Chiara Cremolini

University of Pisa

Azienda Ospedaliero-Universitaria Pisana

ESMO Preceptorship Programme – Colorectal Cancer

Valencia, 12th May 2017

Review of the ESMO consensus conference

on metastatic colorectal cancer –

Basic strategies and groups

Chemotherapy and targeted agents in 1st line

The challenge of precision medicine

QoL

Treatment characteristics

Toxicity profile

Patient clinical characteristics

Age

Comorbidities

Prior adjuvant

treatment

Tumour molecular characteristics

RAS BRAF

Performance

status

Tumour burden and

localisationResectability

Tumour biology

(Aggressiveness)

Tumour clinical characteristics

Related symptoms

Flexibility of tx

administrationSocioeconomic

factors

Main ingredients according to ESMO guidelines

Expectations/Attit

ude

Organ function

Baseline evaluation

• Clinical examination

(assessment of patients’ conditions

independently of their malignant

disease)

• Blood counts

• Liver and renal function

• Tumour marker levels (CEA)

• CT scan/MRI

• RAS and BRAF mutational status

Resectability(aka treatment’s aim)

Key message from 2012 ESMO clinical guidelinesSchmoll et al, Ann Oncol ’12

How to prioritize drivers?

EASILYRESECTABLE

MARGINALLYRESECTABLE

POTENTIALLYRESECTABLE

NEVERRESECTABLE

Group* 0

Multidisciplinary Assessment

Group* 1 Group* 2High load

Group* 3Low load

CURE!!!!!! DISEASE CONTROL

*According to ESMO 2012 clinical guidelines

More intensive tx approach

Less intensive tx approach

Integration with surgery

Resectability(aka treatment’s aim)

RAS status

Molecular revolution?…after FIRE-3 and PEAK

How to prioritize drivers?

Resectability(aka treatment’s aim)

RAS status

Key message from 2014 ESMO clinical guidelinesVan Cutsem et al, Ann Oncol ’14

How to prioritize drivers?

A paradigm shift in mCRC

‘One size of treatment intensity fits all’

‘One size of treatment intensity DOES NOT fit all’

The kingdom of doublets The era of fine tuning

Which is the ‘best’ targeted

agent to be combined with a

chemo doublet?

Which is the most appropriate

treatment intensity?

Modulating treatment intensity in mCRC: available options

MONOCHEMOTHERAPY

DOUBLETS

TRIPLET

FLUOROPYRIMIDINE + BEV

FOLFOX/FOLFIRI/XELOX + BEV

FOLFOX/FOLFIRI + anti-EGFR

FOLFOXIRI + BEV

How to prioritize drivers?

Resectability(aka treatment’s aim)

PATIENT’S

ASSESSMENT (age, PS, patients’ expectations

and motivation, logistics)

RAS status

On top of ESMO algorithm

Van Cutsem et al, Ann Oncol ‘16

a) According to medical condition not due to malignant disease

Monotherapy: need or choice?

ESMO Guidelines 2014

“Without present or imminent

symptoms and limited risk for

rapid deterioration, the aim is

rather prevention of tumour

progression and prolongation of

life with minimal treatment

burden”

In most cases we cannot estimate how ‘indolent’ the

disease is

NEED!

Van Cutsem et al, Ann Oncol ‘14

Goal / condition Molecular Preferred 1st line regimen

Cytoreduction all WT Doublet plus EGFR

(FOLFOXIRI plus beva)

RAS mut Doublet or triplet + beva

BRAF mut FOLFOXIRI + beva

Disease

stabilization

all WT Doublet plus EGFR or

Doublet plus beva

RAS mut Doublet plus beva

BRAF mut FOLFOXIRI +/- beva

„frail“, or chosen

sequential

treatment

no BRAF

mut

Cape or FU + beva

ESMO recommendations: 2016

Van Cutsem et al, Ann Oncol ‘16

MRC FOCUS2

FFCD 2001-02

Aparicio et al. Ann Oncol ‘16

Seymour et al. Lancet ‘11

Clinical trials in elderly/unfit pts – chemo era

AVEX2

Median age, years [range]

76 [70–87]

Treatment (patient number)

Bev + capecitabine (n=140)

Capecitabine(n=140)

Median PFS, months

9.1 5.1

HR [95% CI], p value

0.53 [0.41–0.69];p<0·0001

Median OS, months

20.7 16.8

HR [95% CI]0.79 [0.57–1.09];

p=0.18

ORR 19% 10%

p=0.04

Clinical trials in elderly/unfit pts – biologics era

Cunningham et al, Lancet Oncol ‘13

On top of ESMO algorithm

Van Cutsem et al, Ann Oncol ‘16

a) According to medical condition not due to malignant disease

Treatment goal

Clearlyresectable

mets

Surgery ���� +/- “adjuvant” oxaliplatin-based chemo(favourable prognostic criteria)

Oxa-based doublet ���� Surgery ���� Oxa-based doublet(unfavourable prognostic criteria)

No targeted agents

Treatment goal

OMDClearlyresectable

mets

Other arrows in our quiver

SurgeryLocal and

locoregionalapproaches

ESMO recommendations: oligometastatic disease

Van Cutsem et al, Ann Oncol ‘16

Increasing options in the toolbox of locoregional approaches

Van Cutsem et al, Ann Oncol ‘16

Treatment goal

OMDClearlyresectable

mets

CYTOREDUCTION (Shrinkage)

ESMO recommendations: 2016

Van Cutsem et al, Ann Oncol ‘16

Goal / condition Molecular Preferred 1st line regimen

Cytoreduction all WT Doublet plus EGFR

(FOLFOXIRI plus beva)

RAS mut Doublet or triplet + beva

BRAF mut FOLFOXIRI + beva

Disease

stabilization

all WT Doublet plus EGFR or

Doublet plus beva

RAS mut Doublet plus beva

BRAF mut FOLFOXIRI +/- beva

„frail“, or chosen

sequential

treatment

no BRAF

mut

Cape or FU + beva

FIRE-3 and PEAK: Depth of response

Stintzing et al, Lancet Oncol ‘16

p<0.0001

CI, confidence interval; DoR, durat

0

Me

an

Ch

an

ge

Fro

mB

as

eli

ne

, %

-20

-40

-60

-80

-100

0 8 16 24 32 40 48 56 64 72 80

Pmab + mFOLFOX6 88 80 70 63 53 42 42 27 25 17 17Bmab + mFOLFOX6 81 74 66 57 45 36 26 22 13 11 8

Weeks

Bmab + mFOLFOX6Pmab + mFOLFOX6

Rivera et al, ECC ‘15

FOIB1

n=57

TRIBE2

n=252

OPAL3

n=97

STEAM4

n=93

MOMA5

n=232*

CHARTA6

n=125

RegimenFOLFOXIRI/

Bev

FOLFIRI/Bev

+/- Oxa

FOLFOXIRI/

Bev �

FU/Bev

maintenance

FOLFOXIRI/

Bev vs

FOLFIRI/Bev

FOLFOXIRI/

Bev

� Bev ±

metroCT

FOLFOX/Be

v

± 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

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

* >70% patients with RAS or

BRAF mutation

FOLFOXIRI + bev: consistent results

Grade 3/4 Adverse

Events, %

TRIBE1

n=252

OPAL2

n=97

STEAM3

n=93

MOMA4

n=232

CHARTA5

n=125

Diarrhoea 18.8% 11% 10% 13% 16%

Stomatitis 8.8% 4% 3% 4% 3%

Neutropenia 50.0% 26% 57% 52% 21%

Hypertension 5.2% 3% 22% 4% 7%

VTE events 7.2% 5.0% 7% 3% 2%

1. Loupakis et al. N Engl J Med 2013 2. Stein et al. Br J Cancer 2015; 3. Bendell et al. ASCO GI 2017

4. Falcone et al. ESMO 2016; 5. Schmoll et al. ASCO GI 2017

FOLFOXIRI + bev: safety results

FOLFOXIRI plus bev: WHO?

Patient selection

• NEVER over 75

• NEVER 71–75 years old with ECOG PS >0

• NEVER in the case of contraindications

to single drugs

Patients previously exposed to oxa-based adjuvant are NOT the optimal candidates

Loupakis et al. N Engl J Med 2014

Intensification of the chemotherapy backbone: WHEN?

Primary endpoint: radical resection rate

mFOLFOX-6 + bev

n=39

FOLFOXIRI + bev

n=41

Overall response rate 62% 81% p=0.061

R0/R1/R2 surgery 49% 61% p=0.327

R0 surgery 23% 49% 0.017

PFS (median) 11.5 18.6 HR: 0.43 (0.26–0.72)

RFS (median) 8.1 17.1 HR: 0.31 (0.12–0.75)

OS (median) 32.2 Not reached –

Phase II random OLIVIA study

Gruenberger et al. Ann Oncol 2014

Intensification of the chemotherapy backbone: WHEN?

Pooled analysis of patients with liver-limited disease (LLD)

from FOIB, TRIBE and MOMA

Characteristics,

% patientsn=205

Synchronous metastases 90%

≥4 metastases 61%

Bilobar distribution 79%

Larger metastasis >5cm 42%

Patients with clearly initially

unresectable LLD, not

selected with conversion

intent

n=205

RECIST

response

n=137 (69%)

R0/R1

resection

n=75 (37%)

R0/R1 resected

(n=75)

R0 resected

(n=63)

Median PFS,

months18.1 18.3

5-year PFS rate 10% 12%

Median OS,

months44.3 56.6

5-year OS rate 42% 43%

Cremolini et al, Eur J Cancer ‘17

Treatment goal

OMDClearlyresectable

mets

CYTOREDUCTION (Shrinkage)

DISEASE CONTROL

Goal / condition Molecular Preferred 1st line regimen

Cytoreduction all WT Doublet plus EGFR

(FOLFOXIRI plus beva)

RAS mut Doublet or triplet + beva

BRAF mut FOLFOXIRI + beva

Disease

stabilization

all WT Doublet plus EGFR or

Doublet plus beva

RAS mut Doublet plus beva

BRAF mut FOLFOXIRI +/- beva

„frail“, or chosen

sequential

treatment

no BRAF

mut

Cape or FU + beva

ESMO recommendations: 2016

Van Cutsem et al, Ann Oncol ‘16

BRAF assessment: 2016 ESMO guidelines

50%

RAS

mutations

RAS

mutant

RAS/BRAF

wild-type

BR

AF

mu

tati

on

40% 50%10%

• Minimal impact of anti-EGFR moAbs

• If possible, treat with FOLFOXIRI plus

bev

• Consider targeted strategies in clinical

trials

BRAF inhibitor + EGFR inhibitor +/-

MEK/PIK3CA inhibitor

Study

ReferenceN RR Median PFS Median OS

FOIBMasi, Lancet Oncol ‘10

10 90% 12.8 23.8

Prospective phase IILoupakis, EJC‘13

15 60% 9.2 24.1

TRIBECremolini et al, Lancet Oncol’15

16 56% 7.5 19.0

FOLFOXIRI plus bev in BRAF mutant mCRC: summary

Events Median

28 41.7 months

32 33.5 months

88 27.3 months

93 23.9 months

14 19.0 months

11 10.7 months

RAS and BRAF wild-type – arm B RAS and BRAF wild-type – arm A

RAS mutant – arm B RAS mutant– arm A

BRAF mutant – arm B BRAF mutant– arm A

TRIBE: treatment effect in molecular subgroups - OS

Cremolini et al, Lancet Oncol ’15

Resected liver mets: outcome according to RAS/BRAFmutations - RFS

Cremolini et al, Eur J Cancer ‘17 Schirripa et al, Br J Cancer ‘15

Resected after FOLFOXIRI + bev No previous chemotherapy

QoL

Treatment characteristics

Toxicity profile

Patient clinical characteristics

Age

Comorbidities

Prior adjuvant

treatment

Tumour molecular characteristics

RAS BRAF

Performance

status

Tumour burden and

localisationResectability

Tumour biology

(Aggressiveness)

Tumour clinical characteristics

Related symptoms

Flexibility of tx

administrationSocioeconomic

factors

Main ingredients according to ESMO guidelines

Expectations/Attit

ude

Organ function

Primary tumour location

How to interpret subgroup analyses?

p value p value

RAS wt Study population

Right-sided primary

Left-sided primary

Arm A Arm AArm B Arm B

RAS wt Study population

Right-sided primary

Left-sided primary

Arm A

How to interpret subgroup analyses?

Arm AArm B Arm B

HRHR

p for interaction

If significant (p<0.10) ���� hypothesis-generating

Right versus Left: metanalysis of first-line trials - OS

Arnold et al., Ann Oncol ’17

Right versus Left: metanalysis of first-line trials - PFS

Arnold et al., Ann Oncol ’17

Right versus Left: metanalysis of first-line trials - ORR

Arnold et al., Ann Oncol ’17

BRAF V600E mutation

BRAF-like signature

RAS mutations

PIK3CA mutations

dMMR

CIMP-high

Low AREG-EREG expression

CMS1(Immune)

HER-2 overexpression

High AREG-EREG expression

EGFR amplification

Lee et al., Br J Can ’16Missiaglia et al., Ann Oncol ’14

Guinney et al., Nat Med ’15Laurent-Puig et al., ESMO ’16

Puzzoni et al, ASCO GI ’17Pietrantonio et al, JNCI ‘17

miR-31-3p high

miR-31-3p low

Right versus Left: Molecular make-up

EGFR promoter methylation

ALK/ROS1/NTRK rearrangements

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).

Key messages

Arnold et al, Ann Oncol ‘17

Goal / condition Molecular Preferred 1st line regimen

Cytoreduction all WT Left: Doublet/EGFR

Right: FOLFOXIRI/beva (Doublet/EGFR)

RAS mut FOLFOXIRI/beva

BRAF mut FOLFOXIRI/beva

Disease

stabilization

all WT Left: Doublet/EGFR

Right: Doublet (FOLFOXIRI)/beva

RAS mut Doublet (FOLFOXIRI)/beva

BRAF mut FOLFOXIRI (Doublet)/beva

„frail“, or chosen

sequential

treatment

no BRAF ! Capecitabine or 5FU/beva

Incorporating primary tumour location

Arnold et al, Ann Oncol ‘17

TRIBE: Subgroup analyses of OS

Cremolini et al., Lancet Oncology ‘16

QoL

Treatment characteristics

Toxicity profile

Patient clinical characteristics

Age

Comorbidities

Prior adjuvant

treatment

Tumour molecular characteristics

RAS BRAF

Performance

status

Tumour burden and

localisationResectability

Tumour biology

(Aggressiveness)

Tumour clinical characteristics

Related symptoms

Flexibility of tx

administrationSocioeconomic

factors

Main ingredients according to ESMO guidelines

Expectations/Attit

ude

Organ function

Primary tumour locationHER-2???

Microsatellite instability

Treatment strategies in mCRC

Treatment 1 PD Treatment 2 PD Treatment 3

1st line 2nd line 3rd line

Treatment 1 PD Treatment 2 PD Treatment 3

Maintenance with bevacizumab

Progression-free survival

Favours active tx. Favours no tx.

Stein et al, Clin Color Can ‘15

Overall survival

Maintenance with bevacizumab

Van Cutsem et al, Ann Oncol ‘16

Treatment strategies in mCRC

Treatment 1 PD Treatment 2 PD Treatment 3

1a linea 2a linea 3a linea

Treatment 1Maintenance

PD Treatment 1 PD

Treatment 1 PD Treatment 2 PD Treatment 3

Take home message

• The choice of the first-line treatment has a crucial mission in

mCRC: to achieve disease control, in order to allow further

interventions (systemic treatments and locoregional tools)

• Though recognizing the importance of exposing mCRC patients

to all available treatment options across different lines of

treatment (sequencing, continuum of care…), the impact of the

first-line treatment on the disease history is the most relevant

• Today a mix of clinical and molecular factors contributes to the

therapeutic decision-making process…the contribution of

molecular markers will probably increase in the next future

chiaracremolini@gmail.com