Algoritmo terapéutico actual en cáncer colorrectal metastásico
Dra. Pilar García AlfonsoJefe de Sección de Oncología MédicaHGU Gregorio Marañón de Madrid
Disclosure
Advisory Boards:
- Merck, Roche, Bayer, Lilly. Sanofi, Servier, Amgen
« A continuum of care »El tratamiento es una estrategia continua con una secuencia terapéutica en función de la biologia tumoral y de las características del paciente
Fluoropirimidinas: 5FU, capecitabina, TAS102, Oxaliplatino, Irinotecán
Van Cutsem E . ESMO consensus guidelines for management of patients
with mCRC. Annals of oncology 0:1-37, 2016.
30 months overall survival
10 months 6 months 3 months few monthsPFS
Bevacizumab, Cetuximab/panitumumab, Aflibercept, Ramucirumab , Regorafenib Anti-PD-1: Pembrolizumab, Nivolumab
Selección de Tratamiento
Marcadores Clínicos
Marcadores Moleculares
Factores socioeconómicos y preferencias del
paciente
Caracteristicasdel pacienteEdadPSComorbilidadesQT adyuvante
Características Tumorales Volumen tumoral- Posible cirugía
rescate- Síntomas y
agresividad- Localización
Biomarcadores
Grado histológico CEAMSIKRASNRASBRAF
Calidad de vidaPerfil de toxicidad
Selección de Tratamiento
Marcadores Clínicos
Marcadores Moleculares
Factores socioeconómicos y preferencias del
paciente
Caracteristicasdel pacienteEdadPSComorbilidadesQT adyuvante
Características Tumorales Volumen tumoral- Posible cirugía
rescate- Síntomas y
agresividad- Localización
Biomarcadores
Grado histológico CEAMSIKRASNRASBRAF
Calidad de vidaPerfil de toxicidad
Localización tumoral
¿Que marcadores tengo que pedir?
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)
BRAF Mutations in CRC
• BRAF es el primer efector de lasseñales de KRAS (cromosoma 7)– Ocurre con más frecuencia en exon 15
(V600E)
– Aparece en 4%-8% de los pacientes con CCRm
– Mutuamente exclusiva con la mutaciónRAS
– Pronóstico negativo con mediana OS de 10 meses
– Más frecuente en mujeres, ancianos, colon decho, alto grado histológico
– Mas frecuente la diseminación peritoneal y ganglionar
Raf
MEK
Erk
P
P P
P
Tumor cellproliferationand survival
EGF
Tumor Cell
Ras
Yarden. Nat Rev Mol Cell Biol. 2001;2:127; Di Nicolantonio. J Clin Oncol. 2008;26:5705; Artale. J Clin Oncol. 2008;26:4217.
• Predictor de respuesta la inmunoterapia
(Categoría IIB)
• Pronóstico desfavorable
• Orienta en el Consejo Genético
– Determinación: Puede determinarse por dos métodos en tumor:
– Pérdida de expresión por IHQ de alguna de las proteínas
reparadoras de DNA, hMLH1, hMSH2, hMSH6 y hPMS2.
– Existencia de Inestabilidad de microsatélites por PCR.
MSI
*NCCN guidelines validate testing for MSI-H 1. Sargent DJ et al. J Clin Oncol. 2010; 28(20):3219-3226. 2. NCCN Guidelines V.1.2017. 3. Venderbosch S et al. Clin Cancer Res. 2014; 20(20):5322-5330. 4.Richman S. Int J Oncol. 2015; 47(4):1189-1202 9. 5. Van Cutsem E et al. Ann Oncol. 2016; 27(8):1386–1422.
VALIDACIÓN DEL HER-2 COMO BIOMARCADOR PREDICTIVO
10Raghav JCO 2019
Genomic markers in metastatic CRC
BRAF V600EBRAF non-V600
MSIMSI + otherPOLE mut
HER2 ampl
MET ampl
Gene fusion
RAS mut +/-PIK3CA/PTEN
mut PIK3CA/PTEN mut
Wild-type
anti-EGFR
anti-BRAF + anti-EGFR/MEKPD1 inhibitors
double anti-HER2
Kinase inhibitors
45% 8%
26%
8%2%2%
1%
1%
2%
2%
2%
Genotipado del Colon Cancer:
RAS
BRAF MUT
MSI
RAS/BRAFWT
Colon Derecho
HER-2
Anti-EGFR
RAS MUT
Antiangiogénicos
13
31%
24%
26%
Colon derecho 9%
10%
27%
56%
3%
15%
31%
51%
Colon Izquierdo
Recto
*Tumor location data are in stage I–IV CRC; survival after relapse data are in stage I–III CRC
1.00
0.75
0.50
0.25
0.00
Pro
po
rtio
n e
ven
t-fr
ee
0 12
meses
24 36 48 60 72
Supervivencia después de la Recurrencia (n=405)
CMS1
CMS4CMS3
HR (95% CI)P
valueCMS4 vs. CMS1
0.60 (0.40‒0.88)
9.04 E-02
CMS3 vs. CMS1
0.60 (0.38‒0.97)
3.71 E-02
CMS2 vs. CMS1
0.35 (0.24‒0.52)
1.26 E-07
Log-rank p-value: 4.01 E-07
Guinney J, et al. Nat Med 2015;21:1350–1356
Clasificación Molecular: CMS 2 es más frecuente en lado Izdo y es de mejor pronóstico
19%CMS2
1. Stintzing S, et al. ASCO 2017 (Abstract No. 3510);2. Lenz H-J, et al. ASCO 2017 (Abstract No. 3511);3. Heinemann V et al. Lancet Oncol 2014;15:1065–1075;4. Venook A, et al JAMA. 2017;317:2392-2401.
FIRE-3 did not meet its primary endpoint of significantly improving overall response rate (ORR) based on investigators’ read in patients with KRAS (exon 2) wt mCRC.3 The CALGB/SWOG 80405 study did not meet its primary endpoint of significantly improving overall survival in the cetuximab + CT arm vs bevacizumab + CT arm in patients with KRAS (exon 2) wt mCRC4
Diferente impacto del CMS en los estudios retrospectivos Fase III en CCRm RAS wt
Tipo de paciente
• ¿Está en condiciones de recibir un tratamiento estándar?
Patients not appropriate for intensive therapy
Pacientes apropiados para tratamiento intensivo
¿Cúal es el objetivo terapéutico?
Tournigand C et al., J Clin Oncol 22:229-237, 2004
Ove
rall
Surv
ival
(%
)
21.5 months
20.6 months
Estudios comparativos entre Beva y antiEGFR en CCRm primera línea
OVERALL RESPONSE
OS PFS
FIRE-3: Does depth of Response (DpR) correlates with OS?
•Localización Tumoral
Embriología Factores ambientales
Clínica
Distribución de subtipos moleculares
Factores genéticos
Diferencias del cáncer de colon derecho vs izquierdo
CALGB 80405: OS in all RAS WT patients
by tumor location
Lenz et al. ESMO 2016.
Right or left metastatic colon cancer:
will the side change your treatment?
12 24 36 48 60 72 84
13.6 29.2
0 12 24 36 48 60 72 84 96
32.6 39.3
1.0
0.8
0.6
0.4
0.2
0
OS
esti
mat
e
108
Time (months) Time (months)
Left-sided tumors Right-sided tumors1.0
0.8
0.6
0.4
0.2
0
OS
esti
mat
e
0
BEV: 32.6 months (n=152)Cetuximab: 39.3 months (n=173)
BEV: 29.2 months (n=78)Cetuximab: 13.6 months (n=71)
HR=1.36 (95% CI: 0.93–1.99)Adjusted p=0.10
HR=0.77 (95% CI: 0.59–0.99)Adjusted p=0.04
N=325 N=149
∆5.7 mos ∆15.6 mos
ESMO primary tumour location pooled analysisPredictive analysis of tumour location (pooled
analysis, right vs left)
• Tratamiento intensivo con tripletes
v
FOIB1 TRIBE2 OPAL3 STEAM4 MOMA5 CHARTA6
n=57 n=252 n=97 n=93 n=232* n=125
RegimenFOLFOXIRI/
Bev
FOLFIRI/Bev
+/- Oxa
FOLFOXIRI/
Bev
FU/Bev
maintenance
FOLFOXIRI/
Bev vs
FOLFIRI/Bev
FOLFOXIRI/
Bev
Bev ±metroCT
FOLFOX/Be
± IRI
Response rate 77% 65% 64% 60% 63% 70%
Disease control rate 100% 90% 87% 91% 91% N/A
Median PFS, months 13.1 12.3 11.1 11.9 9.5 12.0
Median OS, months 30.9 29.8 32.2 34.0 Too early Too early
* >70% patients with RAS or BRAF mutation
1. Masi et al. Lancet Oncol 2010; 2. Cremolini et al. Lancet
Oncol 2015
3. Stein et al. Br J Cancer 2015; 4. Bendell et al. ASCO GI 2017
5. Falcone et al. ESMO 2016; 6. Schmoll et al. ASCO GI 2017
FOLFOXIRI + bev: consistent results
Results: Objective Response Rate
87.3
60.6
90.6
68.0 70.0
37.5
86.0
64.7
85.7
22.2
Full Analysis Set
by Tumor Sidedness
by Genotype
N = 96Left
N = 78Right
N = 18
RAS/BRAF wtN = 60
BRAF mut
N = 16
P = 0.004 P = 0.021P =
0.345P =
0.081P =
0.041
OR = 4.47 OR = 4.52OR = 3.89
OR = 3.36
OR = 21.0
95%CI 1.61 –12.38
1.30 –15.72
0.54 –27.89
0.90 –12.55
1.50 –293.25
CI= confidence interval
Geissler M, et al. VOLFI: mFOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild-type metastatic colorectal cancer (mCRC): A randomized phase II trial of the AIO (AIO-KRK-0109)
FOLFOXIRI/Anti-EGFR
Metástasis Hepáticas Irresecables o Potencialmente resecables
Kopetz, S. et al. J Clin Oncol 2009; 27:3677-368
Anti-EGFR en Metástasis Hepáticas de CCR
CELIMFolfox/Folfiri+Cetuximab
PLANET
Abad et al. Presented at the 2014 European Society of Medical Oncology Meeting, September 26-30, 2014, Madrid, Spain; Abstract # 7823
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
• ¿Como hago el tratamiento de mantenimiento?
CAIRO-3: Cape-Bev Maintenance vs Observation
• ¿Podemos hacer mantenimiento en pacientes tratados con anti-EGFR?
MACRO-2
Estudio fase II Sapphire: FOLFOX/Pani x 12 semanas: FOLFOX/Pani vs FU-LV /Pani hasta progresión
ASCOGI 2018 # 729
VALENTINO
Results: PFS
HR =1.55; 95% CI: 1.09-2.20; p=0.011
10-months PFS Median PFS
Rate 95% CI Months 95% CI
Arm A
(5-FU/LV + pan)62.8% 54.0-73.1 13.0 10.5-16.0
Arm B
(pan)52.8% 43.4-64.3 10.2 8.9-12.2
Median Follow Up, months (IQR): 13.8 (8.6-18.3)
Pietrantonio F et al. ASCO 2018.; Abstract 3505 (and oral presentation)
Pietrantonio F et al. WCGIC 2018; Abstract O-016 (and oral presentation)
2ª line
Antiangiogénicos en 2º línea asociados a FOLFIRI
2º line: Anti-EGFR combination
• New RCT have to stratify by location
• If all the sequence matters we need prospective RCT based on molecular characteristics, in a dynamic scenario
• Primary endpoint: 2nd progression/exitus free rate. (PFS1+PFS2): 30 vs 20 months. Total of 332 patients
CR-SEQUENCE: Planned study design
▪ PD, progressive disease.
Unresectable
left-side
mCRC
WT RAS/
WT BRAF
R
FOLFOX +bevacizumab
FOLFOX +panitumumab
N cycles until PD, toxicity orconversion surgery
FOLFIRI +panitumumab
N cycles until PD or toxicity
FOLFIRI +bevacizumab
▪ SEQUENCE 29/03/2017
Pro
gressio
nP
rogre
ssion
Seq 1
Seq 2
Investigator choice:1st line
reintroductionOr
RegorafenibOr
Other
mCRC Treatment Decision Recommendations: Second Line
2L1L 3L 4L
RASmutation
RASwild type
RASwild type
RASwild type
Chemo + anti-VEGF
Chemo + anti-VEGF
Chemo + anti-VEGF
Chemo + anti-VEGF
Chemo + anti-VEGF
Chemo + anti-EGFR
Chemo + anti-EGFR
Chemo + anti-VEGF
Chemo + anti-EGFR
Other anticancer therapy, BSC, or clinical trial
Other anticancer therapy, BSC, or clinical trialOther anticancer therapy, BSC, or clinical trial
Other anticancer therapy, BSC, or clinical trial
Left-sided cancers only
Anti-VEGF
Anti-EGFRBevacizuma
bRamucirum
abZiv-
aflibercept
CetuximabPanitumum
ab
van Cutsem. Ann Oncol. 2016;27:1386.
Regorafenibor TAS-102
Regorafenibor TAS-102
Regorafenibor TAS-102
Regorafenibor TAS-102
3ª and 4ª line
≥ 3rd line - anti-EGFR therapy
Karapetis et al., NEJM 2008 359 (17) 1757-1765
≥ 3rd line - anti-EGFR therapy
Price T. Lancet Oncol 2014; 15: 569–79.
ASPECCT trial: Panitumumab non inferior to
Cetuximab
Regorafenib and trifluridine/tipiracil in refractory mCRC:
Grothey, Van Cutsem E et al, Lancet 2013; Mayer R, Van Cutsem E, Ohtsu A et al NEJM, 2015
CORRECT: regorafenib
RECOURSE: trifluridine/tipiracil
mCRC Treatment Decision Recommendations: Third Line and Beyond
2L1L 3L 4L
RASmutation
RASwild type
RASwild type
RASwild type
Chemo + anti-VEGF
Chemo + anti-VEGF
Chemo + anti-VEGF
Chemo + anti-VEGF
Chemo + anti-VEGF
Chemo + anti-EGFR
Chemo + anti-EGFR
Chemo + anti-VEGF
Chemo + anti-EGFR
Other anticancer therapy, BSC, or clinical trial
Other anticancer therapy, BSC, or clinical trialOther anticancer therapy, BSC, or clinical trial
Other anticancer therapy, BSC, or clinical trial
Left-sided cancers only
Anti-VEGF
Anti-EGFRCetuximab
Panitumumab
van Cutsem. Ann Oncol. 2016;27:1386.
Regorafenibor TAS-102
Regorafenibor TAS-102
Regorafenibor TAS-102
Regorafenibor TAS-102
Slide credit: clinicaloptions.com
Braf mutado
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
BRAF INHIBITION IN mCRC
Adapted from Van Geel et al. ASCO 2014
1. Corcoran et al. Nature 2012, 2. Prahallad et al. Cancer Discovery 2012
EGFR signaling is inhibited by hyperactive BRAF. In the presence of BRAF inhibitor, EGFR
signaling is reactivated either by the BRAF-MEK pathway or the PI3K-AKT pathway,
resulting in cellular proliferation and survival1,2
Prevalence ~ 8%
PF
S (
%) HR: 0.48 (95% CI: 0.31-0.75;
P = .001)
Events, n mPFS (95% CI)
VIC 40 4.3 (3.6-5.7)
IC 48 2.0 (1.8-2.1)
Kopetz S, et al. ASCO 2017
0
20
40
60
80
10
0
0 3 6 8 10 12 14
Months
SWOG S1406
Phase II1-2 prior linesNo prior anti-EGFR/BRAF/MEK
VIC – Vemurafenib, Irinotecan, CetuximabIC – Irinotecan, Cetuximab
BRAF V600E predictive value in metastatic CRC
J Clin Oncol 37, 2019 (suppl 4; abstr 688)
ANCHOR-CRC will investigate the cetuximab + encorafenib + binimetinib combination in 1st-line BRAF mt mCRC
ANCHOR-CRC1,2: a multicenter, open-label, single-arm Phase II study to evaluate the antitumor activity of the combination of binimetinib + encorafenib + cetuximab in adults with previously untreated BRAF V600 mt mCRC
• The study is recruiting: estimated primary completion date is June 2020
Primary endpoint: confirmed ORR based on local tumorassessment
Secondary endpoints: confirmed ORR based on central tumorassessment; ORR, DOR, TTR, PFS, OS (all based on local and central tumor assessment); safety; pharmacokinetic parameters; quality of life
Key inclusion criteria: RAS wt, BRAF V600E* mCRC with measurable disease; no prior systemic therapy for metastatic disease
Key exclusion criteria: previous treatment with RAF, MEK or EGFR inhibitors; symptomatic brain metastases or leptomeningeal disease; retinal vein occlusion (or risk factors for); Crohn’s disease, inflammatory bowel disease, or impaired cardiovascular function
*BRAF mt status must be determined in tumor tissue by PCR or NGS local assay prior to screening, and confirmed by the central laboratory2
CR, complete response; PR, partial response.
Patients with BRAF V600E mCRC who have had no prior treatment for metastatic disease
Cetuximab 400mg/m2 i.v cycle 1, day 1, 250mg/m2 q1w for the first 28 weeks, then 500mg/m2 q2w from Week 29
(cycle 8, day 1) + encorafenib 300mg q1d PO + binimetinib45mg BID PO (40 subjects to be treated)
STUDY DESIGN
If ≥12 patients achieve CR or PR, 50 additional
patients will be treated
If ≤11 patients achieve CR or PR, the study will be
stopped
Treatment will be given in 28-day cycles until disease progression, unacceptable toxicity, initiation of subsequent
anticancer therapy, death, or withdrawal of consent
1. https://clinicaltrials.gov/ct2/show/NCT0369317
0;2. ANCHOR-CRC protocol.
MSI
Le DT et al. ASCO 2015. Le DT et al. NEJM 2015
• PFS 71% (12 months)
• OS 85% (12 months)
• Not only SS but clinically significant with meaningful improvements in patient-reported
outcomes (functioning, symptoms, and QoL).
PFS – OS (mFUP 13.4 months)
Overman et al. J Clin Oncol 2018
Nivolumab/Ipilimumab
ORR: 55%; Disease control > 12 weeks: 80%
HER-2 +
RO: 32% IC 95% (20-45)Siena et al, AACR 2017
HERACLES trialPhase IITrastuzumab + Lapatinib
Rechallenge
Rossini et al. Asco Meeting 2018; Cremolini C et al. Jama Oncology 2018
Tratamientos específicos
• FOLFOXIRI/Beva
• EGFR + BRAF + MEK inhibitors
BRAF mutado
• InmunoterapiaMSI
• Herceptin + Lapatinib
• Herceptin+ PertuzumabHER-2+
Future Treatments
Slide 32
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