1
Continuum of care en cáncer de colon
metastásico no curable

• Mauricio Lema Medina MD
• Clínica de Oncología Astorga Clínica SOMA
  Medicáncer
• Medellín, Colombia

2
Quimioterapia

• A qué llegamos?

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.
2005239441-9442.
www.clinicaloptions.com
4
IFL vs FOLFOX vs IROX (N9741)
diseño
IFL(n264)
Bolo (IFL) vs infusión (FOLFOX)
R
n795

Primary endpoint PFS
Goldberg et al, JCO 2004
5
N9741 Sanoff HK. J Clin Oncol 265721-5727.
6
N9741 Resultados
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
Goldberg et al, JCO 2004
7
Trial of Bevacizumab plus FOLFIRI/mIFL (BICC-C)
design
Initial design
FOLFIRI(n144)
R
n430
Feb 2003 April 2004
Primary endpoint PFS
Celecoxib data not shown
Fuchs et al, JCO 2008
Courtesy of Paulo Hoff
8
BICC-C Study FOLFIRI vs mIFL vs CapeIRI
Progression-Free Survival
Overall Survival
FOLFIRI vs mIFL P .004
FOLFIRI vs mIFL P .09
100
FOLFIRI vs Capelri P .015
FOLFIRI vs Capelri P .27
100

mIFL vs Capelri P .46
mIFL vs Capelri P .93
75
75
FOLFIRI
FOLFIRI
mIFL
mIFL
50
50
Progression Free ()
Alive ()
Capelri
Capelri
25
25
0
0
0
10
20
30
40
0
10
20
30
40
50
Months
Months
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. 200725(30)4779-4786.
Reprinted with permission from the American
Society of Clinical Oncology.
Fuchs CS, et al. J Clin Oncol. 2007254779-4786.
9
Access to Chemotherapy Improves Survival
22
First-line therapy
Infusional 5-FU/LV irinotecan
20
Infusional 5-FU/LV oxaliplatin
18
Median OS (Mos)
Bolus 5-FU/LV irinotecan
16
Irinotecan oxaliplatin
14
Bolus 5-FU/LV
LV5FU2
12
0
20
40
60
80
Patients With 3 Drugs ()
Grothey A, et al. J Clin Oncol. 2005239441-9442.
10
Efficacy Sequence FOLFIRI/FOLFOX
Results Arm A Arm A Arm B Arm B
Results FOLFIRI ? FOLFOX FOLFIRI ? FOLFOX FOLFOX ? FOLFIRI 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 21.5 20.6 20.6

• No statistically significant differences in
  first- or second-line therapy RR or TTP and OS

Tournigand C, et al. J Clin Oncol.
200422229-237.
11
FOLFOXIRI vs FOLFIRI Trial Design
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)
Patients with unresectable, previously untreated
metastatic colorectal cancer (N 244)
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)
Primary endpoint RR Stratification study
center, PS (0/1-2), adjuvant chemotherapy
Falcone A, et al. ASCO 2006. Abstract 3513.
12
FOLFOXIRI vs FOLFIRI Efficacy and Tolerability
FOLFOXIRI, (n 122) FOLFIRI, (n 122) P Value
RR
Complete 7 6 lt .0001
Partial 53 28 lt .0001
Stable disease 21 34 --
Median PFS, mos 9.8 6.9 .0006
Median OS, mos 22.8 16.7 .032
Grade 3/4 toxicity Grade 3/4 toxicity Grade 3/4 toxicity Grade 3/4 toxicity
Neutropenia 50 28 .0008
Neurotoxicity 20 0 lt .0001
Diarrhea 20 12 .08
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.
13
Quimioterapia más Bevacizumab
14
VEGF es expresado durante toda la historia natural
bFGF TGFb-1
bFGF TGFb-1
bFGF TGFb-1
bFGF
VEGF
VEGF
VEGF
VEGF
VEGF
PIGF PD-ECGF Pleiotrophin
TGFb-1
PIGF
PIGF PD-ECGF
Evolución tumoral
bFGF basic fibroblast growth factorTGFb-1
transforming growth factor b-1PIGF placenta
growth factor PD-ECGF platelet-derived
endothelial cell growth factor
Adapted from Folkman. Cancer.Principles and
practice of oncology 2005
www.clinicaloptions.com
15
Bevacizumab (Avastin) Mecanismo de Acción
16
Bevacizumab (Avastin) Mecanismo de Acción
BLOQUEO de la activación del VEGFR
17
Phase III Trial With Bevacizumab Therapy in
First-Line MCRC
R A N D O M I Z E
Bolus IFL placebo (n 412)
Untreated MCRC
Bolus IFL BV (n 403)
5-FU/LV BV (n 110) Closed due to lack of
efficacy
Hurwitz. NEJM, 2004
Courtesy of Paulo Hoff
18
Phase III Trial PFS
Median PFS (months)IFL placebo 6.2 (95 CI
5.67.7)IFL bevacizumab 10.6 (95 CI
9.01.0)HR0.54 (95 CI 0.450.66) plt0.001
1.0 0.8 0.6 0.4 0.2 0
IFL bevacizumab IFL placebo
Probability of being progression-free
6.2
10.6
0 10 20 30
PFS (months)
Hurwitz H et al. N Engl J Med 2004350233542
Courtesy of Paulo Hoff
19
Phase III Trial Survival
Median survival (months)IFL placebo 15.6 (95
CI 14.317.0) vs IFL bevacizumab 20.3 (95
CI 18.524.2) HR0.66 (95 CI 0.540.81) plt0.001
1.0 0.8 0.6 0.4 0.2 0
IFL bevacizumab IFL placebo
Probability of survival
15.6
20.3
0 10 20 30 40
Survival (months)
Hurwitz H et al. N Engl J Med 2004350233542
Courtesy of Paulo Hoff
20
Trial of Bevacizumab plus FOLFIRI/mIFL (BICC-C)
design
Amended design
Initial design
FOLFIRI(n144)
FOLFIRIBev.
(n60)
mIFLBev.
R
R
(n57)
n430
n117
May 2004 Dec 2004
Feb 2003 April 2004
Protocol amended due to approval of bevacizumab
Primary endpoint PFS
Celecoxib data not shown
Fuchs et al, JCO 2008
Courtesy of Paulo Hoff
21
Overall Survival
Regimen Median OS (months) 1 Year P Value
FOLFIRI BEV 28 87 --
mIFL BEV 19.2 61 0.01
1
0.9
0.8
0.7
0.6
Proportion of Subjects Who Survived
0.5
0.4
0.3
FOLFIRI Bevacizumab mIFL Bevacizumab
0.2
0.1
0
0
10
20
40
30
Survival Time (months)
Fuchs et al. JCO 2008
Courtesy of Paulo Hoff
22
Phase III Trial of Bevacizumab Panitumumab-CT
With Bev-CT in CRC (PACCE)
Hecht JR, et al. JCO 2008
23
Impact of bevacizumab on OS in mCRC a
population-based study
Patients with mCRC (n1,417) 20032004
(pre-bevacizumab) versus 2006 (post-bevacizumab)
Proportion of patients receiving
Irinotecan or oxaliplatin and 5-FU no change
(p0.68)
Anti-EGFR therapy no change (p0.63)
Bevacizumabtherapyincreased 5.9 vs
30.6(plt0.001)
Addition of bevacizumab to systemic chemotherapy
significantly improved OS23.6 vs 18.6 months
(plt0.001)
Renouf, et al. ASCO GI 2009
24
Impact of bevacizumab in mCRC significantly
improved OS
1.0 0.8 0.6 0.4 0.2 0
Bevacizumab era (2006)30.6 received bevacizumab
Estimated probability
Pre-bevacizumab (20032004)5.9 received
bevacizumab
plt0.001
Bevacizumab standard chemotherapy
significantly improved OS23.6 vs 18.6 months
(plt0.001)
0
6
12
18
24
30
OS (months)
Bevacizumab era (2006), n448Pre-bevacizumab
(20032004), n969
Renouf, et al. ASCO GI 2009
25
Phase IV BRiTETherapy in First-Line MCRC
E N R O L L
Untreated MCRC
Bev CT
Grothey, et al. JCO 2008
26
Phase IV BRiTETherapy in First-Line MCRC
E N R O L L
PFS FOLFOX Bev 10 m (n1092)
Untreated MCRC
Bev CT
PFS FOLFIRI Bev 10.4 m (n280)
Grothey, et al. JCO 2008
27
BRiTE continuation of bevacizumab post-first
progression significantly increases OS (time from
initiation of first-line treatment to death)
Post-progression therapy
1.0 0.8 0.6 0.4 0.2 0
Bevacizumab post-PD (n642)No bevacizumab
post-PD (n531) No treatment (n253)
Estimated probability
Post-progression bevacizumabHR0.48 (95 CI
0.410.57)
plt0.001
12.6
19.9
31.8
0 5 10 15 20 25 30 35
OS (months)
Grothey, et al. ASCO 2007 (poster) Grothey, et
al. JCO 2008
Non-randomised, observational trial
28
Quimioterapia más cetuximab
29
Phase III MRC COIN
R A N D O M I Z E
XELOX/OxMdG (n 815)
Untreated MCRC
XELOX/OxMdG Cetuximab (n 815)
XELOX/OxMdG Cetuximab (n 815) Intermitent
ESMO, 2009
30
COIN K-ras WT OS
Survival probability
Arm A (XELOX/FOLFOX) Arm B (XELOX/FOLFOX
cetuximab)
1.00 0.75 0.50 0.25 0
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 0.901.20p0.68
0
6
12
18
24
30
36
42
Time (months)
No. at riskArm AArm B
367 362
316 306
250 238
154 149
83 80
44 42
19 17
1 3
ITT analysis
Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)
31
COIN K-ras WT PFS
Survival probability
Arm A (XELOX/FOLFOX) Arm B (XELOX/FOLFOX
cetuximab)
1.00 0.75 0.50 0.25 0
Arm A Arm B Diff.
Median PFS, months 8.6 8.6 0.07
HR point estimate 0.95995 CI 0.841.09p0.60
6
12
18
24
30
36
42
0
No. at riskArm A Arm B
367 361
245 249
92 103
41 42
18 22
11 9
6 6
1 0
ITT analysis
Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)
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.
33
ITT Survival WT K-Ras (n729)
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
34
COIN K-RAS and Response
All patients All patients K-ras WT K-ras WT K-ras MT K-ras MT
FOLFOX/XELOX(n815) Cetuximab FOLFOX/XELOX(n815) FOLFOX/XELOX(n367) Cetuximab FOLFOX/XELOX(n362) FOLFOX/XELOX(n268) Cetuximab FOLFOX/XELOX(n297)
Best overall response () 51 53 57 64 46 43
Odds ratio 1.08 (p0.428) 1.08 (p0.428) OR1.35 (p0.049) OR1.35 (p0.049) OR0.88 (p0.449) OR0.88 (p0.449)
Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)
35
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

Tveit KM, ESMO 2010
36
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 FCet StopGo-Cet
PFS 7.9 8.3 7.3
RR 41 49 47
OS 20.4 19.7 20.3

• Endpoint
• PFS
• Randomized patients 571

Tveit KM, ESMO 2010
37
TRIALS IN mCRC 1st Line treatmentK-Ras status WT
TRIAL PH PFS PFS PFS OS OS OS
CRYSTAL 3 FOLFIRI FOLFIRI CETUXIMAB P FOLFIRI FOLFIRI CETUXIMAB P
CRYSTAL 3 8.4 9.9 0.0017 20 23.5 0.0094
OPUS 2 FOLFOX FOLFOX CETUXIMAB P FOLFOX FOLFOX CETUXIMAB P
OPUS 2 7.2 8.3 0.006 18.5 22.8 0.3854
COIN 3 XELOX/ FOLFOX XELOX/FOLFOXCETUXIMAB P XELOX/ FOLFOX XELOX/FOLFOX CETUXIMAB P
COIN 3 8.6 8.6 0.6 17.9 17 0.68
NORDIC 3 FLOX FLOX CETUXIMAB P FLOX FLOX CETUXIMAB P
NORDIC 3 7.9 8.3 0.3 20.4 19.7 0.30
38
EPIC Cetuximab Irinotecan after
Fluoropyrimidine Oxaliplatin failure
Cetuximab 400 mg/m2 initial dose cycle 1, wk 1,
250 mg/m2 weekly Irinotecan 350 mg/m2 (n648)
mCRC with progression after 1st line
fluoropyirimidine and Oxaliplatin (n1298)
R
Irinotecan (n650)
Primary endpoint Overall survival
Sobrero AF. J Clin Oncol. 26 2311-2319, 2008
39
Cetuximab Irinotecan vs Irinotecan in 2nd line
- EPIC
Cet Iri (n648) Iri (n650) P value
RR 16.4 4.2 Plt0.05
PFS 4 months 2.6 months Plt0.005
OS 10.7 m 10 m P0.71
Sobrero AF. J Clin Oncol. 26 2311-2319, 2008
40
Cetuximab versus BSC
R A N D O M I Z E
Cetuximab BSC (287)
Metastatic colorectal cancer with prior 5-FU,
irinotecan and oxaliplatin (572 pts)
BSC (285)
Jonker et al. NEJM 2007 357 2040
Courtesy of Paulo Hoff
41
NCIC CTG C0.17 Overall Survival in K-ras
Wild-Type Patients
Study arm MS (months) 95 CI
Cetuximab BSC 9.5 7.7 10.3
BSC alone 4.8 4.2 5.5
HR 0.55 95 CI (0.41,0.74) Log rank p-value
lt0.0001
Courtesy of Paulo Hoff
Karapetis C et al, New Engl J Med 2008
42
Continuum of care
43
OPTIMOX2 Study Design
Until progression
OPTIMOX1 (n 100)
mFOLFOX7 6 cycles
s5-FU/LV2
mFOLFOX7 6 cycles
Patients with metastatic colorectal cancer (N
202)
OPTIMOX2 (n 102)
mFOLFOX7 6 cycles
mFOLFOX7 6 cycles
Chemotherapy- free interval

• Primary endpoint duration of disease control
  (DDC)
• Median duration 20 weeks

Started before tumor progression reached baseline
measurements
Maindrault-Goebel F, et al. ASCO 2006. Abstract
3504.
44
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.
45
Alternating vs Continuous FOLFIRI
Continuous FOLFIRIEvery 2 wks for 6 mos (n 168)
Patients with advanced colorectal cancer without
prior chemotherapy in the advanced setting (N
331)
Alternating FOLFIRIEvery 2 wks, 2 mos (n 163)
Alternating FOLFIRIEvery 2 wks, 2 mos
No treatment 2 mos
Evaluation for PD 2 mos from randomization, then
every 4 mos thereafterPrimary endpoint OS
Labianca R, et al. ASCO 2006. Abstract 3505.
46
Alternating vs Continuous FOLFIRI in Advanced
Colorectal Cancer (contd)

• 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.
47
MACRO Maintenance Bev vs Continued Bev XELOX
in Patients With mCRC
XELOX Bevacizumab (n 239)
Induction Therapy XELOX Bevacizumab 6 cycles
Patients with previously untreated mCRC (N 480)
Disease progression, severe toxicity, or consent
withdrawal
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.
48
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.
49
BRiTE continuation of bevacizumab post-first
progression significantly increases OS (time from
initiation of first-line treatment to death)
Post-progression therapy
1.0 0.8 0.6 0.4 0.2 0
Bevacizumab post-PD (n642)No bevacizumab
post-PD (n531) No treatment (n253)
Estimated probability
Post-progression bevacizumabHR0.48 (95 CI
0.410.57)
plt0.001
12.6
19.9
31.8
0 5 10 15 20 25 30 35
OS (months)
Grothey, et al. ASCO 2007 (poster) Grothey, et
al. JCO 2008
Non-randomised, observational trial
50
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.
51
Continuum of care
1o línea
6 meses
Hasta progresión
FOLFOX Bevacizumab
Bevacizumab
Tabernero J, et al. ASCO 2010. Abstract 3501.
2o línea
6 meses
Hasta progresión
Fluoruracilo Bevacizumab
FOLFIRI Bevacizumab

Grothey A, et al. JCO Nov 20, 20085326-5334
3o línea
Hasta progresión
Hasta progresión
Cetuximab /- Irinotecán
Mitomicina-FU

Cunningham D, et al. N Engl J Med 2004351337-45.
52
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)