Transcript PowerPoint Template

“Continuum of care” en cáncer de colon
metastásico no curable
Mauricio Lema Medina MD
Clínica de Oncología Astorga – Clínica SOMA – Medicáncer
Medellín, Colombia
Quimioterapia
A qué llegamos?
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
12-35
 de Gramont (LV5-FU2)
28-33
 AIO (cada semana, 24-hour infusion)
25-44
Capecitabina
20-25
Grothey A, et al. J Clin Oncol. 2005;23:9441-9442.
Page  3
www.clinicaloptions.com
IFL vs FOLFOX vs IROX (N9741)
diseño
IFL
(n=264)
R
n=795
FOLFOX
(n=267)
IROX
(n=264)
Primary endpoint: PFS
Goldberg et al, JCO 2004
Page  4
Bolo (IFL) vs infusión
(FOLFOX)
Page  5
N9741: Sanoff HK. J Clin Oncol 26:5721-5727.
N9741
Resultados
n
IFL
264
FOLFOX
267
IROX
264
RR (%)
31
45
35
PFS (m)
6.9
8.7
6.5
OS (m)
15
19.5
17.4
p
Goldberg et al, JCO 2004
Page  6
0.0001
Trial of Bevacizumab plus
FOLFIRI/mIFL (BICC-C): design
Initial design
FOLFIRI
(n=144)
R
n=430
mIFL
(n=141)
XELIRI
(n=145)
Feb 2003 – April 2004
Primary endpoint: PFS
* Celecoxib data not shown
Fuchs et al, JCO 2008
Page  7
Courtesy of: Paulo Hoff
BICC-C Study: FOLFIRI vs mIFL
vs CapeIRI
Overall Survival
FOLFIRI vs mIFL: P = .004
FOLFIRI vs Capelri: P = .015
mIFL vs Capelri: P = .46
100
75
FOLFIRI
mIFL
Capelri
50
75
25
0
0
10
20
Months
30
40
FOLFIRI
mIFL
Capelri
50
25
0
FOLFIRI vs mIFL: P = .09
FOLFIRI vs Capelri: P = .27
mIFL vs Capelri: P = .93
100
Alive (%)
Progression Free (%)
Progression-Free Survival
0
10
20
30
Months
40
50
Fuchs CS, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in firstline treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007;25(30):47794786. Reprinted with permission from the American Society of Clinical Oncology.
Fuchs CS, et al. J Clin Oncol. 2007;25:4779-4786.
Access to Chemotherapy Improves
Survival
Median OS (Mos)
22
First-line therapy
Infusional 5-FU/LV
+ irinotecan
Infusional 5-FU/LV
+ oxaliplatin
Bolus 5-FU/LV
+ irinotecan
Irinotecan
+ oxaliplatin
Bolus 5-FU/LV
LV5FU2
20
18
16
14
12
0
20
40
60
Patients With 3 Drugs (%)
Grothey A, et al. J Clin Oncol. 2005;23:9441-9442.
80
Efficacy: Sequence FOLFIRI/FOLFOX
Arm A
Arm B
Results
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
No statistically significant differences in first- or
second-line therapy RR or TTP and OS
Page  10
Tournigand C, et al. J Clin Oncol. 2004;22:229-237.
FOLFOXIRI vs FOLFIRI: Trial Design
FOLFOXIRI
Irinotecan 165 mg/m2 Day 1
Oxaliplatin 85 mg/m2 Day 1
LV 200 mg/m2 over 2 hours Day 1
5-FU 3200 mg/m2 48-hour infusion Days 2, 3
Every 2 wks
Patients with
unresectable, previously
untreated metastatic
colorectal cancer
(N = 244)
Primary endpoint: RR
Stratification: study center,
PS (0/1-2), adjuvant
chemotherapy
Falcone A, et al. ASCO 2006. Abstract 3513.
(n = 122)
FOLFIRI
Irinotecan 180 mg/m2 Day 1
LV 100 mg/m2 over 2 hours Days 1, 2
5-FU 400 mg/m2 bolus,
then 600 mg/m2 22-hour infusion Days 1, 2
Every 2 wks
(n = 122)
FOLFOXIRI vs FOLFIRI:
Efficacy and Tolerability
FOLFOXIRI, %
(n = 122)
FOLFIRI, %
(n = 122)
Complete
7
6
Partial
53
28
Stable disease
21
34
--
Median PFS, mos
9.8
6.9
.0006
Median OS, mos
22.8
16.7
.032
Neutropenia
50
28
.0008
Neurotoxicity†
20
0
< .0001
Diarrhea
20
12
.08
P Value
RR
< .0001*
Grade 3/4 toxicity
*External review; 95% CI for overall response: 0.25-0.43 for FOLFIRI, 0.51-0.68 for FOLFOXIRI.
†Includes
grade 2 events.
Falcone A, et al. ASCO 2006. Abstract 3513.
Quimioterapia más Bevacizumab
VEGF es expresado durante toda la historia natural
bFGF
bFGF
bFGF
TGFb-1 TGFb-1
VEGF VEGF VEGF VEGF
TGFb-1
PIGF
bFGF
TGFb-1
VEGF
PIGF
PIGF
PD-ECGF PD-ECGF
Pleiotrophin
Evolución tumoral
bFGF = basic fibroblast growth factor
TGFb-1 = transforming growth factor b-1
PIGF = placenta growth factor
PD-ECGF = platelet-derived endothelial cell growth factor
Page  14
www.clinicaloptions.com
Adapted from Folkman. Cancer.
Principles and practice of oncology 2005
Bevacizumab (Avastin®): Mecanismo de Acción
Bevacizumab
VEGF
P
P
Page  15
P
P
Bevacizumab (Avastin®): Mecanismo de Acción
Bevacizumab
VEGF
P
P
P
P
BLOQUEO de la activación del VEGFR
Page  16
Phase III Trial With Bevacizumab
Therapy in First-Line MCRC
Untreated
MCRC
R
A
N
D
O
M
I
Z
E
Bolus IFL + placebo
(n = 412)
Bolus IFL + BV
(n = 403)
5-FU/LV + BV
(n = 110):
Closed due to lack of
efficacy
Hurwitz. NEJM, 2004
Page  17
Courtesy of: Paulo Hoff
Probability of being progression-free
Phase III Trial : PFS
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
1.0
0.8
0.6
IFL + bevacizumab
0.4
IFL + placebo
0.2
6.2
0
0
10.6
10
20
30
PFS (months)
Hurwitz H et al. N Engl J Med 2004;350:2335–42
Page  18
Courtesy of: Paulo Hoff
Phase III Trial: Survival
Median survival (months)
IFL + placebo: 15.6 (95% CI: 14.3–17.0) vs
IFL + bevacizumab: 20.3 (95% CI: 18.5–24.2)
HR=0.66 (95% CI: 0.54–0.81) p<0.001
Probability of survival
1.0
0.8
0.6
IFL + bevacizumab
IFL + placebo
0.4
0.2
15.6
0
0
10
20.3
20
Survival (months)
30
40
Hurwitz H et al. N Engl J Med 2004;350:2335–42
Page  19
Courtesy of: Paulo Hoff
Trial of Bevacizumab plus
FOLFIRI/mIFL (BICC-C): design
R
n=430
Initial design
Amended design
FOLFIRI
(n=144)
FOLFIRI+Bev.
(n=60)
mIFL
(n=141)
XELIRI
(n=145)
R
n=117
Feb 2003 – April 2004
Primary endpoint: PFS
mIFL+Bev.
(n=57)
May 2004 – Dec 2004
Protocol amended due
to approval of
bevacizumab
* Celecoxib data not shown
Fuchs et al, JCO 2008
Page  20
Courtesy of: Paulo Hoff
Proportion of Subjects
Who Survived
Overall Survival
Regimen
Median OS
(months)
1 Year
P Value
1
FOLFIRI+ BEV
28
87%
--
0.9
mIFL + BEV
19.2
61%
0.01
0.8
0.7
0.6
0.5
0.4
0.3
0.2
FOLFIRI + Bevacizumab
0.1
mIFL + Bevacizumab
0
0
Fuchs et al. JCO 2008
Page  21
10
20
30
40
Survival Time (months)
Courtesy of: Paulo Hoff
Phase III Trial of Bevacizumab + Panitumumab-CT
With Bev-CT in CRC (PACCE)
Hecht JR, et al. JCO 2008
Page  22
Impact of bevacizumab on OS in mCRC:
a population-based study
Patients with mCRC (n=1,417): 2003–2004 (pre-bevacizumab)
versus 2006 (post-bevacizumab)
Proportion of patients receiving
Irinotecan or
oxaliplatin
and 5-FU:
no change (p=0.68)
Anti-EGFR
therapy:
no change
(p=0.63)
Bevacizumab
therapy:
increased
5.9% vs 30.6%
(p<0.001)
Addition of bevacizumab to systemic chemotherapy
significantly improved OS:
23.6 vs 18.6 months (p<0.001)
Page  23
Renouf, et al. ASCO GI 2009
Impact of bevacizumab in mCRC: significantly
improved OS
Estimated probability
1.0
0.8
Bevacizumab era (2006)
30.6% received
bevacizumab
0.6
0.4 Pre-bevacizumab (2003–2004)
p<0.001
5.9% received bevacizumab
Bevacizumab + standard chemotherapy
significantly improved OS:
23.6 vs 18.6 months (p<0.001)
0.2
0
0
Page  24
6
12
18
OS (months)
Bevacizumab era (2006), n=448
Pre-bevacizumab (2003–2004), n=969
24
30
Renouf, et al. ASCO GI 2009
Phase IV BRiTE
Therapy in First-Line MCRC
Untreated
MCRC
Page  25
E
N
R
O
L
L
Bev + CT
Grothey, et al. JCO 2008
Phase IV BRiTE
Therapy in First-Line MCRC
PFS FOLFOX + Bev: 10 m (n=1092)
Untreated
MCRC
E
N
R
O
L
L
Bev + CT
PFS FOLFIRI + Bev: 10.4 m (n=280)
Page  26
Grothey, et al. JCO 2008
BRiTE:* continuation of bevacizumab post-first progression significantly
increases OS (time from initiation of first-line treatment to death)
Post-progression therapy
Estimated probability
1.0
Bevacizumab post-PD (n=642)
No bevacizumab post-PD (n=531)
No treatment (n=253)
0.8
0.6
0.4 Post-progression bevacizumab
HR=0.48 (95% CI: 0.41–0.57)
p<0.001
0.2
12.6
0
Page  27
0
5
10
*Non-randomised, observational trial
19.9
15
20
OS (months)
31.8
25
30
35
Grothey, et al. ASCO 2007 (poster)
Grothey, et al. JCO 2008
Quimioterapia más cetuximab
Phase III MRC COIN
Untreated
MCRC
Page  29
R
A
N
D
O
M
I
Z
E
XELOX/OxMdG
(n = 815)
XELOX/OxMdG +
Cetuximab
(n = 815)
XELOX/OxMdG +
Cetuximab
(n = 815)
Intermitent
ESMO, 2009
COIN: K-ras WT OS
Survival probability
Arm A (XELOX/FOLFOX)
Arm B (XELOX/FOLFOX + cetuximab)
1.00
0.75
Arm A
Arm B
Diff.
Median OS,
months
17.9
17.0
–0.92
2-year
survival, %
36.1
34.4
-1.66
0.50
HR point estimate = 1.038
95% CI 0.90–1.20
p=0.68
0.25
0
0
No. at risk
Arm A
367
362
Arm B
6
12
18
24
30
Time (months)
36
42
316
306
250
238
154
149
19
17
1
3
83
80
44
42
Page  30
ITT analysis
Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)
COIN: K-ras WT PFS
Arm A (XELOX/FOLFOX)
Arm B (XELOX/FOLFOX + cetuximab)
Survival probability
1.00
0.75
Median PFS,
months
0.50
Arm A
Arm B
Diff.
8.6
8.6
+0.07
HR point estimate = 0.959
95% CI 0.84–1.09
p=0.60
0.25
0
No. at risk
Arm A
Arm B
0
6
12
18
24
30
36
367
361
245
249
92
103
41
42
18
22
11
9
6
6
42
1
0
Page  31
ITT analysis
Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)
COIN: No Significant Difference in OS, PFS
Between Treatment Arms, Pt Subsets
Survival Outcome,
Mos
Cetuximab +
Chemotherapy
Chemotherapy
HR (95% CI)
P Value
 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
 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
 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
Wild-type KRAS
All wild-type patients
Patients with mutated
KRAS, NRAS, or BRAF
Page  32
Maughan TS, et al. ASCO 2010. Abstract 3502.
ITT Survival: WT K-Ras (n=729)
XELOX/OxMdG
OS
17,9
XELOX/OxMdG +
HR
Cetuximab
(p value)
17,0
1,038
(months)
2y OS (%)
36,1
34,4
PFS
8,6
8,6
(months)
Page  33
(0,68)
0,95
(0,60)
ESMO, 2009
COIN: K-RAS and Response
All patients
K-ras WT
K-ras MT
Cetuximab
Cetuximab
Cetuximab
FOLFOX/
FOLFOX/
FOLFOX/
+ FOLFOX/
+ FOLFOX/
+ FOLFOX/
XELOX
XELOX
XELOX
XELOX
XELOX
XELOX
(n=815)
(n=367)
(n=268)
(n=815)
(n=362)
(n=297)
Best overall
response
(%)
51
Odds ratio
1.08 (p=0.428)
Page  34
53
57
64
OR=1.35 (p=0.049)
46
43
OR=0.88 (p=0.449)
Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)
NORDIC VII: Cetuximab in First Line mCRC
Nordic FLOX (FU 500 mg/m2 + LV
60 mg/m2, d1,2 Q2W)
mCRC
R
Nordic FLOX + Cetuximab
Nordic FLOX stop & go + Cetuximab
Endpoint:
• PFS
Randomized patients: 571
Page  35
Tveit KM, ESMO 2010
NORDIC VII: Cetuximab in First Line mCRC
Nordic FLOX (FU 500 mg/m2 + LV
60 mg/m2, d1,2 Q2W)
mCRC
R
Nordic FLOX + Cetuximab
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
Endpoint:
• PFS
Randomized patients: 571
Page  36
Tveit KM, ESMO 2010
TRIALS IN mCRC 1st Line treatment
K-Ras status WT
TRIAL
CRYSTAL
OPUS
COIN
NORDIC
Page  37
PH
PFS
FOLFIRI
FOLFIRI+
CETUXIMAB
P
FOLFIRI
FOLFIRI +
CETUXIMAB
P
8.4
9.9
0.0017
20
23.5
0.0094
FOLFOX
FOLFOX +
CETUXIMAB
P
FOLFOX
FOLFOX +
CETUXIMAB
P
7.2
8.3
0.006
18.5
22.8
0.3854
XELOX/
FOLFOX
XELOX/FOLFOX
+CETUXIMAB
P
XELOX/
FOLFOX
XELOX/FOLFOX
+ CETUXIMAB
P
8.6
8.6
0.6
17.9
17
0.68
FLOX
FLOX +
CETUXIMAB
P
FLOX
FLOX +
CETUXIMAB
P
7.9
8.3
0.3
20.4
19.7
0.30
3
2
3
OS
3
EPIC: Cetuximab + Irinotecan after Fluoropyrimidine +
Oxaliplatin failure
Cetuximab 400 mg/m2 initial dose
mCRC with
progression after 1st
line fluoropyirimidine
and Oxaliplatin
(n=1298)
cycle 1, wk 1, 250 mg/m2 weekly
Irinotecan 350 mg/m2
(n=648)
R
Primary endpoint:
Overall survival
Page  38
Sobrero AF. J Clin Oncol. 26: 2311-2319, 2008
Irinotecan
(n=650)
Cetuximab + Irinotecan vs Irinotecan in 2nd line - EPIC
Page  39
Cet + Iri
Iri
(n=648)
(n=650)
RR
16.4%
4.2%
P<0.05
PFS
4 months
2.6 months
P<0.005
OS
10.7 m
10 m
P=0.71
Sobrero AF. J Clin Oncol. 26: 2311-2319, 2008
P value
Cetuximab versus BSC
Metastatic
colorectal cancer
with prior 5-FU,
irinotecan and
oxaliplatin
(572 pts)
R
A
N
D
O
M
I
Z
E
Cetuximab
+ BSC
(287)
BSC
(285)
Jonker et al. NEJM 2007; 357: 2040
Page  40
Courtesy of: Paulo Hoff
NCIC CTG C0.17: Overall Survival in
K-ras Wild-Type Patients
1
Proportion Alive
0.8
Study arm
MS (months)
95% CI
Cetuximab + BSC
9.5
7.7 – 10.3
BSC alone
4.8
4.2 – 5.5
0.6
HR 0.55 95% CI (0.41,0.74)
Log rank p-value: <0.0001
0.4
0.2
Cetuximab
BSC
0
0
Cetuximab 117
113
BSC
Page  41
2
108
92
4
95
69
6
8
10
12
14
Time from Randomization (Months)
81
36
Karapetis C et al, New Engl J Med 2008
52
24
34
17
20
12
9
5
16
18
6
3
2
3
Courtesy of: Paulo Hoff
Continuum of care
OPTIMOX2: Study Design
Until progression
OPTIMOX1
(n = 100)
mFOLFOX7
6 cycles
Patients with
metastatic
colorectal cancer
(N = 202)
s5-FU/LV2
mFOLFOX7
6 cycles
Chemotherapyfree interval*
mFOLFOX7
6 cycles
OPTIMOX2
(n = 102)
mFOLFOX7
6 cycles
Primary endpoint: duration
of disease control (DDC)
*Median duration: 20 weeks
Maindrault-Goebel F, et al. ASCO 2006. Abstract 3504.
Started before tumor
progression reached
baseline measurements
OPTIMOX2: DDC and PFS
 No difference observed in duration of disease control
between study arms
 Longer median PFS with OPTIMOX1 regimen
Results, mos
OPTIMOX1
OPTIMOX2
P Value
DDC
12.9
11.7
.41
Median PFS
8.7
6.9
.009
Maindrault-Goebel F, et al. ASCO 2006. Abstract 3504.
Alternating vs Continuous FOLFIRI
Patients with
advanced colorectal
cancer without prior
chemotherapy
in the advanced
setting
(N = 331)
Continuous FOLFIRI
Every 2 wks for 6 mos
(n = 168)
Alternating FOLFIRI
Every 2 wks, 2 mos
(n = 163)
No treatment
2 mos
Alternating FOLFIRI
Every 2 wks, 2 mos
Evaluation for PD 2 mos from randomization, then every 4 mos thereafter
Primary endpoint: OS
Labianca R, et al. ASCO 2006. Abstract 3505.
Alternating vs Continuous FOLFIRI in
Advanced Colorectal Cancer (cont’d)
 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)
Labianca R, et al. ASCO 2006. Abstract 3505.
MACRO: Maintenance Bev vs Continued
Bev + XELOX in Patients With mCRC
Patients with
previously
untreated mCRC
(N = 480)
Induction
Therapy
XELOX +
Bevacizumab
6 cycles
XELOX + Bevacizumab
(n = 239)
Bevacizumab
(n = 241)
Maintenance cycles administered q3w:
Oxaliplatin 130 mg/m2 IV on Day 1
Capecitabine 1000 mg/m2 BID PO on Days 1-14
Bevacizumab 7.5 mg/kg IV on Day 1
Tabernero J, et al. ASCO 2010. Abstract 3501.
Disease
progression,
severe
toxicity, or
consent
withdrawal
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)
--
49
46
--
0.89
(0.62-1.27)
Confirmed objective
response, %
*Median follow-up: 20.4-21.1 mos.
Tabernero J, et al. ASCO 2010. Abstract 3501.
BRiTE:* continuation of bevacizumab post-first progression significantly
increases OS (time from initiation of first-line treatment to death)
Post-progression therapy
Estimated probability
1.0
Bevacizumab post-PD (n=642)
No bevacizumab post-PD (n=531)
No treatment (n=253)
0.8
0.6
0.4 Post-progression bevacizumab
HR=0.48 (95% CI: 0.41–0.57)
p<0.001
0.2
12.6
0
Page  49
0
5
10
*Non-randomised, observational trial
19.9
15
20
OS (months)
31.8
25
30
35
Grothey, et al. ASCO 2007 (poster)
Grothey, et al. JCO 2008
Advanced/mCRC Patients Can Tolerate
Intensive Therapy
Primera línea
FOLFOX ±
bevacizumab
CapeOx ± bevacizumab
FOLFIRI + bevacizumab
FOLFIRI ± cetuximab*
5-FU/leucovorin +
bevacizumab
FOLFOXIRI (2B)
Segunda línea
FOLFIRI
Irinotecan
FOLFOX
CapeOx
Tercera línea
Irinotecan + cetuximab*†
FOLFOX
CapeOx
Irinotecan → Irinotecan +
cetuximab*†
Clinical trial
BSC
*KRAS no mutado.
NCCN Clinical Practice Guidelines in Oncology. Colon Cancer. V1.2010.
“Continuum of care”
1o línea
6 meses
FOLFOX +
Bevacizumab
Hasta progresión
Bevacizumab
Tabernero J, et al. ASCO 2010. Abstract 3501.
2o línea
6 meses
FOLFIRI +
Bevacizumab
Hasta progresión
Fluoruracilo +
Bevacizumab
Grothey A, et al. JCO Nov 20, 2008:5326-5334
≥3o línea
Page  51
Hasta progresión
Cetuximab +/Irinotecán
Cunningham D, et al. N Engl J Med 2004;351:337-45.
Hasta progresión
Mitomicina-FU
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)