RUTH VERAONCOLOGÍA MÉDICA CHN Madrid, 12 de Febrero de 2015

ENCAJE CLÍNICO DE AFLIBERCEPT EN EL CONTEXTO ACTUAL

DEL CCRM

5-FU/LV Capecitabine Irinotecan

Oxaliplatin Bevacizumab

Panitumumab

Cetuximab

Aflibercept

Regorafenib*

*Not approved by the EMA or for use in the Czech Republic

CÁNCER COLORRECTAL METASTÁSICO

Advances in the treatment of Stage IV CRC

1980 1985 1990 1995 2000 2005 2010 2015 +

BSC

5-FU

Irinotecan

CapecitabinaOxaliplatino

CetuximabBevacizumab

RegorafenibAflibercept

PanitumumabSurvival benefit

from 6 months to 24-30 months

Braun MS, et al. Ther Adv Med Oncol. 2011;3:43-52.

CONCEPTOS IMPORTANTES

2nd line

3rd line

1st line

70 %

CONDICIONADO POR LAS LÍNEAS

ANTERIORES

ESTRATEGIA “Continnium of care”

“GOALS”

• Prolongation of survival• Cure• Improving tumour-related symptoms• Stopping tumour progression• And/or Quality of life

“Backbone of first Chemotherapy”

• Fluoropiridin-based chemotherapy:

Oxaliplatin

Irinotecan

• Similar activity• Both partners for biological agents• Different toxicity profile

FOLFIRI → FOLFOX

FOLFOX → FOLFIRIR

“Exposure to All Drugs Is Important”

• Exposure to all three active cytotoxic drugs improves survival1

• No clear survival advantage to any one specific first-line regimen1

• The availability of biologic therapies has improved survival further

1. Grothey et al, J Clin Oncol 2004; 2. Falcone et al ASCO 2013; 3. Stintzing et al ASCO 2013, 4. Takahari et al ASCO 2013

Ox + iri

FU/Lv + iriIFL

FU/Lv + OxP=.0008

“ only trials with a combination of citotoxics and bilogical agents

… SURVIVAL > 24 months”

2nd line

3rd line

1st line

70 %

TRATAMIENTO DE SEGUNDA LÍNEA CON TERAPIAS ANTIEGFR

CETUXIMAB en 2ª Linea

EPIC (SOBRERO) Irinotecán vs Irinotecán + CETUXIMAB

ERBITUX + irinotecan

(n=648)Irinotecan

(n=650)Hazard

ratio p-value

ORR 16% 4% - <0.0001

PFS meses 4.0 2.6 0.69 ≤0.0001

OS, meses 10.7 10.0 0.975 0.71

47% CET 20% K-ras

13% BV previo

PEETERS (181) FOLFIRI vs FOLFIRI + PANITUMUMAB

TRATAMIENTO DE SEGUNDA LÍNEA CON TERAPIAS ANTIEGFR

PANITUMUMAB en 2ª Linea

Peeters M, et al. J Clin Oncol 2010; 28:4706-13.

Metastatic CRC

(n=1186)R

1:1

Stratification by:• ECOG score: 0-1 vs. 2• Prior oxaliplatin exposure for mCRC• Prior bevacizumab exposure for mCRC

End

of

treat

ment

Long

term follow

up

Study endpoints: PFS/OS (co-1°); ORR, safety, HRQoL

FOLFIRI (Q2W) +panitumumab 6 mg/kg

(Q2W*)

FOLFIRI (Q2W*)

Peeters M, et al. J Clin Oncol 2010; 28:4706-13.

Panitumumab + FOLFIRI(n = 303)

FOLFIRI(n = 294)

Median PFS, months 5.9 3.9

Hazard ratio (P-value)

0.73(P = 0.004)

Median OS, months 14.5 12.5

Hazard ratio (P-value)

0.85(P = 0.12)

ORR, n (%)(95% CI)

(35)(30–41)

(n = 297)

(10)(7–14)

(n = 285)

20050181 study RAS analysis

Peeters M, et al. J Clin Oncol 2014; 32 (suppl 3):LBA387 (and oral presentation).

Prevalence is defined as mutations detected in a population of WT KRAS exon 2 patients whose tissues were deemed evaluable

for RAS testing; #The KRAS exon 2 data is from the overall population; WT RAS, KRAS & NRAS exons 2/3/4

EXON 2# EXON 3 EXON 4EXON 1

12 13 61 117 146

EXON 2 EXON 3 EXON 4EXON 1

1213 61 117 146

44.9% 4.4% 7.7%

2.2% 5.6% 0%

59

59

12 13 61 117 14659

12 13 61 117 14659

NRAS

KRAS

18% (107/597) of WT KRAS exon 2 tumours have RAS mutations

Overall RAS ascertainment rate: 85%

20050181 study RAS analysis PFS (primary analysis)

Peeters M, et al. J Clin Oncol 2014; 32 (suppl 3):LBA387 (and oral presentation).

HR = 0.695 (95% CI, 0.536–0.903)

Log-rank p-value = 0.006

Eventsn (%)

Median (95% CI) months

Panitumumab + FOLFIRI (n = 204)

117 (57) 6.4 (5.5–7.4)

FOLFIRI (n = 211) 138 (65) 4.4 (3.7–5.5)

Months

20

40

60

80

100

90

70

50

30

10

Pro

po

rtio

n e

ven

t-fr

ee

(%

)

0

0 4 8 12 16 18141062

20050181 study RAS analysis OS (primary analysis)

Peeters M, et al. J Clin Oncol 2014; 32 (suppl 3):LBA387 (and oral presentation).

20

40

60

80

100

90

70

50

30

10

220 3082 4 6 10 12 14 18 20 24 26 28 32 3416

0

Months

Pro

po

rtio

n a

live

%

Eventsn (%)

Median (95% CI) months

Panitumumab + FOLFIRI (n = 204)

127 (62) 16.2 (14.5–19.7)

FOLFIRI (n = 211) 141 (67) 13.9 (11.9–16.1)

HR = 0.803 (95% CI, 0.629–1.024)

Log-rank p-value = 0.08

ECOG 3200 Folfox4 vs Folfox4 + BEVACIZUMAB (10 mg)

TML BEVACIZUMAB (5 mg) + Múltiples QT

TRATAMIENTO DE SEGUNDA LÍNEA CON TERAPIAS ANTIANGIOGENICAS

BEVACIZUMAB en 2ª Linea

Estudio ECOG E3200 (GIANTONIO)

Pacientes con CCRm tratados previamente con Fluoropirimidinas e Irinotecán

N= 820 pac.

BEVACIZUMAB

N= 243 pac.

Objetivo Primario: SG.Objetivo Secundario: SLP, TR y Seguridad.

FOLFOX4 + BEVACIZUMAB

N= 286 pac.

No estaba permitido el uso previo de Oxaliplatino o Bevacizumab.

FOLFOX4

N= 291 pac.

Giantonio et al. J Clin Oncol 2007; 25(12):1539-44

Giantonio et al. J Clin Oncol 2007; 25(12):1539-44

HR=0.61 HR=0.75

Régimen QT 2ª LineaBEV + QT(n=407) %

QT(n=407) %

QT basada en Irinotecan 43% 42% FOLFIRI (64) 16% (57) 14%

LV5FU2 + CPT11 (Douillard regimen1) (27) 7% (30) 7%

XELIRI (49) 12% (49) 12%

Other regimens (27) 7% (41) 10%

QT basada en Oxaliplatino 57% 58% FOLFOX4 (37) 9% (35) 9%

mFOLFOX4 (38) 9% (35) 9%

FOLFOX6 (64) 16% (53) 13%

FUFOX (23) 6% (37) 9%

XELOX (58) 14% (46) 11%

Other regimens (37) 9% (37) 9%

SG SLP

J. Bennouna. Lancet Oncology 2013; 14: 29-37

VELOUR FOLFIRI vs FOLFIRI+ AFLIBERCEPT

TRATAMIENTO DE SEGUNDA LÍNEA CON TERAPIAS ANTIANGIOGENICAS

AFLIBERCEPT en 2ª Linea

Estudio VELOUR

Pacientes con CCRm tras fallo a un régimen previo basado en oxaliplatino.

N= 1.226 pac.FOLFIRI + Aflibercept

N= 612 pac.

FOLFIRI

N= 614 pac.

R 1:1

Estratificación: ECOG: 0 vs. 1 vs. 2 Bevacizumab previo s/n

Objetivo Primario: SG.Objetivo Secundario: SLP, TR, Seguridad y FC

Van Cutsem et al, JCO 2012 Vol 30 (28): 3499-3506.

OS

HAY CONSENSO EN EL MANEJO DEL CCRm ?

ESMO

NCCN NICE

Group Clinical presentation Treatment goal Treatment intensity

GROUP 0 Clearly R0-resectable liver and/orlung metastases

Cure, decrease risk of relapse

Nothing or moderate (FOLFOX)

GROUP 1Not R0-resectable liver and/orlung metastases only, may become resectable after induction CT

Maximum tumor shrinkage

Upfront most active combination

GROUP 2Multiple metastases/sites, with rapid progression and/or tumor-related symptoms

Clinically relevant tumor shrinkage

as soon as possible, control PD

Upfront active combination: at

least doublet

GROUP 3Multiple metastases/sites with no option for resection and/or initially asymptomatic with limited risk for rapid deterioration

Prevent further progression, low

toxicity

Watchful waiting or sequential approach

(triplet regimens only in selected

patients)

ESMO guidelines: Treatment goals and strategies determined by patient and tumor characteristics

Schmoll H-J, et al. Ann Oncol 2012;23:2479–2516• CT, chemotherapy• PD, progressive disease

QT+ Biológico

• Ningún estudio de secuencia …

2ª Línea1ª Línea

Progresión

FOLFOX FOLFIRI

Anti-EGFR

Anti-VEGF

RAS wt

AFLIBERCEPT

5-FU/LV Capecitabine Irinotecan

Oxaliplatin Bevacizumab

Panitumumab

Cetuximab

Regorafenib* Aflibercept

• Importancia de la segunda línea en la estrategia de tratamiento (70% 2ª Línea)

• La elección de la 2ª línea va ligada directamente a la 1ª línea

• Aflibercept + FOLFIRI aumentan de forma significativa la Supervivencia Global, la Supervivencia libre de progresión y la Respuesta en pacientes con CCRm tratados previamente con un régimen basado en oxaliplatino (Nivel 1 de evidencia)

• Incluido en las Guías de NCCN, ESMO en base a su evidencia

• Hoy desconocemos la secuencia óptima de tratamiento

Conclusiones