current standard of care of metastatic colorectal …

CURRENT STANDARD OF CARE OF METASTATIC COLORECTAL CANCER: THE EVOLUTION OF ESMO CLINICAL

PRACTICE GUIDELINES

Fortunato Ciardiello

ESMO Past-President 2018-2019

Dipartimento di Medicina di

Precisione

Università degli Studi della

Campania Luigi Vanvitelli

CONFLICT OF INTEREST DISCLOSURE

Advisory Boards:

Roche, Amgen, Lilly, Merck, Servier, Bayer, Symphogen

Institutional Research Funding:

Roche, Amgen, Bayer, Merck

Drivers for first line treatment choices in

metastatic colorectal cancer

Adapted from Van Cutsem et al, ESMO Consensus Conference, Annals of Oncology 2016

• Clinical presentation (tumour burden, primary tumour localisation)

• Tumour biology

• RAS mutation status

• BRAF mutation status

*Tumour

Characteristics

• Age

• Performance status

• Organ function

• Comorbidities

• Patient attitude, expextations, preference

Patient

characteristics

• Toxicity profile

• Flexibility of treatment admnistration

• Socioeconomic factors

• Quality of life

Treatment

characteristics

*Additional tumour characteristics: HER2 amplification; MSI-H status

Twenty-one consensus reccomendation statements on diagnosis and

treatment options and sequences for oligometastatic as well as for

extended metastatic disease.

and

Three consensus reccomedation statements on the use of cytotoxics

and biologicals in the first and subsequent lines of treatment.

The results of the Consensus Conference

on metastatic colorectal cancer were summarized in:

Recommendation 3: RAS testing

RAS is a predictive biomarker for therapeutic choices involving EGFR antibody

therapies in the metastatic disease setting [1, A].

RAS testing is mandatory prior to treatment with EGFR-targeted monoclonal

antibodies cetuximab and panitumumab [1, A].

Primary or metastatic colorectal tumour tissue can be used for RAS testing (see

also Recommendation 3).

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).

Turnaround time for RAS testing (expanded RAS analysis) should be ≤7 working

days from the time of receipt of the specimen by the testing laboratory to the time of

issuing of the final report, for >90% of specimens.

Molecular Pathology and Biomarkers

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].


ESMO consensus guidelines for the management ofpatients with metastatic colorectal cancer

ESMO Special Symposia manuscript for submission to Annals of Oncology 06.02.17

Final submission draft

18#

Table 1. Source of patients for the analyses

Trial name

Trial characteristics

Phase of trial

Chemo-therapy

backbone

Bevacizumab in control

arm?

Anti-EGFR therapy

Treatment line

Randomised With KRAS

evaluable

With KRAS

Wt*

With all RAS

wt

With all RAS wt and

tumour side confirmed

CRYSTAL [28, 42, 43]

III FOLFIRI No Cetuximab 1st

1217 1063 666 367%

364

FIRE-3

[28, 36]

III FOLFIRI Yes Cetuximab 1st

752 NA 609£ 400

%% 394

PEAK [35] II FOLFOX6 Yes Panitumumab 1st

285 285 285 170$

143

PRIME [40, 41]

III FOLFOX4 No Panitumumab 1st

1183 1096 656 512 416

20050181

[45]

III FOLFIRI No Panitumumab 2nd

1186 1083 597 421 368

CALGB

80405 [27, 38]

III FOLFIRI/

FOLFOX6

Yes Cetuximab 1st 1137 1137 1137 526

$$ 474

*Not always easy to determine, taken from publication or slide presentation. Sometimes refers to all ITT population (PRIME, PEAK, AMGEN181) sometimes from the KRAS wt exon 2 (CRYSTAL, FIRE-3) sometimes from available tissue to test (CALGB 80405). %

Only 430 patients were evaluable for other RAS mutations; %%

475 patients were tested successfully for the other KRAS mutations; $

Extended RAS analysis was performed in

250 patients with 233 patients with KRAS or RAS results. Out of the 221 patients with KRAS exon 2 wt at this stage, 170 were RAS wt; $$

Out of 670 patients tested for all RAS; £592 patients if only those receiving study treatment are considered and 493 patients if only those receiving study treatment and had assessable CT-scan are considered.

EGFR, epidermal growth factor receptor; NA, not available; wt, wild-type



30#

Figure 1.



31#

Figure 2.

A

Prognostic effect on OS

in the CT + Anti-EGFR Arm



32#

B

Prognostic effect on PFS




33#

C

Prognostic effect on RR




34#

Figure 3.

A

Prognostic effect on OS

in the CT +/- Bevacizumab Arm



35#

B

Prognostic effect on PFS




36#

C

Prognostic effect on RR




37#

Figure 4.

A

Predictive effect on OS



38#

B

Predictive effect on PFS



39#

C

Predictive effect on RR



16"

are strong negative prognostic markers but might be (non-significant) predictive markers for intensive

therapy [54].

Therefore, with all of the caveats resulting from this analysis, which was performed retrospectively,

and involved a limited number of patients from the individual trials, a relatively small number of right-

sided patients, and – most importantly – did not consider a preference for distinct treatment

sequences, as only the randomization to the respective treatment line was analysed, it provides

evidence in the first-line treatment setting to:

i. Reinforce the use of EGFR antibody therapy in patients with mCRC and left-sided RAS wt

tumours.

ii. Promote the idea that patients with right-sided RAS wt tumours might be better treated with

chemotherapy alone or chemotherapy plus bevacizumab - except maybe if the goal is

tumour size reduction as the ORRs were higher (but not PFS and OS).

iii. Emphasise that in the absence of data on specific treatment sequences, there is no reason

that EGFR-antibody therapy should be avoided in cases of disease progression or treatment

intolerance independent of primary tumour location.

iv. Promote the concept of a “continuum of care” and the sequential use of all therapies,

including bevacizumab where appropriate, in the treatment of patients with mCRC.

However the developmental, genetic, physiological and biological differences associated with the

different locations in the colon and rectum are clearly more complex than simple right- and left-

sidedness and one might predict that a comprehensive evaluation of molecular features in left- and

right-sided CRCs will contribute to improvements in treatment outcomes in the future. Going forward,

new randomised controlled trials should have to stratify patients according to primary tumour location

and if the sequence in which the currently available therapies are delivered matters we need more

trials based on tumour location and molecular characteristics.

acknowledgements

Anne Kinsella (Cancer Communications and Consultancy Ltd, Knutsford, Cheshire UK) is

acknowledged for her assistance in the preparation of the manuscript, funded by ESMO.

funding

All expenses relating to the special symposia were covered by ESMO.

author disclosures

DA has reported honoraria/consultancy for Roche, Merck-Serono, Bayer, Amgen; research funding

from Roche."J-YD has reported advisory boards/symposia/lectures for Amgen, Roche, Merck-Serono,

Sanofi and Bayer. MP has reported honoraria/consultancy/advisory boards for Amgen, Bayer, Sanofi

Pan-Asia adapted ESMO consensus guidelines

for the management of patients with metastatic

colorectal cancer

JSMO/ESMO joint initiative endorsed by CSCO, KACO,

MOS, SSO and TOS

Expert Face-to-Face Meeting

Kobe, July 30, 2017

My first line treatment choices in February 2018

(in fit patients)

Goal Mutation Preferred first line option

Cytoreduction RAS and

BRAF WT

Left: DOUBLET + anti-EGFR

Right: FOLFOXIRI + bevacizumab

(DOUBLET + anti-EGFR?)

RAS mut FOLFOXIRI + bevacizumab

BRAF mut FOLFOXIRI + bevacizumab

Disease

stabilization

RAS and

BRAF WT

Left: DOUBLET + anti-EGFR

Right: FOLFOXIRI or DOUBLET + bevacizumab

RAS mut FOLFOXIRI or DOUBLET + bevacizumab

BRAF mut FOLFOXIRI + bevacizumab

current standard of care of metastatic colorectal …

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