review of the esmo consensus conference on metastatic ......chiara cremolini university of pisa...

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


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


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


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


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


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


Disease

stabilization

all WT Doublet/anti-EGFR or

Doublet/bev

RAS mut Doublet/bev

BRAF mut FOLFOXIRI/bev


First-line options: “disease stabilization” intent

Goal /

condition


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



1° - Patient



1° - Patient

2° - RAS/BRAF

3° - Tumor location

1st line treatment of mCRC: future perspectives


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


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

[email protected]

review of the esmo consensus conference on metastatic ......chiara cremolini university of pisa...

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