“Estrategia terapeutica del cáncer colorrectal: Selección
individualizada del tratamiento”
P. García Alfonso
Jefe de Sección de Oncología Médica
HGU Gregorio Marañón de Madrid
Metastatic Colorectal Cancer
0 10 20 30 40 50
FOLFOXIRI-Bev 2wt
FOLFOX-Pani 2wt
FIRE Ras wt
CALGB
FOLFOX-Pani
FOLFIRI-Cetu
FOLFOX-Cetu
FOLFOX-Bev
FOLFOX->FOLFIRI
IFL-Bev
FOLFOX
FOLFIRI
IFL
5FU i.c.
5FU bolus
BSC
41,7 41,3
33,1 29
25,8 23,5
22,8 21,3
20,6 20,3
19,5 17,4
14,8 14,1
12,6 5
Mediana Sup FOLFOXIRI-Bev 2wt
FOLFOX-Pani 2wt
FIRE Ras wt
CALGB
FOLFOX-Pani
FOLFIRI-Cetu
FOLFOX-Cetu
FOLFOX-Bev
FOLFOX->FOLFIRI
IFL-Bev
FOLFOX
FOLFIRI
IFL
5FU i.c.
5FU bolus
BSC
ESMO GUIDELINES 2015
(1) Referencia: Van Cutsem, Arnold and Cervantes. Session XIX: Metastatic Colorectal Cancer. World Congress on Gastrointestinal Cancer
Características
del tumor (1) Presentación clínica:
Localización del tumor Carga tumoral
Edad Performance status Función del órgano Comorbilidades
Perfil de toxicidad Flexibilidad Factores socio- económicos Calidad de vida Preferecias y expectativas del paciente
Para la toma de decisión de la1L de tratamiento en CCRm
Medicina Personalizada significa:
Biología del tumor Estatus mutacional de RAS Estatus mutacional de BRAF
Tournigand C et al., J Clin Oncol 22:229-237, 2004
Overa
ll S
urv
ival
(%)
21.5 months
20.6 months
Significant improvement in
Trial Fluoropyrimidine Irinotecan or
oxaliplatin EGFR
inhibitor RR PFS OS
CRYSTAL Inf + bolus 5-FU Irinotecan Cetuximab + + +
COIN Inf + bolus 5-FU Oxaliplatin Cetuximab + + –
Capecitabine Oxaliplatin Cetuximab – – –
NORDIC Bolus 5-FU Oxaliplatin Cetuximab – – –
PRIME Inf + bolus 5-FU Oxaliplatin Panitumumab + + +
Resultados de los ensayos fase III con inhibidores de EGFR
Grothey & Lenz. J Clin Oncol 2012
Resultados de los ensayos fase III con Bevacizumab en
primera línea de CCRm
1. Hurwitz, et al. NEJM 2004; 2. Saltz, et al. JCO 2008; 3. Tebbutt, et al. JCO 2010 4. Cunningham, et al. ASCO GI 2013; Falcone NE Med 2014
Regimen
Tx
line N Post-study therapy
ORR
(%)
Median
PFS
(months)
Median
OS
(months)
Dobletes
IFL
IFL + bevacizumab1 1L 813 2L: ~50%
2L: ~50%
35
45*
6.2
10.6*
15.6
20.3*
XELOX/FOLFOX
XELOX/FOLFOX + bevacizumab2 1L 1,401 2L: 53%
2L: 46%
38
38
8.0
9.4*
19.9
21.3
Monoterapia
Capecitabine
Capecitabine + bevacizumab3 1L 313 68%
62%
30
38
5.7
8.5*
18.9
18.9
Capecitabine
Capecitabine + bevacizumab4 1L 280 37%
37%
10
19*
5.1
9.1*
16.8
20.7
*Statistically significant difference vs the control arm
NR = not reported
12,1 vs 9,7 p 0,003
31 vs 25,8 p 0,054
Estudio TRIBE
508 pacientes CCR EIV
FOLFOXIRI + beva
FOLFIRI + beva
OR: 62.7 % vs 51.9%; p=0.025
Marcadores moleculares
Mutaciones RAS
RAS wild-type
KRAS codon 12 mutant
KRAS codon 13 mutant
KRAS Exon 3 mutant
KRAS Exon 4 mutant
NRAS Exon 2 mutant
NRAS Exon 3 mutant
NRAS Exon 4 mutant
KRAS Exon 2
KRAS wild-type
KRAS codon 12 mutant
KRAS codon 13 mutant
Extended RAS wild-type
(2014) KRAS exon 2 wild-type
(2008)
OS con inhibidores de EGFR en CCRm RAS/KRAS exon 2 MT
EGFR inhibitors are authorised only for RAS WT mCRC Sorich, et al. Ann Oncol 2015
Meta-analysis of >5,000 patients from randomised clinical trials
20020408
20050181
CRYSTAL
OPUS
PICCOLO
PRIME
Summary
213
593
460
167
148
548
1.06 (0.79–1.42)
0.91 (0.76–1.10)
1.05 (0.86–1.28)
1.29 (0.91–1.84)
1.22 (0.85–1.76)
1.21 (1.01–1.45)
1.08 (0.97–1.21)
p=0.14
N Study OS
Hazard ratio (95% CI)
Any RAS MT
0.5 1 2
Favours no cetux/panit
Favours cetux/panit
184
486
397
136
103
440
1.02 (0.75–1.39)
0.94 (0.76–1.15)
1.03 (0.83–1.28)
1.29 (0.87–1.91)
1.05 (0.69–1.61)
1.15 (0.94–1.41)
1.05 (0.95–1.71)
p=0.32
N
KRAS exon 2 MT
0.5 1 2
Favours no cetux/panit
Favours cetux/panit
OS Hazard ratio (95% CI)
AVF2107g: OS con bevacizumab acorde a estado mutacional de KRAS
Hurwitz, et al. Oncologist 2009
1.0
0.8
0.6
0.4
0.2
0
0 15 25 30 5 10 20
1.0
0.8
0.6
0.4
0.2
0
KRAS MT (n=78)
KRAS WT (n=152)
Time (months)
OS
es
tim
ate
OS
es
tim
ate
Time (months)
Bevacizumab + IFL (n=44)
Placebo + IFL (n=34)
HR=0.69; p=0.26
Bevacizumab + IFL (n=85)
Placebo + IFL (n=67)
HR=0.58; p=0.04
0 15 25 30 5 10 20
13.6 19.9 27.7 17.6
BRAF MT se asocia con peor pronóstico
Seligmann, et al. ASCO 2015
1L treatment OS for BRAF MT vs BRAF WT
BRAF MT patients have a significantly shorter median OS in 1L; only 39% of BRAF MT patients vs 60% BRAF WT received 2L treatment
OS
esti
mat
e
Time (months)
0 6 12 18 24 30 36 42
0
0.25
0.50
0.75
1.00
OS
esti
mat
e
Time (months)
0 3 6 9 12 15 18 24
0
0.25
0.50
0.75
1.00
BRAF WT BRAF MT
HR=1.48 p<0.001
BRAF WT BRAF MT
HR=1.17 p=0.33
21
6.9 10.2 10.8 16.4
2L treatment OS for BRAF MT vs BRAF WT
OS con inhibidores de EGFR en CCRm BRAF MT
EGFR inhibitors are authorised only for RAS WT mCRC Pietrantonio, et al. Eur J Cancer 2015
Meta-analysis of randomised clinical trials of cetuximab or panitumumab
Bokemeyer 2012
Douillard 2013
Karapetis 2013
Seymour 2013
Peeters 2014
Stintzing 2014
Total (95% CI)
–0.478
–0.105
–0.174
0.61
–0.446
–0.139
Log (hazard ratio) Study
0.275
0.342
0.736
0.263
0.354
0.314
0.62 (0.36–1.06)
0.90 (0.46–1.76)
0.84 (0.20–3.56)
1.84 (1.10–3.08)
0.64 (0.32–1.28)
0.87 (0.47–1.61)
0.91 (0.62–1.34)
Hazard ratio (95% CI) SE
0.2 1 5
Favours control
Favours EGFR inhibitors
20.7
17.0
6.0
21.5
16.4
18.5
100.0
Weight (%)
Heterogeneity: Tau2=0.11; Chi2=10.09 df=5 (p=0.07); I2=50% Test for overall effect: Z=0.48 (p=0.63)
2 0.5
TRIBE Predictive impact - OS
0 20 40 600
25
50
75
100
Months
Pe
rce
nt s
urv
iva
l
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]
R&B evaluable 375 25.8 31.0 0.86 [0.65-1.12]
RAS mutated 218 23.1 30.8 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]
RAS mutated – FOLFOXIRI plus bev
RAS mutated – FOLFIRI plus bev
BRAF mutated – FOLFOXIRI plus bev
BRAF mutated – FOLFIRI plus bev
All wt – FOLFOXIRI plus bev
All wt – FOLFIRI plus bev
VISNÚ PROGRAM CTC Screening (n= 750 pts)
47%
≥3 CTC
(n=350)
VISNÚ 1 (TTD-12-01)
FOLFOX
+
Avastin
(n = 193)
R
FOLFOXIRI
+
Bevacizumab
(n = 175)
FOLFOX
+
Bevacizumab
(n = 175)
Design Randomized Phase III
Primary endpoint: PFS (superiority 8 m vs 11,2 m, HR: 0.71)
Secondary endpoint: RR, OS. R0 surgery, toxicity, CTC level
basal, KRAS, BRAF, PI3K, Pten
VISNÚ 2 (TTD-12-02)
KRAS
mut
(n=191)
53%
FOLFIRI
+
Cetuximab
N=97
< 3 CTC
(n=400)
BRAF WT, PI3K WT
(n=194)
R
FOLFIRI
+
Bevacizumab
N=97
KRAS WT N = 240
60%
BRAF MUT o PI3K MUT
(n=46)
Design: Randomized Phase II
Primary endpoint:
-Group without mutation: minimum value 8.5 months optimum value 13 months
and 1 year PFS rate IC less than (+/-10%)
- Group with mutation: minimum value 2,5 months optimum value 6 months
Secondary endpoint: TR, OS, R0 surgery, toxicity, CTC level basal, Pten
FOLFIRI
+
Cetuximab
N=23
R
FOLFIRI
+
Bevacizumab
N=23
VISNÚ
ESMO 2015: Consensus on treatment of advanced mCRC
Progressive disease Disease control Cytoreduction
(shrinkage) Progressive disease
Unusual, see publication CT + Bevacizumab CT + biological agent Triplet + Bevacizumab Combination +
Bevacizumab Doublet + anti-EGFR
Continue; maintenance, or pause
Continue; maintenance, or pause Continue
BSC
2L
FP +/- Bevacizumab Reduced dose doublet
Anti-EGFR
Cure
Surgery alone Surgery with perioperative/ postoperative CT
Unfit (but may be suitable) Unfit Fit
Cytoreduction Disease control
2L
Re-evaluation/assessment of response every 2-3 months
RAS WT RAS MT BRAF MT RAS WT RAS MT BRAF MT
Draft
Van Cutsem, Arnold and Cervantes. Session XIX: Metastatic Colorectal Cancer. World Congress on Gastrointestinal Cancer, 2015
ESMO 2015: Consensus on treatment of advanced mCRC
Progressive disease Disease control Cytoreduction
(shrinkage) Progressive disease
Unusual, see publication CT + Bevacizumab CT + biological agent Triplet + Bevacizumab Combination +
Bevacizumab Doublet + anti-EGFR
Continue; maintenance, or pause
Continue; maintenance, or pause Continue
BSC
2L
FP +/- Bevacizumab Reduced dose doublet
Anti-EGFR
Cure
Surgery alone Surgery with perioperative/ postoperative CT
Unfit (but may be suitable) Unfit Fit
Cytoreduction Disease control
2L
Re-evaluation/assessment of response every 2-3 months
RAS WT RAS MT BRAF MT RAS WT RAS MT BRAF MT
Draft
Van Cutsem, Arnold and Cervantes. Session XIX: Metastatic Colorectal Cancer. World Congress on Gastrointestinal Cancer, 2015
Metástasis Hepáticas Irresecables o Potencialmente resecables
CELIM: Cetuximab + FOLFOX o FOLFIRI en metástasis hepáticas de CCR irresecables o mas de 5 metástasis
PLANET study
Response rate and resectability
†percentages calculated over the total number of patients with surgical resection in each group; ORR: Objective response rate
(not confirmed*); *patients resected before response confirmation
Criteria for unresectability
• Patients had to meet at least one of the following criteria:
– no upfront R0/R1 resection of all hepatic lesions possible
– less than 30% estimated residual liver after resection
– disease in contact with major vessels of the remnant liver
• FDG-PET was performed to exclude extrahepatic metastases
• Primary endpoint: overall resection rate (R0/R1/R2)
Previously untreated,
unresectable colorectal
cancer with metastases
confined to the liver
N=80 Bevacizumab + mFOLFOX6
Bevacizumab 5 mg/kg, oxaliplatin 85 mg/m2, folinic acid 400 mg/m2, bolus 5-FU 400 mg/m2 then 5-FU 2400 mg/m2
46-hr infusion on day 1 q2w
Bevacizumab + FOLFOXIRI Bevacizumab 5 mg/kg, oxaliplatin
85 mg/m2, irinotecan 165 mg/m2, folinic acid 200 mg/m2 and 5-FU 3200 mg/m2
46-hr infusion on day 1 q2w
Stratification factors:
• Centre
• ECOG performance status
• No. of metastatic lesions
Randomization 1:1
Gruenberger, et al. Annals of Oncology 2014
Resection and response rates
% (95% CI)
Bev + FOLFOXIRI (n=41)
Bev + mFOLFOX6 (n=39)
Difference
p-value
Resection rate
R0/R1/R2a 61.0 (44.5–75.8) 48.7 (32.4–65.2) 12.3 (–11.0–35.5) 0.271
R0/R1 51.2 (35.1–67.1) 33.3 (19.1–50.2) 17.9 (–5.0–40.7) 0.106
R0 48.8 (32.9–64.9) 23.1 (11.1–39.3) 25.7 (3.9–47.5) 0.017
Overall response rate 80.5 (65.1–91.2) 61.5 (44.6–76.6) 18.9 (–2.1–40.0) 0.061
Intent to treat population. aOnly two-stage hepatectomy
Bridgewater, et al. ECC 2013. Abstract 2159
Tratamiento de Metástasis Hepáticas: Revaluación de la respuesta cada 2 meses
Citoreducción
RAS y BRAF wt
RAS mutado BRAF
mutado
Doblete + Anti-EGFR* Doblete o Triplete + Bevacizumab
Triplete + Bevacizumab
ESMO 2015: Consensus on treatment of advanced mCRC
Progressive disease Disease control Cytoreduction
(shrinkage) Progressive disease
Unusual, see publication CT + Bevacizumab CT + biological agent Triplet + Bevacizumab Combination +
Bevacizumab Doublet + anti-EGFR
Continue; maintenance, or pause
Continue; maintenance, or pause Continue
BSC
2L
FP +/- Bevacizumab Reduced dose doublet
Anti-EGFR
Cure
Surgery alone Surgery with perioperative/ postoperative CT
Unfit (but may be suitable) Unfit Fit
Cytoreduction Disease control
2L
Re-evaluation/assessment of response every 2-3 months
RAS WT RAS MT BRAF MT RAS WT RAS MT BRAF MT
Draft
Van Cutsem, Arnold and Cervantes. Session XIX: Metastatic Colorectal Cancer. World Congress on Gastrointestinal Cancer, 2015
Phase 2 PEAK study mFOLFOX6 + panitumumab or bevacizumab in 1st-line treatment of
WT KRAS exon 2 mCRC
Schwartzberg LS, et al. J Clin Oncol 2014;32:2240−7;
Protocol ID: 20070509; ClinicalTrials.gov identifier: NCT00819780. mFOLFOX6, modified FOLFOX6.
• Study endpoints: PFS (1); OS, ORR, resection rate, safety, exploratory biomarker analysis
• No formal hypothesis testing was planned
Follow-up • Survival: Q3M (± 28
days) • Safety: 30 days after
last study drug administration
mCRC WT KRAS exon 2 (n = 285)
Tumour assessment Q8W (± 7 days); Treatment administered until disease progression, unacceptable toxicity, death, or withdrawal from study
1:1
mFOLFOX6 (Q2W) +
panitumumab 6 mg/kg (Q2W)
mFOLFOX6 (Q2W) + bevacizumab 5 mg/kg (Q2W)
R
PEAK: PFS & OS WT KRASKRAS WT RAS
Schwartzberg LS. J Clin Oncol. 2014 Jul 20;32(21):2240-7
RAS WT
FIRE-3 study design
Heinemann V et al. Lancet 2014;.
Fire-3: Tasa de Respuestas
Heinemann V et al. Lancet 2014
FIRE-3: PFS and OS
Heinemann V et al. Lancet 2014
FIRE-3: Depth of Response (DpR) Correlates With OS
CALGB/SWOG 80405: <br /> FINAL DESIGN
Presented By Alan Venook at 2014 ASCO Annual Meeting
CALGB 80405: RAS-WT - Supervivencia Global
Lenz, et al. ESMO 2014. abstract 501O
31.2 32.0
% li
bre
de
eve
nto
s
Grupo N Mediana RR p (Eventos) (IC 95%) (IC 95%)
No. en riesgo Meses desde el ingreso al estudio
CALGB 80405 RAS-WT: Resultados de SLP
Lenz, et al. ESMO 2014. abstract 501O
% li
bre
de
eve
nto
s
Grupo N Mediana RR p (Eventos) (IC 95%) (IC 95%)
No. en riesgo Meses desde el ingreso al estudio
ORR: Chemo+cetux: 68,6% vs Chemo + Beva: 53,6% (p<0,01)
FIRE-3: diferencias en eficacia en tumores del lado derecho vs lado
izquierdo
Heinemann, et al. ASCO 2014
Cetuximab + FOLFIRI Bevacizumab + FOLFIRI
HR (95% CI) p value HR (95% CI) p value
OS 0.34 (0.20–0.57)
<0.0001 1.04 (0.60–1.81)
0.89
PFS 0.43 (0.27–0.68)
0.0003 1.13 (0.73–1.75)
0.059
Multivariate Cox regression analysis (OS and PFS): location (left- vs right-sided tumour)
Cetuximab + FOLFIRI (n=167)
Bevacizumab + FOLFIRI (n=166)
Right-sided (n=30)
Left-sided (n=137)
OR (p value)
Right-sided (n=39)
Left-sided (n=127)
OR (p value)
ORR, % 46.7 70.1 2.7 (0.019)
48.7 62.2 1.7 (0.14)
PFS, months 6.9 10.8 0.35 (>0.001) 8.8 10.5 0.69 (0.065)
OS, months 16.1 38.7 0.26 (<0.0001)
22.7 28.0 0.63 (0.034)
Effect of primary tumour location on outcomes
Tratamiento de mantenimiento
CAIRO-3: Cape-Bev Maintenance vs Observation
• Primary endpoint: PFS2
– Time from randomization to progression upon reintroduction of CAPOX-B
– PFS2 considered equal to PFS1 in patients who do not receive CAPOX-B again (for any reason)
• Median follow-up: 40 mos
Patients with
mCRC and SD or
better after 6
cycles CAPOX-B,
WHO PS 0-1
(N = 558)
Observation
(n = 279)
Capecitabine +
Bevacizumab
(n = 279)
PD
Reintroduce
CAPOX-B PD
PFS1 PFS2
OR
Any treatment,
including
CAPOX-B
PD
TT2PD
Koopman M, et al. ASCO 2013. Abstract 3502.
CAIRO3: Maintenance Cape-Beva
Meta-analisis Beva maintenance
Clin Colorectal Cancer 2015
PFS
OS
Opciones terapéuticas en segunda línea
Lancet Oncol 2013 Jan;14(1):29-37.
Median: BEV + CT 11.2 months, CT 9.8 months
Median: BEV + CT 5.7 months, CT 4.1 months
42
Aflibercept
1. Adapted from Holash. Proc Natl Acad Sci. 2002;99:11393–11398. 2. Adapted from Tew. Clin Cancer Res. 2010;16:358–366.
Aflibercept
Tabernero et al. Eur J Cancer. 2011;47(2): Abstract 6LBA
RAISE: Ramucirumab en CCR
OR: 13.4% vs 12.5% p : 0.6
Antiangiogénicos en 2º línea
asociados a FOLFIRI
2º line: Anti-EGFR combination
Ciardielo F et al. Annals of Oncology Advanced Acess 2016
Cetuximab + 1L
FOLFIRI (n=153)
kras wt
Cetu + FOLFOX
FOLFOX
R
• Primary endpoint: PFS from randomisation
• Secondary endpoints: OS from randomisation, best ORR, safety
PD
PD
CAPRI: PFS wt/mutated
Opciones terapéuticas en tercera y cuarta línea
ASPECCT study
Panitumumab vs. cetuximab in 3rd-
line treatment of WT KRAS exon 2
mCRC (open-label, phase 3)
Price T, et al. EJC 2013; 49 (suppl 3):LBA 18 (and oral presentation); Protocol ID: 20080763; ClinicalTrials.gov identifier: NCT01001377. WT KRAS, WT KRAS in codons 12/13
• Study endpoints: OS (1°); PFS, ORR, safety
• Crossover between arms during study treatment was not allowed
1:1
R
1:1
Panitumumab
6 mg/kg IV (Q2W)
Cetuximab
400 mg/m2 loading dose,
250 mg/m2 IV (QW)
Metastatic mCRC
WT KRAS exon 2
(n = 999)
S
u
r
v
i
v
a
l
PD
PD
ASPECCT study: OS (primary analysis)
Price T, et al. EJC 2013; 49 (suppl 3):LBA 18 (and oral presentation).
HR = 0.97 (95% CI, 0.84–1.11)
P = 0.0007
Z-score = -3.19
Retention score = 1.06 (95% CI, 0.82–1.29)
Events
n (%)
Median (95% CI)
months
Panitumumab
(n = 499) 383 (76.8) 10.4 (9.4–11.6)
Cetuximab
(n = 500) 392 (78.4) 10.0 (9.3–11.0)
Pro
port
ion a
live (
%)
100
90
70
60
80
50
40
30
20
10
0
Months
0 6 12 18 24 30 36
• Multicenter, randomized, double-blind, placebo-controlled, phase III
– Stratification: prior anti-VEGF therapy, time from diagnosis of metastatic disease, geographical region
• Global trial: 16 countries, 114 centers
• Recruitment: May 2010 to March 2011
Regorafenib: Estudio CORRECT
Regorafenib 160 mg daily
3 weeks on / 1 week off (4-week cycle)
n = 136
Placebo n = 68
Stratification
• Metastases: single vs multiple
• Time from mCRC diagnosis:
>18 vs <18 months
• All patients received best supportive care
• Treat until progression, unacceptable toxicity, or withdrawal
Asian patients with mCRC who progressed after standard
therapies 25 Centers: mainland China,
Hong Kong, South Korea, Taiwan, Vietnam
CONCUR trial design Clinicaltrials.gov NCT01584830
Primary endpoint: overall survival (OS) • One-sided alpha 0.2 and assumed 33.3% OS improvement
(HR=0.75 favoring regorafenib) with 154 events had 80% power
Secondary endpoints: progression-free survival,
response rate , disease control rate
R 2:1
J. Li, et al. WCGI 2014. Abstract O-0023. Presented at WCGI 2014, Barcelona, Spain. Kim TW et al Presented at ESMO 2014, 26 – 30 September, Madrid Li J et al. Lancet 2015
CORRECT CONCUR
SLP
SG
SLP
SG
Regorafenib 1.9 m
Placebo 1.7 m
Regorafenib 6.4 m
Placebo 5.0 m
Regorafenib 8.8 m
Placebo 6.3 m
Regorafenib 3.2 m
Placebo 1.7 m
Mayer RJ et al. NEJM 2015
TAS 102 EN CCR m REFRACTARIO, FASE III
• Mayer & Van Cutsem et al.
Exposure to as many agents as
possible prolongs OS
Adapted from Grothey & Sargent. JCO 2005
OS (months) = 13.2 + (3 drugs % x 0.1), R2=0.85
Infusional 5-FU/LV
+ irinotecan
Infusional 5-FU/LV
+ oxaliplatin
Bolus 5-FU/LV
+ irinotecan
Irinotecan
+ oxaliplatin
Bolus 5-FU/LV
LV5FU2
First-line therapy
Me
dia
n O
S (
mo
nth
s)
Patients with 3 drugs (%)
2007
22
21
20
19
18
17
16
15
14
13
12
0 10 20 30 40 50 60 70 80
p=0.0001
FOLFOXIRI
CAIRO
CR-SEQUENCE Planned study design
Unresectable
mCRC
WT RAS
R1
1:1
FOLFOX +
bevacizumab
FOLFOX +
panitumumab
N cycles until PD, toxicity or
conversion surgery FOLFIRI +
bevacizumab
FOLFIRI +
panitumumab
N cycles until PD or toxicity
R2
Investigator choice:
1st-line reintroduction
or
Regorafenib
or
other
FOLFIRI +
bevacizumab
Futuro en CCR
CRC consensus molecular subtypes characteristics
Liquid Biopsy
Can Targeting EGFR Overcome Resistance to BRAF + MEK Inhibitors in BRAFm CRC?
Presented By Chloe Atreya at 2015 ASCO Annual Meeting
Best Response With Confirmation <br />Percent Change from Baseline at Maximum Reduction in Tumor Measurement
Presented By Chloe Atreya at 2015 ASCO Annual Meeting
Pembrolizumab: 10m g/k cada 2 semanas iv
Pembrolizumab en CCRm con MSI
NR NR
2.2 m 5.0 m
HER2 como diana en CCRm: HERACLES trial: Lapatinib + Trastuzumab
• Primary endpoint was met with 8/23 objective responses (as per protocol, 6/27 needed to declare the study positive)
• Disease control rate (DCR): 78%
Siena, et al. ASCO 2015
Response n (%)
ORR 8 (34.7)
CR 1 (4.3)
PR 7 (30.4)
SD ≥4 months 7 (30.4)
SD <4 months 3 (13.0)
PD 5 (21.7)
Response rate TTP
Surv
ival
pro
bab
ility
Time (months)
1.0
0.6
0.4
0.2
0
0 3
HER2 3+ (95% CI: 1.8–NR)
HER2 2+ (95% CI: 1.9–NR)
0.8
15
p=ns
6 9 12
4.2 7.3
N: 54 previamente tratados HER2 +
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0 10 20 30 40 50
FOLFOXIRI-Bev 2wt
FOLFOX-Pani 2wt
FIRE Ras wt
CALGB
FOLFOX-Pani
FOLFIRI-Cetu
FOLFOX-Cetu
FOLFOX-Bev
FOLFOX->FOLFIRI
IFL-Bev
FOLFOX
FOLFIRI
IFL
5FU i.c.
5FU bolus
BSC
41,7 41,3
33,1 29
25,8 23,5
22,8 21,3
20,6 20,3
19,5 17,4
14,8 14,1
12,6 5
Mediana Sup FOLFOXIRI-Bev 2wt
FOLFOX-Pani 2wt
FIRE Ras wt
CALGB
FOLFOX-Pani
FOLFIRI-Cetu
FOLFOX-Cetu
FOLFOX-Bev
FOLFOX->FOLFIRI
IFL-Bev
FOLFOX
FOLFIRI
IFL
5FU i.c.
5FU bolus
BSC