“Continuum of care” en cáncer de colon metastásico no curable Mauricio Lema Medina MD Clínica...

“Continuum of care” en cáncer de colon metastásico no curableMauricio Lema Medina MDClínica de Oncología Astorga – Clínica SOMA – MedicáncerMedellín, Colombia

QuimioterapiaA 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

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

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

N9741: Sanoff HK. J Clin Oncol 26:5721-5727.

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

FOLFIRI(n=144)

RmIFL

(n=141)

XELIRI(n=145)

Feb 2003 – April 2004

Initial design

n=430


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

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

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

Bevacizumab (Avastin®): Mecanismo de Acción

PP

PP

VEGFBevacizumab

VEGFBevacizumab

PP

PP

BLOQUEO de la activación del VEGFR

Bevacizumab (Avastin®): Mecanismo de Acción

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


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


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


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


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


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

Phase III Trial of Bevacizumab + Panitumumab-CT With Bev-CT in CRC (PACCE)

Hecht JR, et al. JCO 2008

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)

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

Phase IV BRiTETherapy in First-Line MCRC

Bev + CTBev + CT

EE

NN

RR

OO

LL

LL


Grothey, et al. JCO 2008

Phase IV BRiTETherapy in First-Line MCRC

Bev + CTBev + CT

EE

NN

RR

OO

LL

LL


Grothey, et al. JCO 2008

PFS FOLFIRI + Bev: 10.4 m (n=280)

PFS FOLFOX + Bev: 10 m (n=1092)

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

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


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

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

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.

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

Maughan, 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)

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

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

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

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

Cetuximab + Irinotecan vs Irinotecan in 2nd line - EPIC

Sobrero AF. J Clin Oncol. 26: 2311-2319, 2008

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)


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


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.


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.

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


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)

“Continuum of care” en cáncer de colon metastásico no curable Mauricio Lema Medina MD Clínica...

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