Review of the ESMO consensus conference on metastatic CRC ... · Clinical presentation: Tumour...

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Review of the ESMO consensus conference on metastatic CRCBasis strategies ad groups (RAS, BRAF, etc)

Michel Ducreux

Disclosure• Participation to advisory boards:

– ROCHE

– MERCK SERONO

– AMGEN

– SANOFI

– BAYER

– LILLY

– CELGENE

– SERVIER

• Speaker in symposiums:

– ROCHE

– MERCK SERONO

– SANOFI

– LILLY

– CELGENE

• Research funding:

– ROCHE

– MERCK SERONO

– PFIZER

ESMO consensus on mCRC 2016

Chairs: Co-Chairs of working groups

E Van Cutsem A Sobrero Advanced mCRC

D Arnold R Adam Local and ablative treatment, oligometastasis

A Cervantes H Van Krieken Molecular Pathology and Biomarkers

Contributors

D Aderka

E Aranda

A Bardelli

A Benson

G Bodoky

F Ciardiello

A D’Hoore

A Diaz Rubio

JY Douillard

M Ducreux

A Falcone

A Grothey

T Gruenberger

K Haustermans

V Heinemann

P Hoff

K Köhne

R Labianca

P Laurent-Puig

B Ma

T Maughan

K Muro

N Normanno

P Österlund

W Oyen

D Papamichael

G Pentheroudakis

P Pfeiffer

T Price

C Punt

J Ricke

A Roth

R Salazar

W Scheithauer

HJ Schmoll

J Tabernero

J Taieb

S Tejpar

H Wassan

T Yoshino

A Zaanan

First step is biology…

Akt

SOS

FOS Myc

P13K

FKHRmTOR

PTEN

MEK 1/2

MAPK

BADGSK-3

Shc

Grb-2

Ras

Raf

Junp27

Cyclin D-1

LigandLigand

Signal

Adapters

and Enzymes

Signal

Cascade

EGFR dimer

Transcription

Factors

STAT

Extended Ras and RAF

testing

EXON 1 EXON 2 EXON 3 EXON 4

EXON 1 EXON 2 EXON 3 EXON 4

EXON 1 EXON 15 EXON 16

KRAS

NRAS

BRAF

N/A 4% 7%

12 13 59 61 117 146

5% 6% 0%

12 13 59 61 117 146

6%

600

Schwartzberg LS et al. ASCO 2013 (abst. 3631)

Recommendation 3: RAS testing

RAS mutational status is a negative predictive biomarker for

therapeutic choices involving EGFR antibody therapies in the

metastatic disease setting [I, A]

RAS testing should be carried out on all patients at the time of

diagnosis of mCRC [I, A]

RAS analysis should include at least KRAS exons 2, 3 and 4

(codons 12, 13, 59, 61, 117 and 146) and NRAS exons 2, 3 and 4

(codons 12, 13, 59, 61 and 117)

Molecular Pathology and Biomarkers

Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016

Online Ann Oncol, July 2016

Recommendation 5: BRAF testing

Tumour BRAF mutation status should be assessed alongside the

assessment of tumour RAS mutational status for prognostic

assessment (and/or potential selection for clinical trials) [I, B]

Recommendation 6: MSI testing

MSI testing in the metastatic disease setting can assist clinicians in

genetic counselling [II, B]

MSI testing has strong predictive value for the use of immune check-

point inhibitors in the treatment of patients with mCRC [II, B]




Recommendation 9: emerging technologies

Although CTC number correlates with prognosis in patients with

mCRC, the clinical utility of CTC assessments is not yet clear and

therefore cannot be recommended [IV, D].

The utility of liquid ctDNA biopsies to guide treatment decisions is

currently under investigation in clinical trials, but cannot yet be

recommended in routine practice [V, D].

Whole genome, whole exome and whole transcriptome analysis

should be carried out only in a research setting [V, D].




HER2 positive patients.. A specific

subgroup??

S.artore-Bianchi et al. Lancet Oncol 2016;17:738

ORR 35%, DCR 78% in refractory patients

PFS : 5.5 months (7.3 months HER2 +++ vs 4.2 months HER2 ++)

-100-90-80-70-60-50-40-30-20-10

0102030405060708090

Ch

an

ge

in

ta

rge

t le

sio

n fro

m b

ase

line

(%)

+

++

++

++

+

HER2 3+ HER2 2+ Ongoing treatmentRR

Consensus

classification: not yet…

Guinney J et al. Nature Medicine 2015;21:1350-6

CMS classification: a

prgnostic effect in mCRC

H-J. Lenz , et al., ASCO 2017, abs 3511

OS

1.00

0.75

0.50

0.25

0.00

0 12 24 36 48 60 72Months from randomization

Pro

po

rtio

nsw

ith

ou

t ev

ent

CMS Events/Total Median (95% CI)

CMS1 85/104 15.0 (11.7-22.4)

CMS2 173/242 40.3 (36.1-43.1)

CMS3 58/68 24.3 (16.4-29.0)

CMS4 127/167 31.4 (26.3-36.9)

Logrank P-value : < .0001

Similar patterns in FIRE3

S. Stintzing, et al., ASCO 2017, abs 3510

100%

80%

60%

40%

20%

0%CMS1 CMS2 CMS3 CMS4

Cetu

xim

ab A

rm

Be

va

ciz

um

ab

Arm

Cetu

xim

ab A

rm

Be

va

ciz

um

ab

Arm

Cetu

xim

ab A

rm

Be

va

ciz

um

ab

Arm

Cetu

xim

ab A

rm

Be

va

ciz

um

ab

Arm

57.2%50.0%

86.7%

70.0%73.7%

41.7%

77.8%

53.2%

0.76*

0.045*

0.13* 0.017*

ORR acccording to CMS in RAS wt patients

* = two-sided Fisher s p

Tumour

characteristics

Patient

characteristics

Treatment

characteristics

Clinical presentation:

Tumour burden

Tumour localisation

Age Toxicity profile

Tumour biology Performance statusFlexibility of treatment

administration

RAS mutation status Organ function Socio-economic factors

BRAF mutation status

Comorbidities, patient

attitude, expectation and

preference

Quality of life

Table 4.

Drivers for first-line treatment



Figure 3. Standard treatment algorithm for patients with oligometastatic

disease.

RFA = radiofrequency ablation;

SBRT = stereotactic body radiation

therapy

SIRT = selective internal radiation

therapy



Recommendation 13: conversion therapy.

In potentially resectable patients (if conversion is the goal), a regimen leading

to high RRs and/or a large tumour size reduction (shrinkage) is

recommended [II, A].

There is uncertainty surrounding the best combination to use as only few

trials have addressed this specifically:

✓ In patients with RAS wild-type disease, a cytotoxic doublet plus an anti-

EGFR antibody seems to have the best benefit risk/ratio, although the

combination of FOLFOXIRI plus bevacizumab may also be considered

and, to a lesser extent, a cytotoxic doublet plus bevacizumab [II, A].

✓ In patients with RAS-mutant disease: a cytotoxic doublet plus

bevacizumab or FOLFOXIRI plus bevacizumab [II, A].

Patients must be re-evaluated regularly in order to prevent the overtreatment

of resectable patients as the maximal response is expected to be achieved

after 12–16 weeks of therapy in most patients.



Local and ablative treatment

(including surgery)

Treatment of metastatic disease



Figure 5. Maintenance and second-line treatment options. CT, chemotherapy;

PS, performance status. Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016



Recommendation 21: Third-line therapy

❖ In RAS wild-type and BRAF wild-type patients not previously treated with EGFR

antibodies cetuximab or panitumumab therapy should be considered

Cetuximab and panitumumab are equally active as single agents [I, A]

The combination of cetuximab with irinotecan is more active than cetuximab alone, in

irinotecan refractory patients [II, B]

There is no unequivocal evidence to administer the alternative EGFR antibody, if a patient is

refractory to one of the EGFR antibodies [I, C].

❖ Regorafenib is recommended in patients pre-treated with fluoropyrimidines,

oxaliplatin, irinotecan, bevacizumab and in RAS wild-type patients with EGFR

antibodies [I, B]

Regorafenib is superior to placebo in terms of OS although there are toxicity concerns in frail

patients.

❖ Trifluridine/tipiracil is recommended for patients pre-treated with

fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab and in RAS wild-type

patients with EGFR antibodies [I, B].




A work in progress: the colorectal tract

is highly heterogeneous

Bufill. Ann Intern Med 1990; Missiaglia et al. Ann Oncol 2014; Brule. ASCO 2013 Cancer

Genome Atlas Network. Nature 2012; Bendardaf. Anticancer Res 2008

• Incidence: ~40%

(increasing)

• Older patients

• Female patients

• Microsatellite

instability

• Hypermethylation,

higher mutation

rates

• PI3KCA mutation

• BRAF mutations

• KRAS mutations

Right-sided tumours

• Incidence: ~60%

• Younger patients

• Predominantly WT

• p53 mutation

• EGFR gain

• High EGFR ligand

expression

• HER2 gain

• Better prognosis

Left-sided tumours

Review of the ESMO consensus conference on metastatic CRC ... · Clinical presentation: Tumour...

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