Presentación realizada por la Dra. Pilar Escudero del HCU Lozano Blesa, en el marco de la I Jornada de actualización e innovación en Oncología que tuvo lugar en el CIBA en enero de 2015.

1. I JORNADA DE ACTUALIZACIÓN E
INNOVACIÓN EN ONCOLOGÍA
•
CANCER DE COLON
Pilar Escudero
HCU Lozano Blesa
Zaragoza, 20 de Enero 2015

2. 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

4. Advances in the treatment of Stage IV CRC
1980 1985 1990 1995 2000 2005 2010 2015 +
BSC
5-FU
Irinotecan
Capecitabina
Oxaliplatino
Cetuximab
Bevacizumab
Regorafenib
Aflibercept
Panitumumab
Survival benefit
from 6 months to 24-30 months
Braun MS, et al. Ther Adv Med Oncol. 2011;3:43-52.

5. mCRC
Heterogeneous disease
Elevada heterogeneidad:
Primario vs metástasis
Entre las diferentes metástasis
En las localizaciones metastásicas
Gerlinger M, et al. N Engl J Med. 2012;366:883-892.

8. 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).

9. 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).

10. DECISIÓN DEL TRATAMIENTO:
•FACTORES
•OBJETIVOS

11. Factores/Objetivos

12. Extensión de la enfermedad/Resecabilidad
Nordlinger et al, Ann Oncol 2009.

13. • 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

14. ENSAYOS CLÍNICOS 1ª LÍNEA

15. ENSAYOS 2ª LÍNEA

16. Group Clinical presentation Treatment goal
Treatment
intensity
GROUP 0
Clearly R0-resectable liver and/or
lung metastases
Cure, decrease
risk of relapse
Nothing or
moderate (FOLFOX)
GROUP 1
Not R0-resectable liver and/or
lung metastases only, may become
resectable after induction CT
Maximum
tumor shrinkage
Upfront most active
combination
GROUP 2
Multiple 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

17. Factores/Objetivos

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

21. ANTIBODY NECESSARY IN 1st LINE TRETAMENT
RAS WT mCRC?
BEVACIZUMAB

22. ANTIBODY NECESSARY IN 1st LINE TRETAMENT
RAS WT mCRC?
EGFR INHIBITORS

23. ANTIBODY NECESSARY IN 1st LINE TRETAMENT
RAS WT mCRC?
EGFR INHIBITORS

25. PEAK study
Karthaus M, et al. EJC 2013; 49 (suppl 3):abstract 2262 (and poster);
Protocol ID: 20070509; ClinicalTrials.gov identifier: NCT00819780.
Metastatic CRC
WT 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
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30 days
(+ 3 days)
Every 3 months (±28 days)
until end of study
R

26. 0
20
40
60
80
100
90
70
50
30
10
PEAK study RAS analysis
PFS (longer follow-up analysis)
Karthaus M, et al. EJC 2013; 49 (suppl 3):abstract 2262 (and poster).
WT KRAS exon 2 WT RAS
Proportionevent-free(%)
Proportionevent-free(%)
Months Months
0 364 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
Events
n (%)
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)
Events
n (%)
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)

27. 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
Proportionalive(%)
Proportionalive(%)
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
Events
n (%)
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)
Events
n (%)
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

28. FOLFIRI + Cetuximab
Cetuximab: 400 mg/m2
i.v. 120 min initial dose
250 mg/m2
i.v. 60 min q1wmCRC
1st
-line therapy
KRAS wild-type
N=592
Randomization
1:1
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 %

31. ∆ = 3,7 months

32. CALGB/SWOG 80405: <br /> FINAL DESIGN

33. Phase III 80405 Trial: First-line CT + Either Cetux
or Bev in KRAS-WT mCRC (Expanded ras
analyses)
Lenz H et al. ESMO, 2014.

34. Phase III 80405 Trial: First-line CT + Either Cetux
or Bev in KRAS-WT mCRC (Expanded ras
analyses)
Lenz H et al. ESMO, 2014.

35. 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

36.  HAY CONSENSO EN EL
MANEJO DEL CCRm ?

42. 2ª Línea1ª Línea
Progresión
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

43.  CONCLUSIONES

44. 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

45. El CCR es una enfermedad muy
heterogénea y subclasificaciones son
necesarias.
HAY CONSENSO …