algoritmo terapéutico actual en cáncer colorrectal metastásico · colon derecho 9% 10% 27% 56%...

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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