Chiara Cremolini
University of Pisa
Azienda Ospedaliero-Universitaria Pisana
ESMO Preceptorship Programme – Colorectal Cancer
Valencia, 17th May 2019
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, Merck, Roche, Servier
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
On top of ESMO algorithm
Van Cutsem et al, Ann Oncol ‘16
a) According to medical condition not due to malignant disease
1° - Patient
AVEX trial
Stratification factors:
ECOG PS (0–1 vs 2)
Geographic region
Key inclusion criteria
– ECOG PS 0–2
– Prior adjuvant chemotherapy allowed if completed >6 month before inclusion
– Not optimal candidates for a combination chemotherapy with irinotecan or
oxaliplatin
R
280 mCRC pts
1st line mCRC
age ≥70 years
Capecitabine
Capecitabine + bev
Modificato da Cunningham et al, Lancet Oncol 2013
Phase III
Cunningham et al, Lancet Oncol 2013
AVEX trial: PFS e OS
PFS: endpoint primario
OS
Van Cutsem et al, ESMO GI ‘18
TASCO-1 study
Ph. 2 random:Primary endpoint PFS
Is capecitabine’s time over?
R
mCRC pts
1st line
Unresectable
Unfit for intensive 1st
line
Capecitabine + Bev
Trifuridine/tipiracil + Bev
P
D
Phase III random
Primary endpoint: PFS
Target accrual: 1096 pts
Phase III SOLSTICE trial
EudraCT number: 2017-004059-22
Stratification factors:•PS 0 vs 1 vs 2; •primary tumor location (right vs left); •Neutrophil/lymphocyte ratio (<3 vs ≥3)
1st-line stratum
N=10
2nd-line stratum
N=30
Overall population
N=40
Response rate 4 (40%) 9 (30%) 13 (32.5%)
Disease control rate 7 (70%) 26 (86%) 29 (72.5%)
Median PFS, mos 7.0 6.2 6.4
Median OS, mos 12.3 14.7 14.3
Panitumumab monotherapy
Pietrantonio et al, The Oncologist 2015
RA
ND
OM1st line
unresectablemCRC
≥70 yrs
FOLFOX + PANI
up to 12 cycles PANImaintenance
5FU + PANI
up to 12 cycles
PANImaintenance
PR
OG
RES
SIO
N
Primary endpoint: median PFS
p0: mPFS < 6.0 months (literature-based), mPFS > 9.5 months
Design: Fleming single-stage
Alpha error: 0.05, Beta error: 0.10
90 patients per arm had to be enrolled
Waiting for PANDA
1st line treatment of mCRC: ESMO consensus guidelines
Van Cutsem et al., Ann Oncol ‘16
1° - Patient
2° - Treatment
intent
3° - RAS/BRAF
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
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
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
1° - Patient
2° - Treatment
intent
3° -
RAS/BRAF
4° - Primary
location
1st line treatment of mCRC: ESMO/Pan-Asian consensus guidelines
Yoshino et al., Ann Oncol ‘18
Right versus Left RAS wt: metanalysis of head-to-head trials - OS
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
1° - Patient
2° - Treatment
intent
3° -
RAS/BRAF
4° - Primary
location
1st line treatment of mCRC: ESMO/Pan-Asian consensus guidelines
Yoshino et al., Ann Oncol ‘18
Treatment intent: still relevant?
YES!
EASILY
RESECTABLE
MARGINALLY
RESECTABLE
POTENTIALLY
RESECTABLE
NEVER
RESECTABLE
Multidisciplinary Assessment
CURE!!!!!!
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
Overall survival according to surgical treatment in FIRE-3
Modest, EJC 2017
Resectable Resected
Resectable NOT Resected
Unresectable
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
73%
27%
NEVER RESECTED
Liver-limited mCRC
225 mCRC pts with iNITIALLY UNRESECTABLE liver-limited disease
treated with first-line doublets/triplet + targeted agent (2011-2016)
AT LEAST ONE SURGICAL RESECTION
Ongaro et al, in press ESMO Open
44%
27%
NEVER RESECTED
Liver-limited mCRC
225 mCRC pts with iNITIALLY UNRESECTABLE liver-limited disease
treated with first-line doublets/triplet + targeted agent (2011-2016)
“ONLY” ONE SURGICAL RESECTION
29%
LOCOREGIONAL RE-TREATMENT
Ongaro et al, in press ESMO Open
EASILY
RESECTABLE
MARGINALLY
RESECTABLE
POTENTIALLY
RESECTABLE
NEVER
RESECTABLE
Multidisciplinary Assessment
Surgical and locoregional
approaches
Active systemic regimens
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
Margonis et al, JAMA Surg ‘18
Treatment intent: still relevant? YES!
BUT…
• Cytoreduction is not only a matter of resectability
• Indolent disease does not exist
• Achieving response is a meaningful objective…always!
1st line treatment of mCRC: our evidence-based algorithm
Cremolini et al, Nat Rev Clin Oncol ‘17
1° - Patient
2° - RAS/BRAF
3° - Tumor location
TRIBE2: Study design
R
1:1
FOLFOX +
bev*
FOLFOXIRI
+ bev*
PD15FU/bev
5FU/bev
Progression Free Survival 2
FOLFIRI +
bev* PD25FU/bev
PD1
FOLFOXIRI
+ bev*5FU/bev
PD2
Arm A
Arm B
* Up to 8 cycles
Cremolini et al, ESMO ‘18
Patients’ characteristics – ITT population
N=679
Characteristic, % patients
Arm A
N = 340
Arm B
N = 339
Sex (M / F) 61 / 39 54 / 46
Median Age (range) 61 (30 – 75) 60 (33 – 75)
ECOG PS (0 / 1-2) 86 / 14 87 / 13
Synchronous Metastases (Y / N) 89 / 11 89 / 11
Prior Adjuvant CT (Y / N) 2 / 98 2 / 98
Primary Tumor Side (right / left) 38 / 62 38 / 62
Number Metastatic Sites (1 / >1) 39 / 61 46 / 54
Liver Only Disease (Y / N) 29 / 71 32 / 68
Resected Primary (Y / N) 53 / 47 50 / 50
RAS/BRAF (RAS mut / BRAF mut /
wt / NE)65 / 10 / 20 / 5 63 / 10 / 22 / 6
Cremolini et al, ESMO ‘18
Median follow up = 22.8
mos
Arm A
N = 340
Arm B
N = 339
Events, N (%) 235 (69%) 188 (55%)
Median PFS2, mos 16.2 18.9
HR = 0.69 [95% CI: 0.57-0.83] p<0.001
Primary endpoint: Progression Free Survival 2
1st line - Safety Profile
G3/4 adverse events,
% patients
FOLFOX +
bev
N = 336
FOLFOXIRI +
bev
N = 336
p
Nausea 3 6 0.140
Vomiting 2 3 0.419
Diarrhea 5 17 <0.001
Stomatitis 3 5 0.299
Neutropenia 21 50 <0.001
Febrile neutropenia 3 7 0.050
Neurotoxicity 1 2 0.505
Asthenia 6 7 0.633
Hypertension 10 7 0.223
Venous
thromboembolism6 4 0.204
Cremolini et al, ESMO ‘18
1st line – RECIST Response Rate
Best Response, %
FOLFOX +
bev
N = 340
FOLFOXIRI +
bev
N = 339
OR [95%CI], p
Complete Response 4% 3%
Partial Response 46% 58%
Response Rate 50% 61%1.55 [1.14-2.10]
p=0.005
Stable Disease 40% 31%
Progressive Disease 7% 4%
Not Assessed 3% 4%
Cremolini et al, ESMO ‘18
1st line - Progression Free Survival
Median follow up = 22.8
mos
FOLFOX + bev
N = 340
FOLFOXIRI + bev
N = 339
Events, N (%) 288 (85%) 261 (77%)
Median 1st PFS, mos 9.9 12.0
HR = 0.73 [95% CI: 0.62-0.87] p<0.001
Cremolini et al, ESMO ‘18
2nd line - Progression Free Survival
(Patients alive at the time of PD1)
Median follow
up = 22.8 mos
Arm A
N = 276
Arm B
N = 242
Events, N (%) 223 (81%) 169 (70%)
Median 2nd
PFS, mos5.5 6.0
HR = 0.86 [95%CI: 0.70-1.05]
p=0.120
Cremolini et al, ESMO ‘18
1st line treatment of mCRC: our evidence-based algorithm
Cremolini et al, Nat Rev Clin Oncol ‘17
1° - Patient
2° - RAS/BRAF
3° - Tumor location
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
Geisseler et al, ESMO ‘18
mFOLFOXIRI+pa
n
N=63
FOLFOXIRI
N=33OR p
Response Rate 87.3% 60.6% 4.47 0.004
Resection Rate 33.3% 12.1% 3.63 0.02
Definitive non-resectableN=43 N=22
7.80 0.0814.0% 0%
Potentially resectableN=20 N=11
5.25 0.0575.0% 36.4%
Primary endpoint: Objective Response Rate
Borelli et al, ESMO Open ‘18
TRIPLETE trial
Le et al, Science 2017
A turning point in MSI-high mCRC
CheckMate-142: 1st
line cohort
Lenz et al, ESMO Congress 2018
CheckMate-142 - 1st
line: Activity
Overall Response Rate: 60%
Disease control Rate: 84%
Lenz et al, ESMO Congress 2018
CheckMate-142 - 1st
line: PFS and OS
Lenz et al, ESMO Congress 2018
Median follow-up: 13.8 months
Awaited data from phase III studies
Triplet +
anti-EGFR?
Microsatellite
instability
MSS MSI-high
Immunotx
5-FU/LV+anti-EGFR?
TAS+bev?
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
