I JORNADA DE ACTUALIZACIÓN E INNOVACIÓN EN ONCOLOGÍA

•

CANCER DE COLON Pilar Escudero HCU Lozano Blesa

Zaragoza, 20 de Enero 2015

Colorectal Cancer Epidemiology & Treatment Flow

Cueto C. et al. Journal of American colleage of surgery. Inpress 31-May-2011

SurgerySurgery

SurgerySurgery

Adjuvant Chemotherapy

65% Cured

Stage I Stage IIa Stage IIb Stage III Stage IV

15% 10% 35% 25%15%

progresions

Metastatic

Treated 1L

Treated 2L

Treated 3L

91%

53%

34% BSC

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.

mCRC

Heterogeneous disease

Elevada heterogeneidad:

Primario vs metástasisEntre las diferentes metástasis

En las localizaciones metastásicasGerlinger M, et al. N Engl J Med. 2012;366:883-892.

Diferencias entre colon derecho e izquierdo

Missiaglia E, et al. Proximal and distal colon tumors are distint biological entities and have different prognosis. ASCO 2013 (Abst. 3526).

Diferencias en la sensibilidad a cetuximab entre colon derecho e izquierdo

Brule Y et al. Location of colon cancer (right-sided [RC] versus left-sided [LC]) as a predictor of benefit from cetuximab (CET): NCIC CTG CO.17. J Clin Oncol 31, 2013 (suppl; abstr 3528).

DECISIÓN DEL TRATAMIENTO:

•FACTORES

•OBJETIVOS

Factores/Objetivos

Extensión de la enfermedad/Resecabilidad

Nordlinger et al, Ann Oncol 2009.

• Elección de quimioterapia:• Tipo:

• FOLFOX = FOLFIRI.• XELOX = FOLFOX.• XELIRI (posiblemente más tóxico).

• Contraindicaciones y tratamientos previos.

• La mayoría de los pacientes tolera un doblete de quimioterapia

• Quimioterapia más biológicos mejora los resultados:• Anti-EGFR (cetuximab, panitumumab)• Antiangiogénicos (bevacizumab, aflibercept)

PARADIGMAS EN EL TRATAMIENTO

ENSAYOS CLÍNICOS 1ª LÍNEA

ENSAYOS 2ª LÍNEA

Group Clinical presentation Treatment goalTreatment intensity

GROUP 0Clearly 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 3

Multiple 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

Factores/Objetivos

¿CUAL ES LA MEJOR OPCIÓN EN EL PACIENTE RAS NATIVO?

ANTIBODY NECESSARY IN 1st LINE TRETAMENT RAS WT mCRC?

BEVACIZUMAB

ANTIBODY NECESSARY IN 1st LINE TRETAMENT RAS WT mCRC?

EGFR INHIBITORS

ANTIBODY NECESSARY IN 1st LINE TRETAMENT RAS WT mCRC?

EGFR INHIBITORS

PEAK study

Karthaus M, et al. EJC 2013; 49 (suppl 3):abstract 2262 (and poster);Protocol ID: 20070509; ClinicalTrials.gov identifier: NCT00819780.

Metastatic CRCWT KRAS exon 2(n = 285)

1:1

mFOLFOX6 (Q2W) +panitumumab 6 mg/kg(Q2W)

mFOLFOX6 (Q2W) +bevacizumab 5 mg/kg(Q2W)

• Study endpoints: PFS (1°); OS, ORR, safety, exploratory biomarker analysis

• No formal hypothesis testing was planned

End

of

treatment

Safety

follow

up

Post

treatment

follow

up

End

of

study

30 days(+ 3 days)

Every 3 months (±28 days) until end of study

R

0

20

40

60

80

100

90

70

50

30

10

PEAK study RAS analysisPFS (longer follow-up analysis)

Karthaus M, et al. EJC 2013; 49 (suppl 3):abstract 2262 (and poster).

WT KRAS exon 2 WT RAS

Pro

port

ion

eve

nt-f

ree

(%)

Pro

port

ion

even

t-fr

ee (

%)

Months Months0 364 8 12 16 28 3220 24 40

HR* = 0.84 (95% CI, 0.64–1.11) P = 0.22

HR* = 0.66 (95% CI, 0.46–0.95) P = 0.03

0

20

40

60

80

100

90

70

50

30

10

0 324 8 12 16 20 24 28 36 40

Eventsn (%)

Median (95% CI)months

Panitumumab + mFOLFOX6 (n = 142)

100 (70) 10.9 (9.7–12.8)

Bevacizumab +mFOLFOX6 (n = 143)

108 (76) 10.1 (9.0–12.0)

Eventsn (%)

Median (95% CI) months

Panitumumab + mFOLFOX6 (n = 88)

57 (65) 13.0 (10.9–15.1)

Bevacizumab +mFOLFOX6 (n = 82)

66 (80) 10.1 (9.0–12.7)

PEAK study RAS analysis OS (longer follow-up analysis)

Karthaus M, et al. EJC 2013; 49 (suppl 3):abstract 2262 (and poster).

WT RASWT KRAS exon 2

Months Months

Pro

port

ion

aliv

e (%

)

Pro

port

ion

aliv

e (

%)

0

20

40

60

80

100

90

70

50

30

10

0 364 8 12 16 28 3220 24 40

HR* = 0.62 (95% CI, 0.44–0.89) P = 0.01

HR* = 0.63 (95% CI, 0.39–1.02) P = 0.05

44

Eventsn (%)

Median (95% CI) months

Panitumumab + mFOLFOX6 (n = 142)

52 (37) 34.2 (26.6–NR)

Bevacizumab +mFOLFOX6 (n = 143)

78 (55) 24.3 (21.0–29.2)

Eventsn (%)

Median (95% CI) months

Panitumumab + mFOLFOX6 (n = 88)

30 (34) 41.3 (28.8–41.3)

Bevacizumab +mFOLFOX6 (n = 82)

40 (49) 28.9 (23.9–31.3)

0 324 8 12 16 20 24 28 36 0

20

40

60

80

100

90

70

50

30

10

4440

FOLFIRI + Cetuximab

Cetuximab: 400 mg/m2 i.v. 120 min initial dose 250 mg/m2 i.v. 60 min q1wmCRC

1st-line therapyKRAS wild-type

N=592

Randomization1:1

Heinemann et al., ASCO 2013, # 3506

Key inclusion criteria - Patients >18 years with histologically confirmed diagnosis of mCRC - ECOG PS 0-2 - Prior adjuvant chemotherapy allowed if completed > 6 months before inclusion

FOLFIRI + Bevacizumab

Bevacizumab: 5 mg/kg i.v. 30-90 min initial q2w

FOLFIRI q2w: 5-FU: 400 mg/m2 (i.v. biolus); folinic acid: 400 mg/m2

Irinotecan: 180 mg/m2

5-FU: 2,400 mg/m2 (i.v. 46)

FIRE-3: Study design

Primary objective: Overall response rate (ORR)

Designed to detect a difference of 12% in ORR induced by FOLFIRI + cetuximab (62%) as compared to FOLFIRI + bevacizumab (50%)

284 evaluable patients per arm needed to achieve 80% power for a one-sided Fisher‘s exact test at alpha level of 2.5 %

∆ = 3,7 months

CALGB/SWOG 80405: <br /> FINAL DESIGN

Phase III 80405 Trial: First-line CT + Either Cetux or Bev in KRAS-WT mCRC (Expanded ras analyses)

Lenz H et al. ESMO, 2014.

Phase III 80405 Trial: First-line CT + Either Cetux or Bev in KRAS-WT mCRC (Expanded ras analyses)

Lenz H et al. ESMO, 2014.

80405: OBJECTIVE RESPONSE RATE *

N = 733 CHEMO + BEV

N = 369 (%)

CHEMO + CETUX N = 364 (%)

ORR 57% 66%

CR 3% 7.4%

PR 54% 58%

SD 37% 26%

PD 6% 8%

* INVESTIGATOR ASSESSMENT; DOCUMENTED, NOT AUDITED

HAY CONSENSO EN EL MANEJO DEL CCRm ?

2ª Línea1ª LíneaProgresión

Progresión

FOLFOX

FOLFIRI FOLFOX

FOLFIRI

Anti-EGFR

Anti-VEGF

1. Tournigand J Clin Oncol 2004; 2. NCCN Guidelines. Colon Cancer Version 3.2015; 3. Van Cutsem Ann Oncol. 2014.

RAS wt

RAS wt

CONCLUSIONES

HAY CONSENSO …La estrategia de tratamiento se basa en:- factores relacionados con el tumor (resecabilidad)- factores relacionados con el paciente (edad, ECOG)- objetivos que se deseen alcanzar

El CCR es una enfermedad muy heterogénea y subclasificaciones son necesarias.

HAY CONSENSO …