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TRANSCRIPT
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