progresión2o línea
Cetuximab +/-
IrinotecánMitomicina-FU
Hasta progresión≥3o línea
Hasta progresión
Tabernero J, et al. ASCO 2010. Abstract 3501.
Grothey A, et al. JCO Nov 20, 2008:5326-5334
Cunningham D, et al. N Engl J Med 2004;351:337-45.
Conclusiones
Debe recibir Irinotecán, Oxaliplatino y Fluoruracilo…
Bevacizumab + QT en primera línea metastásica
Cetuximab +/- Irinotecán en última línea
Disminución de intensidad (y toxicidad) es válida (sábados)
Suspender el tratamiento: disminuye la supervivencia (domingos)