Chiara Cremolini
University of Pisa
Azienda Ospedaliero-Universitaria Pisana
ESMO Preceptorship Programme – Colorectal Cancer
Valencia, 18th May 2018
Review of the ESMO consensus conference
on metastatic colorectal cancer –
Basic strategies and groups
Chemotherapy and targeted agents in 1st line
Disclosures
Consultant/Honoraria:
Amgen, Bayer, Eli Lilly, Merck, Roche
QoL
Treatment characteristics
Toxicity profile
Patient clinical characteristics
Age
Comorbidities
Prior adjuvant treatment
Tumour molecular characteristics
RAS BRAF
Performance status
Tumour burden and localisation
Resectability
Tumour biology (Aggressiveness)
Tumour clinical characteristics
Related symptoms
Flexibility of txadministration
Socioeconomic factors
Drivers of first-line choice according to ESMO guidelines
Expectations/Attitude
Organ function
CLINICAL
FACTORS
BIOMARKERS
1st
-line choice TODAY
1st line treatment of mCRC: ESMO consensus guidelines
Van Cutsem et al., Ann Oncol ‘17
1° - Patient
2° - Treatment
intent
3° - RAS/BRAF
On top of ESMO algorithm
Van Cutsem et al, Ann Oncol ‘16
a) According to medical condition not due to malignant disease
1° - Patient
On top of ESMO algorithm
Van Cutsem et al, Ann Oncol ‘16
a) According to medical condition not due to malignant disease
2° - Treatment
intent
1° - Patient
EASILY
RESECTABLE
MARGINALLY
RESECTABLE
POTENTIALLY
RESECTABLE
NEVER
RESECTABLE
Group* 0
Multidisciplinary Assessment
Group* 1 Group* 2
High load
Group* 3
Low load
CURE!!!!!! DISEASE CONTROL
*According to ESMO 2012 clinical guidelines
More intensive
tx approach
Less intensive
tx approach
Integration with
surgery
To cure? …Yes, WE CAN!
Jones and Poston, Annu Rev Med 2017
10yr OS 20%
10yr OS 28%
Survival following hepatectomy for colorectal liver metastases
Treatment goal
Clearly
resectable
mets
Surgery +/- “adjuvant” oxaliplatin-based chemo
(favourable prognostic criteria)
Oxa-based doublet Surgery Oxa-based doublet
(unfavourable prognostic criteria)
No targeted agents
Technically easily resectable disease: which choice?
Adapted from Van Cutsem et al., Ann Oncol 2016
Treatment goal
OMDClearly
resectable
mets
CYTOREDUCTION
(Shrinkage)
Febbraio 2010 embolizzazione portale
41% disagreementFolprecht et al, Lancet Oncol 2010
Resectability: an evolving scenario
1) Surgeons not always agree
Surgical review by surgeons with experience in hepatobiliary surgery in CELIM study
EASILY
RESECTABLE
MARGINALLY
RESECTABLE
POTENTIALLY
RESECTABLE
NEVER
RESECTABLE
Multidisciplinary Assessment
Surgical and locoregional
approaches
Active systemic regimens
Surgical treatment after CT+Cetux or Beva in FIRE-3
22% of patients were considered potentially eligible for surgery at study entry
Modest, EJC 2017
Resected
Technically resectable
after treatment
Overall survival according to surgical treatment in FIRE-3
Modest, EJC 2017
Resectable Resected
Resectable NOT Resected
Unresectable
EASILY
RESECTABLE
MARGINALLY
RESECTABLE
POTENTIALLY
RESECTABLE
NEVER
RESECTABLE
Multidisciplinary Assessment
Surgical and locoregional
approaches
Active systemic regimens
Biologically-informed
estimation of tumor biology
(BRAF – MSI – gene
signatures)
Resected liver mets: outcome according to RAS/BRAF
mutations - RFS
Schirripa et al, Br J Cancer ‘15
No previous chemotherapy
Cremolini et al, Eur J Cancer ‘17
Resected after FOLFOXIRI + bev
New Prognostic Biomarkers
Balachandran et al, Clin Cancer Res 2016
20 genes expression assay
Molecular Risk Score
Heinemann et al, EJC 2016
Doublet + anti-EGFR vs bev in RAS wt mCRC:
meta-analysis of head-to-head trials
Overall Response Rate
FIRE-3 and PEAK: Depth of response
Stintzing et al, Lancet Oncol ‘16
p<0.0001
CI, confidence interval; DoR, duration of response; DpR, depth of response; ETS, early tumor shrinkage; HR, hazard ratio; TTR, time to response
Tumor Response-Related Efficacy –RAS WT Population
Panitumumab + mFOLFOX6 (n = 88) Bevacizumab + mFOLFOX6 (n = 82)
Median DoR, months (95% CI) 11.4 (10.0, 16.3) 9.0 (7.6, 9.5)
HR (95% CI); P value 0.59 (0.39, 0.88); 0.011
Median TTR, months (95% CI) 2.3 (1.9, 3.7) 3.8 (2.1, 5.7)
HR (95% CI); P value 1.19 (0.81, 1.74); 0.37
Median DpR, months (Q1, Q3) 65.0 (45.7, 89.5) 46.3 (29.5, 63.3)
P value 0.0018
Mean (95% CI) Percentage Change From Baseline In Tumor Load Over Time0
Me
an
Ch
an
ge F
ro
m
Ba
se
lin
e, %
-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 + mFOLFOX6
Pmab + mFOLFOX6
Rivera F, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 2014.Rivera et al, ECC ‘15
Gruenberger et al, Ann Oncol 2014
Primary end-point:
Radical resection rate
*no upfront R0/R1 resection
<30% estimated residual liver
Disease in contact with major vessels
*
≥3 mets: 92-95%
FOLFOXIRI + bev
N = 41
mFOLFOX-6 + bev
N = 39
Overall Response Rate 81% 62%
R0/R1/R2 surgery 61% 49%
R0 surgery 49% 23%
Median PFS 18.5 11.5
Median OS NR 32.2
FOLFOXIRI+Bev: OLIVIA trial
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
FOLFOXIRI+Bev in liver-limited mCRC: pooled analysis by GONO
Tomasello et al, JAMA Oncol 2017
FOLFOXIRI+Bev in initially unrectable mCRC: pooled analysis
Ychou et al., ASCO 2016
Triplet + biologic agent vs Doublet + biologic agent:
METHEP-2 trial
Cremolini et al, JAMA Oncol ‘18
116 RAS/BRAF wt
Unresectable mCRC
pts
FOLFOXIRI+Cet
N=57
R
1:1
FOLFOXIRI+Cet
N=59
Primary end-point: 10m-PFR
Maintenance
Cet
Maintenance
Bev
% patients
Arm A
N = 59
Arm B
N = 57
All
N = 116
Overall Response Rate 68% 75% 72%
R0/R1/R2 surgery 47.5% 29.8% 38.8%
R0 secondary surgery 35.6% 21.1% 28.4%
Liver-only subgroup N = 28 N = 24
R0/R1/R2 surgery 75.0% 58.3% 67.3%
R0 secondary surgery 60.7% 41.7% 51.9%
FOLFOXIRI+Cet: MACBETH trial
G3/4 adverse events,
% patients
Arm
A
N =
59
Arm
B
N =
57
Overall
N = 116
Nausea 1.7% 0% 0.9%
Vomiting 3.4% 1.0% 2.6%
Diarrhea 20.3% 15.8% 18.1%
Stomatitis 6.8% 5.3% 6.0%
Neutropenia 28.8% 33.3% 31.0%
Febrile neutropenia 3.4% 1.8% 2.6%
Skin rash 18.6% 12.3% 15.5%
Safety
Cremolini et al, JAMA Oncology ‘18
MACBETH – main results
VOLFI trial: activity results
R
2:1
FOLFOXIRI
up to 12 cycles
mFOLFOXIRI* +
Panitumumab
up to 12 cyclesmCRC pts:
✓ Unresectable disease
✓ Previously untreated
for mts disease
✓ RAS wt
Arm
AA
rm
B
Primary endpoint: Objective Response Rate
*irinotecan 150mg/sqm; oxaliplatin 85 mg/sqm; LV 200 mg/sqm; 5FU: 3000 mg/sqm
Activity
mFOLFOXIRI+pa
n
N=63
FOLFOXIRI
N=33OR p
Response Rate 85.7% 60.6% 3.90 0.0096
RAS/BRAF wtN=43 N=17
3.36 0.080686.0% 64.7%
Left-sided tumorsN=53 N=25
4.52 0.021090.6% 68.0%
Right-sided tumorsN=10 N=8
2.50 0.6460.0% 37.5%
Progression-free Survival 10.8 mos 10.5 mos 1.11 0.66
Resection Rate
(potentially resectable cohort, n=31)70.0% 36.4% - 0.13
Geisseler et al, ESMO Congress 2017
R
RAS and BRAF wt
mCRC pts
1st line
unresectable
mFOLFOX6+pani
(up to max 12 cycles)
mFOLFOXIRI+pani
(up to max 12 cycles)
5-FU/LV +Pani
5-FU/LV +Pani
PD
INDUCTION MAINTENANCE
Phase III random
Stratification factors:• PS 0-1 vs 2; • primary tumor location (right vs left or rectum); • previous adjuvant chemotherapy;• liver-only metastases.
Primary endpoint: Response Rate
Target accrual: 432 pts
TRIPLETE study by G.O.N.O.
Goal /
condition
Molecular Preferred 1st line regimen
Cytoreduction all WT Doublet/anti-EGFR
RAS mut FOLFOXIRI (Doublets)/beva
BRAF mut FOLFOXIRI/beva
First-line options: cytoreduction intent
Van Cutsem et al, Ann Oncol ‘16
QoL
Treatment characteristics
Toxicity profile
Patient clinical characteristics
Age
Comorbidities
Prior adjuvant treatment
Tumour molecular characteristics
RAS BRAF
Performance status
Tumour burden and localisation
Resectability
Tumour biology (Aggressiveness)
Tumour clinical characteristics
Related symptoms
Flexibility of txadministration
Socioeconomic factors
Main ingredients according to ESMO guidelines
Expectations/Attitude
Organ function
Primary tumour location
Right versus Left…colon
Right versus Left
BRAF-like signature
PIK3CA mutations
dMMR
CIMP-high
Low AREG-EREG
expression
CMS1(Immune)
miR-31-3p high
EGFR promoter
methylation
ALK/ROS1/NTRK
rearrangements
Lee et al., Br J Can ’16
Missiaglia et al., Ann Oncol ’14
Guinney et al., Nat Med ’15
Laurent-Puig et al., ESMO ’16
Puzzoni et al, ASCO GI ’17
Pietrantonio et al, JNCI ‘17
Right versus Left RAS wt: metanalysis of head-to-head trials - OS
Right versus Left RAS wt: metanalysis of head-to-head trials - PFS
J. W. Holch et al, EJC 2016
Right versus Left RAS wt: metanalysis of head-to-head trials - RR
FOLFIRI plus bev, left N= 129FOLFOXIRI plus bev, left N = 113FOLFIRI plus bev, right N = 44FOLFOXIRI plus bev, right N = 72
TRIBE: sidedness subgroups- OS
Left-sided: HR= 0.99 [95%CI: 0.73-1.35]
Right-sided: HR= 0.56 [95%CI: 0.37-0.85]
p for interaction=0.030
Cremolini et al, Ann Oncol ’18
0.540.67
0.33
0.85 0.88
1.74
0.500.67
0.22
0.881.02
2.02
-0.4
0.1
0.6
1.1
1.6
2.1
FOLFOXIRI+bev vs FOLFIRI+bev:
HRs according to sidedness and mutational status
HRs for PFSHRs for OS
Modified by Cremolini et al, Ann Oncol ’18
Goal /
condition
Molecular Preferred 1st line regimen
Cytoreduction all WT Left: Doublet/anti-EGFR
Right: FOLFOXIRI/beva
(Doublet/anti-EGFR)
RAS mut FOLFOXIRI (Doublets)/beva
BRAF mut FOLFOXIRI/beva
Arnold et al, Ann Oncol ‘17
Waiting for more robust data with triplet plus anti-EGFR
First-line options: cytoreduction intent
Treatment goal
OMDClearly
resectable
mets
CYTOREDUCTION
(Shrinkage)
DISEASE
CONTROL
Goal /
condition
Molecular Preferred 1st line regimen
Disease
stabilization
all WT Doublet/anti-EGFR or
Doublet/bev
RAS mut Doublet/bev
BRAF mut FOLFOXIRI/bev
Van Cutsem et al, Ann Oncol ‘16
First-line options: “disease stabilization” intent
Goal /
condition
Molecular Preferred 1st line regimen
Disease
stabilization
all WT Left: Doublet/anti-EGFR
Right: Doublet/bev
(FOLFOXIRI/bev)
RAS mut Doublet/bev
BRAF mut FOLFOXIRI/bev
Arnold et al, Ann Oncol ‘17
First-line options: “disease stabilization” intent
1st line treatment of mCRC: updated evidence-based algorithm
Cremolini et al, Nat Rev Clin Oncol ‘17
1° - Patient
FOIB1
n=57
TRIBE2
n=252
OPAL3
n=97
STEAM4
n=93
MOMA5
n=232*
CHARTA6
n=125
QUATTRO7
n=69
JACCRO
CC-118
n=62**
Response rate 77% 65% 64% 60% 63% 70% 72% 76%
Disease
control rate100% 90% 87% 91% 91% N/A 99% NA
Median PFS,
mos13.1 12.3 11.1 11.9 9.5 12.0 13.3 11.5
Median OS,
mos30.9 29.8 32.2 34.0
Too
early28.0
Not
reached
Not
reached
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 2017
7. Yamazaki et al. JSCO 2017; 8. Miyamoto et sl. JSCO 2017
*>70% patients with RAS or BRAF mutation** only RAS mutant
FOLFOXIRI + bev provides consistent efficacy results…
TRIBE: Secondary endpoint - OS
MEDIAN F-UP 48.1 mos (74% events)
FOLFIRI + bev: N = 256 / Died = 200
FOLFOXIRI + bev: N = 252 / Died = 174
FOLFIRI + bev, median OS : 25.8 mos
FOLFOXIRI + bev, median OS : 29.8 mos
HR: 0.80 [0.65-0.98]
p=0.030
Cremolini et al, Lancet Oncol 2015
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 2014
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
…with consistent safety results
FOLFOXIRI plus bev “appropriateness”
“Decision drivers” for FOLFOXIRI plus bev
1st line treatment of mCRC: updated evidence-based algorithm
Cremolini et al, Nat Rev Clin Oncol ‘17
1° - Patient
1st line treatment of mCRC: updated evidence-based algorithm
Cremolini et al, Nat Rev Clin Oncol ‘17
1° - Patient
2° - RAS/BRAF
3° - Tumor location
1st line treatment of mCRC: future perspectives
Cremolini et al, Nat Rev Clin Oncol ‘17
Triplet +
anti-EGFR
Le et al, Science 2017
A turning point in MSI-high mCRC
23rd May 2017
The first “tissue-agnostic” indication
EMA opinion
Nivolumab 74 48 41 32 1217 11 612 3 0
Nivolumab
MonthsNo. at Risk
119Nivolumab + ipilimumab 95 86 78 1239 10 311 0 0
100
90
80
70
60
50
40
30
20
10
0
0 3 6 9 1512 21 2418Pro
gre
ssio
n-f
ree s
urv
ival(%
)c
27 30
Nivolumab + ipilimumab
100
90
80
70
60
50
40
30
20
10
0
0 3 6 9 1512 21 2418
Ov
era
ll S
urv
ival (%
)
27 30 33
Months
119 113 107 104 3378 17 1119 0 0 0
Nivolumab + ipilimumab
74 64 59 55 2137 17 1119 6 1 0
Nivolumab
Nivolumab +
ipilimumaba,d Nivolumab1,e,f
9-mo rate (95% CI), % 87 (80.0, 92.2) 78 [66.2, 85.7]
12-mo rate (95% CI), % 85 (77.0, 90.2) 73 [61.5, 82.1]
Nivolumab +
ipilimumaba,b Nivolumab1,e,f
9-mo rate (95% CI), % 76 (67.0, 82.7) 54 [41.5, 64.5]
12-mo rate (95% CI], % 71 (61.4, 78.7) 50 [38.1, 61.4]
Nivolumab +/- ipilimumab in MSI-high chemorefractory
mCRC
Overman et al, ASCO GI’18 and Lancet Oncol ‘17
Andrè et al, ASCO GI ‘18 and J Clin Oncol ’18
Title NCT Target population TrialDesign
Status PrimaryEndpoint
Study of Pembrolizumab (MK-3475) vs Standard Therapy in ParticipantsWith Microsatellite Instability-High(MSI-H) or Mismatch RepairDeficient (dMMR) Stage IV Colorectal Carcinoma (MK-3475-177/KEYNOTE-177)
02563002 dMMR or H-MSI stage IV CRC not
pretreated formetastatic
disease.
Arm A:Pembrolizumab 200mg IV
q21d for up to 35 administrations.
Arm BStandard of care
(mFOLFOX6 or FOLFIRI + bevacizumab/cetuximab
Active, notrecruiting
PFSOS
Colorectal Cancer MetastaticdMMR Immuno-Therapy (COMMIT) Study: A Randomized Phase III Study of mFOLFOX6/BevacizumabCombination Chemotherapy With or Without Atezolizumab or Atezolizumab Monotherapy in the First-Line Treatment of PatientsWith Deficient DNA MismatchRepair (dMMR) MetastaticColorectal Cancer
02997228 dMMR metastaticCRC
ArmA (control):mFOLFOX6+bevacizumab
ArmBAtezolizumab
ArmCmFOLFOX6+bevacizumab+
atezolizumab
Recruiting PFS
Clinicaltrials.gov
Ongoing phase III trials in first-line
Cremolini et al, Nat Rev Clin Oncol ‘17
Triplet +
anti-EGFR
Microsatellite
instability
MSS MSI-high
Immunotx
1st line treatment of mCRC: future perspectives
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 contribute to the
therapeutic decision-making process…the contribution of
molecular markers will probably increase in the next future