Transcript 95% CI
Slide 1
Construyendo el futuro del
cáncer colorrectal
metastásico paciente a
paciente
Dra. Antonieta Salud
H. Universitario Arnau de Vilanova de Lleida
Slide 2
Grupo 0: pacientes con enfermedad metastásica resecable
Grupo 1: pacientes con enfermedad potencialmente resecable con intención curativa después
de una disminución del tamaño de las metástasis con quimioterapia +/- terapia biológica de
inducción
Grupo 2: enfermedad diseminada, probablemente nunca será resecable
Grupo 3: enfermedad metastásica sin ninguna posibilidad de resección
OBJETIVOS
- Aumentar Supervivencia global
- Aumentar Beneficio Clínico
- Preservar la Calidad de Vida
- Aumentar la Resecabilidad
Annals of Oncology 00 (0): iii1–iii9, 2014
Slide 3
Slide 4
Construyendo el futuro del Cáncer colorrectal metastásico
paciente a paciente
os
Informal comparison as these are not head-to-head clinical trials
*KRAS WT population; #RAS WT population (WT in KRAS and NRAS exons 2, 3, and
4)
40m
1. N Engl J Med 2000; 343:905-14; 2. Lancet 2000; 355:1041-7; 3. J Clin Oncol 2004; 22:23-30; 4. N Engl J Med 2004; 350:2335-42; 5. J Clin Oncol 2008;
26:2013-9; 6. J Clin Oncol 2007; 25:1670-6; 7. J Clin Oncol 2011; 29:2011-9; 8. 1. Douillard JY, et al. N Engl J Med 2013; 369:1023-34;
Slide 5
(RAS)
Schmoll HJ, Annals of Oncol 2012
Slide 6
Construyendo el futuro del Cáncer colorrectal metastásico paciente a
paciente
Slide 7
Cáncer como tejido: Oportunidades para targeting
Hanahan and Weinberg. Cell 2000
Slide 8
Key signalling pathways in CRC tumorogenesis are
rational targets for therapy
HGF
Anti-c-MET
Onartuzumab
C-MET
Anti-EGFR
Cetuximab
Panitumumab
EGF
TGF-
HB-EGF
Epiregulin
EGFR
RAS
Anti-VEGF
Bevacizumab
Aflibercept
VEGF
PlGF
Anti-VEGFR
Regorafenib
Ramucirumab
VEGFR
PI13K
RAS
Normoxia
HIF-1α pVHL
Hypoxia
Proliferation
Survival
Transformation
RAF
Downstream
inhibitors of
MAPK/ERK
pathway under
development
e.g.
selumetinib
Src
PIP2
PTEN
MEK
Akt
ERK
Downstream
inhibitors of
PI3K pathway
under
PIP3
development
E.g. BKM120,
perifosine,
MK2206,
MTOR
everolimus,
Rictor
temsirolimus
MTOR
Raptor
p70s6k
Transcription of
growth factor genes
Adapted from
Siena, et al. JNCI 2009
Slide 9
Angiogénesis y crecimiento tumoral
La angiogénesis se activa cuando el tumor alcanza una masa crítica con
el fin de garantizar suficientes nutrientes y oxígeno.
Mutación
somática
Tumor
avascular
pequeño
El tumor secreta factores
proangiogénicos que
estimulan la angiogénesis
Crecimiento rápido del
tumor y la metástasis
Inhibidores angiogénicos
pueden revertir este proceso
Folkman J. N Engl J Med. 1971;285:1182-1186.
Slide 10
N Engl J Med 2014; 371:1609-18
Slide 11
2013
Clinical Colorectal Cancer 2013
Slide 12
TRIBE: study design
Previously
untreated,
unresectable mCRC
(n=508)
Induction
Maintenance
Avastin
+ FOLFIRI*
Avastin + 5-FU/LV
PD
Avastin
+ FOLFOXIRI*
Avastin + 5-FU/LV
PD
R
*Up to 12 cycles
•
The TRIBE study is a phase III, randomised, multicentre, open-label study of
1L Avastin + FOLFOXIRI or FOLFIRI followed by Avastin until PD
•
•
Primary endpoint: PFS
Secondary endpoints: ORR, secondary R0 resection rate, OS, safety,
biomarker evaluation
•
This was a retrospective analysis of impact of early tumour shrinkage (ETS)
and deepness of response (DoR) on survival
Cremolini, et al. ASCO GI 2014. Abstract 521
Slide 13
TRIBE: (Primary endpoint) 1L FOLFOXIRI + Avastin
compared to FOLFIRI + Avastin
N
FOLFIRI + bev
Arm A
Median PFS
FOLFOXIRI + bev
Arm B
Median PFS
HR [95% CI]
0.75 [0.62-0.90]
p value
0.003
ITT population
508
9.7
12.1
RAS&BRAF
evaluable
375
10.3
12.1
0.80 [0.64-0.99]
RAS mutated
218
9.5
12.0
0.82 [0.61-1.09]
BRAF mutated
28
5.5
7.5
0.55 [0.26-1.18]
All wt patients
129
11.3
13.3
0.75 [0.52-1.10]
Cremolini et al O-007. Presented at WCGIC 2014.
Slide 14
TRIBE: Predictive impact - OS
100
N
FOLFIRI +
bev
Arm A
Median OS
FOLFOXIRI +
bev
Arm B
Median OS
HR [95% CI]
ITT population
508
25.8
31.0
0.79 [0.63-1.00]
RAS&BRAF
evaluable
375
25.8
31.0
0.86 [0.65-1.12]
RAS mutated
218
23.1
28.6
0.86 [0.60-1.22]
BRAF mutated
28
10.8
19.1
0.55 [0.24-1.23]
All wt patients
129
34.4
41.7
0.85 [0.52-1.39]
Percent survival
75
RAS mutated – FOLFOXIRI plus bev
50
RAS mutated – FOLFIRI plus bev
BRAF mutated – FOLFOXIRI plus bev
25
BRAF mutated – FOLFIRI plus bev
0
0
20
40
Months
60
All wt – FOLFOXIRI plus bev
All wt – FOLFIRI plus bev
Cremolini et al O-007. Presented at WCGIC 2014.
Slide 15
TML18147 (Avastin + CT continued beyond first PD in
mCRC): outcomes by KRAS status* and 1L CT
backbone
Avastin + 1L doublet CT
(ITT n=820;
exploratory analysis n=616ǂ)
ǂn=316
KRAS WT; n=300 KRAS MT;
n=355 1L irinotecan; n=261 1L oxaliplatin
1L irinotecan
Median OS, mos
Median PFS, mos
ORR, %
DCR, %
1L oxaliplatin
Median OS, mos
Median PFS, mos
ORR, %
DCR, %
PD
CT switch:
Ox→ Iri;
Iri → Ox
KRAS WT
CT
Avastin + CT
(n=95)
(n=94)
11.4
14.3
4.6
5.8*
7.4
6.4
56.8
74.5
(n=70)
(n=57)
11.0
15.8
4.4
8.1*
2.9
9.1
65.2
72.7
2L doublet CT
(n=411)
PD
Avastin + 2L doublet CT
(n=409)
PD
R
KRAS MT
CT
Avastin + CT
(n=74)
(n=92)
8.5
10.0
3.8
4.8*
2.7
3.3
50.7
65.3
(n=62)
(n=72)
10.6
11.6
4.3
6.1*
3.3
4.2
62.3
75.0
CT
(n=236)
9.3
3.8
4.7
49.1
(n=174)
10.0
4.2
2.9
59.9
ITT
Avastin + CT
(n=240)
10.9*
5.4*
5.4
66.1
(n=169)
12.0
6.2*
5.5
70.9
*p < 0.05 vs CT alone.
*Scorpion ARMS test for KRAS codons 12 and 13; §p<0.05 vs CT alone
Kubicka, et al. ASCO GI 2014. Abstract 520
Slide 16
Mecanismos de escape a tratamientos anti-VEGF-A
Células tumorales
Agentes anti-VEGF-A
VEGF-A
PlGF
Bevacizumab
Sutinib
Sorafenib, etc..
Producción elevada
VEGF-B
Mecanismos compensatorios
de resistencia al tratamiento
Crecimiento tumoral
independiente de VEGF-A
o
o
El bloqueo mantenido de VEGF-A aumenta los niveles de PlGF y VEGF-B1.
o
El bloqueo simultáneo de VEGF-A, VEGF-B y PlGF podría ser una estrategia
clínicamente efectiva1. Aflibercept está diseñado para bloquear todas las isoformas
de: VEGF-A; VEGF-B y PIGF2.
Niveles elevados de VEGF-B y PlGF se relacionan con mecanismos de escape a
tratamientos anti-VEGF-A1.
1. Yihao Cao et al. Science Signaling 2009, 2 (59):1-11
2.Tew. Clin Cancer Res. 2010;16:358-366.
Slide 17
First-line treatment with regorafenib in combination with mFOLFOX6 for
metastatic colorectal cancer : A single-arm, open-label phase II clinical trial
EFFICACY
• KRAS/BRAF/NRAS/PIK3CA status was assessed in 24
patients. Responses were noted in KRAS WT and mutated,
MRAS mutated and BRAF mutated patients. However,
patient numbers were too small to draw conclusions. There
were only 2 NRAS MUT and 1 BRAF MUT patients in the
ITT population.
Efficacy
SAFETY
• TEAEs and drug-related TEAEs were reported in 53 (100%)
patients. Serious TEAEs were reported in 21 patients (40%). No
patients died as a result of AEs. Drug-related serious TEAEs were
reported in 13 patients (25%). AEs leading to discontinuation of a
component of study treatment were reported in 19 patients (36%),
and of full study treatment in 4 patients (8%).
(n=41)
Any Grade
Grade 3
Grade 4
Diarrhea
70%
23%
0%
0%
Decreased neutrophil count
64%
25%
15%
PR
44%
Fatigue
64%
4%
0%
SD
41%
Hypertension
55%
255
4%
Paresthesia
535
9%
0%
Abdominal pain
51%
4%
0%
Nausea
49%
2%
0%
Decreased platelet count
47%
8%
0%
Oral mucositis
45%
2%
0%
Peripheral neuropathy
45%
13%
0%
Anorexia
36%
2%
0%
HFSR
36%
4%
0%
ORR
44%
Safety (n=53)
DCR
85%
CR
Median duration of SD, 95% CI
PD
Response not evaluable, n (%)
Median PFS (n=54), 95% CI
Median OS (n=54), 95% CI
7.6 months
(5.5–8.5)
12%
1 (2%)
8.5 months
(7.4–11.3)
NYR
CONCLUSION: Regorafenib + mFOLFOX6 has clinical activity and resulted
in tumor responses. The regimen had acceptable safety as first-line
Argilés et al. abstract 2367. Esmo 2013
treatment for mCRC.
Off- label
Regorafenib está autorizado en 3ª ó > líneas.
Slide 18
RAISE: A Randomized, Double-blind, Multicenter Phase
III Study of Irinotecan, Folinic Acid, and 5-Fluorouracil
(FOLFIRI) Plus Ramucirumab or Placebo in Patients
with Metastatic Colorectal Carcinoma Progression
During or Following First-line Combination Therapy
with Bevacizumab, Oxaliplatin, and a Fluoropyrimidine
- VEGF and VEGFR-2–mediated signaling and angiogenesis are
important in CRC tumor growth and are established therapeutic targets
- Ramucirumab is a recombinant human IgG1 monoclonal antibody that
binds to the extracellular domain of VEGFR-2, preventing ligand binding
and receptor activation
Josep Tabernero*, Allen Lee Cohn, Radka Obermannova, Gyorgy Bodoky, Rocio Garcia-Carbonero, Tudor-Eliade Ciuleanu, David C. Portnoy, Eric Van Cutsem, Axel
Grothey, Jana Prausová, Pilar Garcia-Alfonso, Kentaro Yamazaki, Philip R. Clingan, Vittorina Zagonel, Tae Won Kim, Lorinda Simms, Shao-Chun Chang, Federico
Nasroulah, Takayuki Yoshino
*On behalf of the RAISE Investigators
Off- Label
Slide 19
RAISE: Overall Survival and Progression-free Survival
Ramucirumab + FOLFIRI
N=536
Placebo + FOLFIRI
N=536
13.3
11.7
(12.4, 14.5)
(10.8, 12.7)
Median, months
(95% CI)
HR (95% CI)
P-value (log-rank)
Median, months
(95% CI)
HR (95% CI)
P-value (logrank)
0.84 (0.73, 0.98) (stratified)
0.0219 (stratified)
Ramucirumab +
FOLFIRI
N=536
Placebo +
FOLFIRI
N=536
5.7
4.5
(5.5, 6.2)
(4.2, 5.4)
0.79 (0.70, 0.90) (stratified)
0.0005 (stratified)
— Ramucirumab + FOLFIRI
— Placebo + FOLFIRI
Off- Label
Abbreviations: CI=confidence interval; HR=hazard ratio; Ram=ramucirumab.
Slide 20
RAISE- Conclusions
• RAISE met its primary endpoint.
– Demonstrated a statistically significant improvement
in overall survival for ramucirumab and FOLFIRI vs
placebo and FOLFIRI
– In second-line metastatic CRC patients who
progressed after first-line treatment with
bevacizumab, oxaliplatin, and a fluoropyrimidine
• Consistent survival benefits were observed across
subgroups.
• Ramucirumab in combination with FOLFIRI was well
tolerated in patients with mCRC. Overall, the adverse
events were considered manageable.
Off- Label
Slide 21
Tratamiento de mantenimiento en CCRm
Tumores irresecables
¿PREGUNTAS?
• Tratar hasta progresión o mantenimiento ?
• Mantenimiento con fluoropirimidinas +
biológicos / biológicos / fluoropirimidinas?
• ¿Qué pacientes se benefician de un
mantenimiento?
• Precio biológicos muy elevado
Slide 22
CAIRO3: study design
PFS1
PFS2
TT2PD
Arm A
Previously
untreated
mCRC
(n=558)
Avastin +
XELOX
(x6)
CR
PR
SD
Observation
(n=279)
PD1
Avastin +
XELOX (n=168)
PD2
Avastin +
Xeloda (n=279)
PD1
Avastin +
XELOX (n=132)
PD2
R
Median follow-up 48 months (cut-off 060114)
Arm B
•
•
•
•
•
The CAIRO3 study is a phase III, randomised, multicentre (74 Dutch hospitals), open-label study
of maintenance Avastin + Xeloda after induction with Avastin + XELOX in mCRC
Primary endpoint: PFS2 (PFS after re-introduction of Avastin + XELOX)
Secondary endpoints: PFS1, OS, TT2PD, ORR, safety
PFS2 was considered to be equal to PFS1 for patients in whom Avastin + XELOX was not
reintroduced after PFS1 for any reason
Upon PD1, 60% of patients received Avastin + XELOX in arm A and 47% in arm B
Koopman, et al. ASCO GI 2014. Abstract LBA388
Slide 23
CAIRO3: patients with a CR/PR as best response on
induction treatment benefit most from maintenance
Avastin + Xeloda in terms of OS
Median
CR/PR (n=366)
1.0
SD (n=191)
0S estimate
0.8
0.6
Observation
18.8 months
Maintenance
24.1 months
Observation
15.2 months
Maintenance
16.9 months
p-value
<0.0001
Induction treatment of 6x cycles Avastin + XELOX
prior to randomisation not included (4-5 months)
0.4
0.2
16.9
15.2
0
0
12
18.8
24.1
24
36
48
60
11
3
11
2
2
0
4
0
Time (months)
No. at
risk:
184
95
182
96
136
62
140
66
65
24
86
26
26
9
32
7
CR-PR/O
SD/O
CR-PR/M
SD/M
Koopman, et al. ASCO GI 2014. Abstract LBA388
Slide 24
EGFR activation may involve downstream signalling pathways that
include RAS proteins
Berg M, Soreide K. Discovery medicine 2012; 14:207-14; Di Fiore F, et al. Br J Cancer 2010;
103:1765-72;
Han W, Lo HW. Cancer Lett 2012; 318:124-34; Herbst RS, Shin DM. Cancer 2002; 94:1593-611.
Slide 25
PRIME RAS/RAF
Results (WT RAS & WT/MT BRAF)
Pmab + FOLFOX
(n=320)
FOLFOX
(n=321)
HR
(95% CI)
Descriptive pvalue
228
218
-
-
Median OS - mos
(95% CI)
28.3
(23.7–NE)
20.9
(18.4–23.8)
0.74
(0.57–0.96)
0.02
Median PFS mos (95% CI)
10.8
(9.4–12.4)
9.2
(7.4–9.6)
0.68
(0.54–0.87)
<0.01
24
29
-
-
Median OS - mos
(95% CI)
10.5
(6.4–18.9)
9.2
(8.0–15.7)
0.90
(0.46–1.76)
0.76
Median PFS mos (95% CI)
6.1
(3.7–10.7)
5.4
(3.3–6.2)
0.58
(0.29–1.15)
0.12
WT RASa &
BRAF, n
MT BRAF, n
aWT
in KRAS and NRAS exons 2, 3, and 4. (RAS ascertainment rate 90%)
Panitumumab está autorizado solo para pacientes RAS nativos
Based on Douillard JY, et al. N Engl J Med 2013; 369:1023-34
Slide 26
PEAK study RAS analysis
OS
WT KRAS exon 2
WT RAS
0 4 8 12 16 20 24 28 32 36 40 44
Months
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)
100
90
80
70
60
50
40
30
20
10
0
Proportion alive (%)
HR* = 0.62 (95% CI, 0.44–0.89)
P = 0.009
Proportion alive (%)
100
90
80
70
60
50
40
30
20
10
0
HR* = 0.63 (95% CI, 0.39–1.02)
P = 0.058
0 4 8 12 16 20 24 28 32 36 40 44
Months
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)
*Stratified Cox proportional hazards model; No formal hypothesis testing was planned; WT RAS, WT KRAS & NRAS exons 2/3/4;
NR, not reached
Panitumumab está autorizado solo para pacientes RAS nativos
Schwartzberg L, et al. J Clin Oncol 31, 2013 (suppl; abstr 3631 and poster).
Slide 27
Cetuximab está autorizado solo para pacientes RAS nativos
Presented By Alan Venook at 2014 ASCO Annual Meeting
Slide 28
“The exposure to all three cytotoxics (FP,
oxaliplatin and irinotecan) in various sequences
may result in the longest survival”
“Only trials with a combination of cytotoxics
and a biological targeted treatment consistently
reported median survival exceeding 24 months”
Annals of Oncology 00 (0): iii1–iii9, 2014
Slide 29
Detección de nuevas resistencias/mutaciones primarias o
secundarias?
Cetuximab treatment
mutations in EGFR, KRAS, NRAS, BRAF and
PIK3CA genes, including novel EGFR mutations (R451C and K467T).
Functionally, EGFR mutations prevent binding to cetuximab but a subset is
permissive for interaction with panitumumab
1.Montagut C, et al. Nat Med 2012; 18:221-3
2.Arenas S, et al. Clin Cancer Res 2015
Slide 30
Construyendo el futuro del Cáncer colorrectal metastásico paciente a
paciente
Bardelli, JCO 2010
Slide 31
Construyendo el futuro del Cáncer colorrectal metastásico paciente a
paciente: combinación de fármacos?
• AntiEGFR + inhibidores BRAF?
• AntiEGFR + inhibidores de MET?
Slide 32
Construyendo el futuro del Cáncer colorrectal metastásico paciente a
paciente: nuevas combinaciones de fármacos?
Antitumor effects of dabrafenib, trametinib, and panitumumab as single agents and in
combination in BRAF-mutant colorectal carcinoma (CRC) models
Abstract number: 3513. Author: LI Liu
Efficacy and tolerability in an open-label phase I/II study of MEK inhibitor trametinib (T), BRAF
inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P) in combination in patients
(pts) with BRAF V600E mutated colorectal cancer (CRC)
Abstract number: 3515 . Author: Johanna C. Bendell
Phase I study of the selective BRAFV600 inhibitor encorafenib (LGX818) combined with
cetuximab and with or without the α-specific PI3K inhibitor BYL719 in patients with advanced
BRAF-mutant colorectal cancer
Abstract number: 3514 . Author: Robin Van Geel
Phase 1B study of vemurafenib in combination with irinotecan and cetuximab in patients with
BRAF-mutated advanced cancers and metastatic colorectal cancer
Abstract number: 3516 . Author: David S. Hong
VE-BASKET, a Simon 2-stage adaptive design, phase II, histology-independent study in
nonmelanoma solid tumors harboring BRAF V600 mutations (V600m): Activity of vemurafenib
(VEM) with or without cetuximab (CTX) in colorectal cancer (CRC)
Abstract number: 3518^ . Author: Josep Tabernero
ONC-2012-001: A single-arm phase II study of tivantinib (ARQ 197) plus cetuximab in EGFR
inhibitor-resistant MET high patients (pts) with locally advanced or metastatic colorectal cancer
(CRC) with wild-type KRAS
Abstract number: TPS3661 . Author: Lorenza Rimassa
ASCO
2014
Slide 33
Construyendo el futuro del Cáncer colorrectal metastásico paciente a
paciente: nuevas combinaciones de fármacos?
Pilot study of vemurafenib and panitumumab combination therapy in patients with
BRAF V600E mutated metastatic colorectal cancer
Abstract number: 611. Author: Rona D. Yaeger
S1406: Randomized phase II study of irinotecan and cetuximab with or without
vemurafenib in BRAF-mutant metastatic colorectal cancer (mCRC)
Abstract number: TPS790. Author: Scott Kopetz
Clinical and molecular characterization of refractory BRAF mutant metastatic colorectal
carcinoma (mCRC): Vall d’Hebron Institute of Oncology phase I program cohort
Abstract number: 587. Author: Enrique Sanz-Garcia
Clinical impact of expanded BRAF mutational status on the outcome for metastatic
colorectal cancer patients with anti-EGFR antibody: An analysis of the BREAC trial
(Biomarker Research for Anti-EGFR Monoclonal Antibodies by Comprehensive Cancer
Genomics)
Abstract number: 573. Author: Kentaro Yamazaki
Acquired mutations in MAPK signaling pathway following initial pharmacological
response in BRAF-mutated metastatic colorectal cancer (mCRC)
Abstract number: 629. Author: Van Karlyle Morris
Pilot Trial of combined BRAF and EGFR inhibition in BRAF mutant metastatic
colorectal cancer patients. Yaeger R et al. Clin Cancer Res 2015
ASCO GI
2015
Slide 34
Construyendo el futuro del Cáncer colorrectal metastásico
paciente a paciente: nuevas combinaciones de fármacos?
Slide 35
Inmunoterapia en cáncer colorrectal
Enfoque Anti-PD-L1
Koido S et al. World J Gastroenterol 2013;19: 8531-8542
Slide 36
Anti-CTLA-4/Anti-PD-1/Anti-PD-L-1 Mechanism of
Action
Momtaz P et al. Pharmgenomics Pers Med 2014; 7: 357-365
Slide 37
El CCR: una prioridad sanitaria
o
o
El cáncer de pulmón, CCR y de
mama son los responsables del
mayor número de años de vida
perdidos ajustado por mortalidad
y por discapacidad.
Carga del cáncer en España
El CCR, debido tanto a la mortalidad
como a la discapacidad asociada,
ocupa la segunda posición en la
carga económica del total de
cánceres en España.
Incidencia
CCR es el más frecuente en España
BMC Public Health 2009, 9:42
Slide 38
Construyendo el futuro del
cáncer colorrectal
metastásico paciente a
paciente
Dra. Antonieta Salud
H. Universitario Arnau de Vilanova de Lleida
Slide 2
Grupo 0: pacientes con enfermedad metastásica resecable
Grupo 1: pacientes con enfermedad potencialmente resecable con intención curativa después
de una disminución del tamaño de las metástasis con quimioterapia +/- terapia biológica de
inducción
Grupo 2: enfermedad diseminada, probablemente nunca será resecable
Grupo 3: enfermedad metastásica sin ninguna posibilidad de resección
OBJETIVOS
- Aumentar Supervivencia global
- Aumentar Beneficio Clínico
- Preservar la Calidad de Vida
- Aumentar la Resecabilidad
Annals of Oncology 00 (0): iii1–iii9, 2014
Slide 3
Slide 4
Construyendo el futuro del Cáncer colorrectal metastásico
paciente a paciente
os
Informal comparison as these are not head-to-head clinical trials
*KRAS WT population; #RAS WT population (WT in KRAS and NRAS exons 2, 3, and
4)
40m
1. N Engl J Med 2000; 343:905-14; 2. Lancet 2000; 355:1041-7; 3. J Clin Oncol 2004; 22:23-30; 4. N Engl J Med 2004; 350:2335-42; 5. J Clin Oncol 2008;
26:2013-9; 6. J Clin Oncol 2007; 25:1670-6; 7. J Clin Oncol 2011; 29:2011-9; 8. 1. Douillard JY, et al. N Engl J Med 2013; 369:1023-34;
Slide 5
(RAS)
Schmoll HJ, Annals of Oncol 2012
Slide 6
Construyendo el futuro del Cáncer colorrectal metastásico paciente a
paciente
Slide 7
Cáncer como tejido: Oportunidades para targeting
Hanahan and Weinberg. Cell 2000
Slide 8
Key signalling pathways in CRC tumorogenesis are
rational targets for therapy
HGF
Anti-c-MET
Onartuzumab
C-MET
Anti-EGFR
Cetuximab
Panitumumab
EGF
TGF-
HB-EGF
Epiregulin
EGFR
RAS
Anti-VEGF
Bevacizumab
Aflibercept
VEGF
PlGF
Anti-VEGFR
Regorafenib
Ramucirumab
VEGFR
PI13K
RAS
Normoxia
HIF-1α pVHL
Hypoxia
Proliferation
Survival
Transformation
RAF
Downstream
inhibitors of
MAPK/ERK
pathway under
development
e.g.
selumetinib
Src
PIP2
PTEN
MEK
Akt
ERK
Downstream
inhibitors of
PI3K pathway
under
PIP3
development
E.g. BKM120,
perifosine,
MK2206,
MTOR
everolimus,
Rictor
temsirolimus
MTOR
Raptor
p70s6k
Transcription of
growth factor genes
Adapted from
Siena, et al. JNCI 2009
Slide 9
Angiogénesis y crecimiento tumoral
La angiogénesis se activa cuando el tumor alcanza una masa crítica con
el fin de garantizar suficientes nutrientes y oxígeno.
Mutación
somática
Tumor
avascular
pequeño
El tumor secreta factores
proangiogénicos que
estimulan la angiogénesis
Crecimiento rápido del
tumor y la metástasis
Inhibidores angiogénicos
pueden revertir este proceso
Folkman J. N Engl J Med. 1971;285:1182-1186.
Slide 10
N Engl J Med 2014; 371:1609-18
Slide 11
2013
Clinical Colorectal Cancer 2013
Slide 12
TRIBE: study design
Previously
untreated,
unresectable mCRC
(n=508)
Induction
Maintenance
Avastin
+ FOLFIRI*
Avastin + 5-FU/LV
PD
Avastin
+ FOLFOXIRI*
Avastin + 5-FU/LV
PD
R
*Up to 12 cycles
•
The TRIBE study is a phase III, randomised, multicentre, open-label study of
1L Avastin + FOLFOXIRI or FOLFIRI followed by Avastin until PD
•
•
Primary endpoint: PFS
Secondary endpoints: ORR, secondary R0 resection rate, OS, safety,
biomarker evaluation
•
This was a retrospective analysis of impact of early tumour shrinkage (ETS)
and deepness of response (DoR) on survival
Cremolini, et al. ASCO GI 2014. Abstract 521
Slide 13
TRIBE: (Primary endpoint) 1L FOLFOXIRI + Avastin
compared to FOLFIRI + Avastin
N
FOLFIRI + bev
Arm A
Median PFS
FOLFOXIRI + bev
Arm B
Median PFS
HR [95% CI]
0.75 [0.62-0.90]
p value
0.003
ITT population
508
9.7
12.1
RAS&BRAF
evaluable
375
10.3
12.1
0.80 [0.64-0.99]
RAS mutated
218
9.5
12.0
0.82 [0.61-1.09]
BRAF mutated
28
5.5
7.5
0.55 [0.26-1.18]
All wt patients
129
11.3
13.3
0.75 [0.52-1.10]
Cremolini et al O-007. Presented at WCGIC 2014.
Slide 14
TRIBE: Predictive impact - OS
100
N
FOLFIRI +
bev
Arm A
Median OS
FOLFOXIRI +
bev
Arm B
Median OS
HR [95% CI]
ITT population
508
25.8
31.0
0.79 [0.63-1.00]
RAS&BRAF
evaluable
375
25.8
31.0
0.86 [0.65-1.12]
RAS mutated
218
23.1
28.6
0.86 [0.60-1.22]
BRAF mutated
28
10.8
19.1
0.55 [0.24-1.23]
All wt patients
129
34.4
41.7
0.85 [0.52-1.39]
Percent survival
75
RAS mutated – FOLFOXIRI plus bev
50
RAS mutated – FOLFIRI plus bev
BRAF mutated – FOLFOXIRI plus bev
25
BRAF mutated – FOLFIRI plus bev
0
0
20
40
Months
60
All wt – FOLFOXIRI plus bev
All wt – FOLFIRI plus bev
Cremolini et al O-007. Presented at WCGIC 2014.
Slide 15
TML18147 (Avastin + CT continued beyond first PD in
mCRC): outcomes by KRAS status* and 1L CT
backbone
Avastin + 1L doublet CT
(ITT n=820;
exploratory analysis n=616ǂ)
ǂn=316
KRAS WT; n=300 KRAS MT;
n=355 1L irinotecan; n=261 1L oxaliplatin
1L irinotecan
Median OS, mos
Median PFS, mos
ORR, %
DCR, %
1L oxaliplatin
Median OS, mos
Median PFS, mos
ORR, %
DCR, %
PD
CT switch:
Ox→ Iri;
Iri → Ox
KRAS WT
CT
Avastin + CT
(n=95)
(n=94)
11.4
14.3
4.6
5.8*
7.4
6.4
56.8
74.5
(n=70)
(n=57)
11.0
15.8
4.4
8.1*
2.9
9.1
65.2
72.7
2L doublet CT
(n=411)
PD
Avastin + 2L doublet CT
(n=409)
PD
R
KRAS MT
CT
Avastin + CT
(n=74)
(n=92)
8.5
10.0
3.8
4.8*
2.7
3.3
50.7
65.3
(n=62)
(n=72)
10.6
11.6
4.3
6.1*
3.3
4.2
62.3
75.0
CT
(n=236)
9.3
3.8
4.7
49.1
(n=174)
10.0
4.2
2.9
59.9
ITT
Avastin + CT
(n=240)
10.9*
5.4*
5.4
66.1
(n=169)
12.0
6.2*
5.5
70.9
*p < 0.05 vs CT alone.
*Scorpion ARMS test for KRAS codons 12 and 13; §p<0.05 vs CT alone
Kubicka, et al. ASCO GI 2014. Abstract 520
Slide 16
Mecanismos de escape a tratamientos anti-VEGF-A
Células tumorales
Agentes anti-VEGF-A
VEGF-A
PlGF
Bevacizumab
Sutinib
Sorafenib, etc..
Producción elevada
VEGF-B
Mecanismos compensatorios
de resistencia al tratamiento
Crecimiento tumoral
independiente de VEGF-A
o
o
El bloqueo mantenido de VEGF-A aumenta los niveles de PlGF y VEGF-B1.
o
El bloqueo simultáneo de VEGF-A, VEGF-B y PlGF podría ser una estrategia
clínicamente efectiva1. Aflibercept está diseñado para bloquear todas las isoformas
de: VEGF-A; VEGF-B y PIGF2.
Niveles elevados de VEGF-B y PlGF se relacionan con mecanismos de escape a
tratamientos anti-VEGF-A1.
1. Yihao Cao et al. Science Signaling 2009, 2 (59):1-11
2.Tew. Clin Cancer Res. 2010;16:358-366.
Slide 17
First-line treatment with regorafenib in combination with mFOLFOX6 for
metastatic colorectal cancer : A single-arm, open-label phase II clinical trial
EFFICACY
• KRAS/BRAF/NRAS/PIK3CA status was assessed in 24
patients. Responses were noted in KRAS WT and mutated,
MRAS mutated and BRAF mutated patients. However,
patient numbers were too small to draw conclusions. There
were only 2 NRAS MUT and 1 BRAF MUT patients in the
ITT population.
Efficacy
SAFETY
• TEAEs and drug-related TEAEs were reported in 53 (100%)
patients. Serious TEAEs were reported in 21 patients (40%). No
patients died as a result of AEs. Drug-related serious TEAEs were
reported in 13 patients (25%). AEs leading to discontinuation of a
component of study treatment were reported in 19 patients (36%),
and of full study treatment in 4 patients (8%).
(n=41)
Any Grade
Grade 3
Grade 4
Diarrhea
70%
23%
0%
0%
Decreased neutrophil count
64%
25%
15%
PR
44%
Fatigue
64%
4%
0%
SD
41%
Hypertension
55%
255
4%
Paresthesia
535
9%
0%
Abdominal pain
51%
4%
0%
Nausea
49%
2%
0%
Decreased platelet count
47%
8%
0%
Oral mucositis
45%
2%
0%
Peripheral neuropathy
45%
13%
0%
Anorexia
36%
2%
0%
HFSR
36%
4%
0%
ORR
44%
Safety (n=53)
DCR
85%
CR
Median duration of SD, 95% CI
PD
Response not evaluable, n (%)
Median PFS (n=54), 95% CI
Median OS (n=54), 95% CI
7.6 months
(5.5–8.5)
12%
1 (2%)
8.5 months
(7.4–11.3)
NYR
CONCLUSION: Regorafenib + mFOLFOX6 has clinical activity and resulted
in tumor responses. The regimen had acceptable safety as first-line
Argilés et al. abstract 2367. Esmo 2013
treatment for mCRC.
Off- label
Regorafenib está autorizado en 3ª ó > líneas.
Slide 18
RAISE: A Randomized, Double-blind, Multicenter Phase
III Study of Irinotecan, Folinic Acid, and 5-Fluorouracil
(FOLFIRI) Plus Ramucirumab or Placebo in Patients
with Metastatic Colorectal Carcinoma Progression
During or Following First-line Combination Therapy
with Bevacizumab, Oxaliplatin, and a Fluoropyrimidine
- VEGF and VEGFR-2–mediated signaling and angiogenesis are
important in CRC tumor growth and are established therapeutic targets
- Ramucirumab is a recombinant human IgG1 monoclonal antibody that
binds to the extracellular domain of VEGFR-2, preventing ligand binding
and receptor activation
Josep Tabernero*, Allen Lee Cohn, Radka Obermannova, Gyorgy Bodoky, Rocio Garcia-Carbonero, Tudor-Eliade Ciuleanu, David C. Portnoy, Eric Van Cutsem, Axel
Grothey, Jana Prausová, Pilar Garcia-Alfonso, Kentaro Yamazaki, Philip R. Clingan, Vittorina Zagonel, Tae Won Kim, Lorinda Simms, Shao-Chun Chang, Federico
Nasroulah, Takayuki Yoshino
*On behalf of the RAISE Investigators
Off- Label
Slide 19
RAISE: Overall Survival and Progression-free Survival
Ramucirumab + FOLFIRI
N=536
Placebo + FOLFIRI
N=536
13.3
11.7
(12.4, 14.5)
(10.8, 12.7)
Median, months
(95% CI)
HR (95% CI)
P-value (log-rank)
Median, months
(95% CI)
HR (95% CI)
P-value (logrank)
0.84 (0.73, 0.98) (stratified)
0.0219 (stratified)
Ramucirumab +
FOLFIRI
N=536
Placebo +
FOLFIRI
N=536
5.7
4.5
(5.5, 6.2)
(4.2, 5.4)
0.79 (0.70, 0.90) (stratified)
0.0005 (stratified)
— Ramucirumab + FOLFIRI
— Placebo + FOLFIRI
Off- Label
Abbreviations: CI=confidence interval; HR=hazard ratio; Ram=ramucirumab.
Slide 20
RAISE- Conclusions
• RAISE met its primary endpoint.
– Demonstrated a statistically significant improvement
in overall survival for ramucirumab and FOLFIRI vs
placebo and FOLFIRI
– In second-line metastatic CRC patients who
progressed after first-line treatment with
bevacizumab, oxaliplatin, and a fluoropyrimidine
• Consistent survival benefits were observed across
subgroups.
• Ramucirumab in combination with FOLFIRI was well
tolerated in patients with mCRC. Overall, the adverse
events were considered manageable.
Off- Label
Slide 21
Tratamiento de mantenimiento en CCRm
Tumores irresecables
¿PREGUNTAS?
• Tratar hasta progresión o mantenimiento ?
• Mantenimiento con fluoropirimidinas +
biológicos / biológicos / fluoropirimidinas?
• ¿Qué pacientes se benefician de un
mantenimiento?
• Precio biológicos muy elevado
Slide 22
CAIRO3: study design
PFS1
PFS2
TT2PD
Arm A
Previously
untreated
mCRC
(n=558)
Avastin +
XELOX
(x6)
CR
PR
SD
Observation
(n=279)
PD1
Avastin +
XELOX (n=168)
PD2
Avastin +
Xeloda (n=279)
PD1
Avastin +
XELOX (n=132)
PD2
R
Median follow-up 48 months (cut-off 060114)
Arm B
•
•
•
•
•
The CAIRO3 study is a phase III, randomised, multicentre (74 Dutch hospitals), open-label study
of maintenance Avastin + Xeloda after induction with Avastin + XELOX in mCRC
Primary endpoint: PFS2 (PFS after re-introduction of Avastin + XELOX)
Secondary endpoints: PFS1, OS, TT2PD, ORR, safety
PFS2 was considered to be equal to PFS1 for patients in whom Avastin + XELOX was not
reintroduced after PFS1 for any reason
Upon PD1, 60% of patients received Avastin + XELOX in arm A and 47% in arm B
Koopman, et al. ASCO GI 2014. Abstract LBA388
Slide 23
CAIRO3: patients with a CR/PR as best response on
induction treatment benefit most from maintenance
Avastin + Xeloda in terms of OS
Median
CR/PR (n=366)
1.0
SD (n=191)
0S estimate
0.8
0.6
Observation
18.8 months
Maintenance
24.1 months
Observation
15.2 months
Maintenance
16.9 months
p-value
<0.0001
Induction treatment of 6x cycles Avastin + XELOX
prior to randomisation not included (4-5 months)
0.4
0.2
16.9
15.2
0
0
12
18.8
24.1
24
36
48
60
11
3
11
2
2
0
4
0
Time (months)
No. at
risk:
184
95
182
96
136
62
140
66
65
24
86
26
26
9
32
7
CR-PR/O
SD/O
CR-PR/M
SD/M
Koopman, et al. ASCO GI 2014. Abstract LBA388
Slide 24
EGFR activation may involve downstream signalling pathways that
include RAS proteins
Berg M, Soreide K. Discovery medicine 2012; 14:207-14; Di Fiore F, et al. Br J Cancer 2010;
103:1765-72;
Han W, Lo HW. Cancer Lett 2012; 318:124-34; Herbst RS, Shin DM. Cancer 2002; 94:1593-611.
Slide 25
PRIME RAS/RAF
Results (WT RAS & WT/MT BRAF)
Pmab + FOLFOX
(n=320)
FOLFOX
(n=321)
HR
(95% CI)
Descriptive pvalue
228
218
-
-
Median OS - mos
(95% CI)
28.3
(23.7–NE)
20.9
(18.4–23.8)
0.74
(0.57–0.96)
0.02
Median PFS mos (95% CI)
10.8
(9.4–12.4)
9.2
(7.4–9.6)
0.68
(0.54–0.87)
<0.01
24
29
-
-
Median OS - mos
(95% CI)
10.5
(6.4–18.9)
9.2
(8.0–15.7)
0.90
(0.46–1.76)
0.76
Median PFS mos (95% CI)
6.1
(3.7–10.7)
5.4
(3.3–6.2)
0.58
(0.29–1.15)
0.12
WT RASa &
BRAF, n
MT BRAF, n
aWT
in KRAS and NRAS exons 2, 3, and 4. (RAS ascertainment rate 90%)
Panitumumab está autorizado solo para pacientes RAS nativos
Based on Douillard JY, et al. N Engl J Med 2013; 369:1023-34
Slide 26
PEAK study RAS analysis
OS
WT KRAS exon 2
WT RAS
0 4 8 12 16 20 24 28 32 36 40 44
Months
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)
100
90
80
70
60
50
40
30
20
10
0
Proportion alive (%)
HR* = 0.62 (95% CI, 0.44–0.89)
P = 0.009
Proportion alive (%)
100
90
80
70
60
50
40
30
20
10
0
HR* = 0.63 (95% CI, 0.39–1.02)
P = 0.058
0 4 8 12 16 20 24 28 32 36 40 44
Months
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)
*Stratified Cox proportional hazards model; No formal hypothesis testing was planned; WT RAS, WT KRAS & NRAS exons 2/3/4;
NR, not reached
Panitumumab está autorizado solo para pacientes RAS nativos
Schwartzberg L, et al. J Clin Oncol 31, 2013 (suppl; abstr 3631 and poster).
Slide 27
Cetuximab está autorizado solo para pacientes RAS nativos
Presented By Alan Venook at 2014 ASCO Annual Meeting
Slide 28
“The exposure to all three cytotoxics (FP,
oxaliplatin and irinotecan) in various sequences
may result in the longest survival”
“Only trials with a combination of cytotoxics
and a biological targeted treatment consistently
reported median survival exceeding 24 months”
Annals of Oncology 00 (0): iii1–iii9, 2014
Slide 29
Detección de nuevas resistencias/mutaciones primarias o
secundarias?
Cetuximab treatment
mutations in EGFR, KRAS, NRAS, BRAF and
PIK3CA genes, including novel EGFR mutations (R451C and K467T).
Functionally, EGFR mutations prevent binding to cetuximab but a subset is
permissive for interaction with panitumumab
1.Montagut C, et al. Nat Med 2012; 18:221-3
2.Arenas S, et al. Clin Cancer Res 2015
Slide 30
Construyendo el futuro del Cáncer colorrectal metastásico paciente a
paciente
Bardelli, JCO 2010
Slide 31
Construyendo el futuro del Cáncer colorrectal metastásico paciente a
paciente: combinación de fármacos?
• AntiEGFR + inhibidores BRAF?
• AntiEGFR + inhibidores de MET?
Slide 32
Construyendo el futuro del Cáncer colorrectal metastásico paciente a
paciente: nuevas combinaciones de fármacos?
Antitumor effects of dabrafenib, trametinib, and panitumumab as single agents and in
combination in BRAF-mutant colorectal carcinoma (CRC) models
Abstract number: 3513. Author: LI Liu
Efficacy and tolerability in an open-label phase I/II study of MEK inhibitor trametinib (T), BRAF
inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P) in combination in patients
(pts) with BRAF V600E mutated colorectal cancer (CRC)
Abstract number: 3515 . Author: Johanna C. Bendell
Phase I study of the selective BRAFV600 inhibitor encorafenib (LGX818) combined with
cetuximab and with or without the α-specific PI3K inhibitor BYL719 in patients with advanced
BRAF-mutant colorectal cancer
Abstract number: 3514 . Author: Robin Van Geel
Phase 1B study of vemurafenib in combination with irinotecan and cetuximab in patients with
BRAF-mutated advanced cancers and metastatic colorectal cancer
Abstract number: 3516 . Author: David S. Hong
VE-BASKET, a Simon 2-stage adaptive design, phase II, histology-independent study in
nonmelanoma solid tumors harboring BRAF V600 mutations (V600m): Activity of vemurafenib
(VEM) with or without cetuximab (CTX) in colorectal cancer (CRC)
Abstract number: 3518^ . Author: Josep Tabernero
ONC-2012-001: A single-arm phase II study of tivantinib (ARQ 197) plus cetuximab in EGFR
inhibitor-resistant MET high patients (pts) with locally advanced or metastatic colorectal cancer
(CRC) with wild-type KRAS
Abstract number: TPS3661 . Author: Lorenza Rimassa
ASCO
2014
Slide 33
Construyendo el futuro del Cáncer colorrectal metastásico paciente a
paciente: nuevas combinaciones de fármacos?
Pilot study of vemurafenib and panitumumab combination therapy in patients with
BRAF V600E mutated metastatic colorectal cancer
Abstract number: 611. Author: Rona D. Yaeger
S1406: Randomized phase II study of irinotecan and cetuximab with or without
vemurafenib in BRAF-mutant metastatic colorectal cancer (mCRC)
Abstract number: TPS790. Author: Scott Kopetz
Clinical and molecular characterization of refractory BRAF mutant metastatic colorectal
carcinoma (mCRC): Vall d’Hebron Institute of Oncology phase I program cohort
Abstract number: 587. Author: Enrique Sanz-Garcia
Clinical impact of expanded BRAF mutational status on the outcome for metastatic
colorectal cancer patients with anti-EGFR antibody: An analysis of the BREAC trial
(Biomarker Research for Anti-EGFR Monoclonal Antibodies by Comprehensive Cancer
Genomics)
Abstract number: 573. Author: Kentaro Yamazaki
Acquired mutations in MAPK signaling pathway following initial pharmacological
response in BRAF-mutated metastatic colorectal cancer (mCRC)
Abstract number: 629. Author: Van Karlyle Morris
Pilot Trial of combined BRAF and EGFR inhibition in BRAF mutant metastatic
colorectal cancer patients. Yaeger R et al. Clin Cancer Res 2015
ASCO GI
2015
Slide 34
Construyendo el futuro del Cáncer colorrectal metastásico
paciente a paciente: nuevas combinaciones de fármacos?
Slide 35
Inmunoterapia en cáncer colorrectal
Enfoque Anti-PD-L1
Koido S et al. World J Gastroenterol 2013;19: 8531-8542
Slide 36
Anti-CTLA-4/Anti-PD-1/Anti-PD-L-1 Mechanism of
Action
Momtaz P et al. Pharmgenomics Pers Med 2014; 7: 357-365
Slide 37
El CCR: una prioridad sanitaria
o
o
El cáncer de pulmón, CCR y de
mama son los responsables del
mayor número de años de vida
perdidos ajustado por mortalidad
y por discapacidad.
Carga del cáncer en España
El CCR, debido tanto a la mortalidad
como a la discapacidad asociada,
ocupa la segunda posición en la
carga económica del total de
cánceres en España.
Incidencia
CCR es el más frecuente en España
BMC Public Health 2009, 9:42
Slide 38