review of the esmo consensus conference on metastatic …

REVIEW OF THE ESMO CONSENSUSCONFERENCE ON METASTATIC

COLORECTAL CANCER

Fortunato Ciardiello

ESMO Past-President 2018-2019

Professor of Medical Oncology,

Department of Precision Medicine,

Dean, School of Medicine and Surgery,

Università degli Studi della Campania Luigi Vanvitelli

DECLARATION OF INTEREST DISCLOSURE

Receipt of honoraria or consultation fees for speaker, consultancy or advisory roles: Amgen, Bayer, Bristol-Myers Squibb, Celgene, Merck Serono, Pfizer, Roche, Servier

Direct research funding as the principal investigator for institutional research projects: Amgen, Bayer, Merck Serono, Roche, Ipsen

Institutional financial interests, financial support for clinical trials or contracted research: Merck Serono, Roche, Symphogen, Array

Leadership Positions in Professional Societies (non financial interests): ESMO Past-President, President of the Associazione Italiana di Oncologia Toracica

Drivers for first line treatment choices in

metastatic colorectal cancer

Adapted from Van Cutsem et al, ESMO Consensus Conference, Annals of Oncology 2016

• Clinical presentation (tumour burden, primary tumour localisation)

• Tumour biology

• RAS mutation status

• BRAF mutation status

*Tumour

Characteristics

• Age

• Performance status

• Organ function

• Comorbidities

• Patient attitude, expextations, preference

Patient

characteristics

• Toxicity profile

• Flexibility of treatment admnistration

• Socioeconomic factors

• Quality of life

Treatment

characteristics

*Additional tumour characteristics: HER2 amplification; MSI-H status

Twenty-one consensus reccomendation statements on diagnosis and

treatment options and sequences for oligometastatic as well as for

extended metastatic disease.

and

Three consensus reccomedation statements on the use of cytotoxics

and biologicals in the first and subsequent lines of treatment.

The results of the Consensus Conference

on metastatic colorectal cancer were summarized in:

Recommendation 3: RAS testing

◆ RAS is a predictive biomarker for therapeutic choices involving EGFR antibody

therapies in the metastatic disease setting [1, A].

◆ RAS testing is mandatory prior to treatment with EGFR-targeted monoclonal

antibodies cetuximab and panitumumab [1, A].

◆ Primary or metastatic colorectal tumour tissue can be used for RAS testing (see

also Recommendation 3).

◆ RAS analysis should include at least KRAS exons 2, 3 and 4 (codons 12, 13, 59,

61, 117 and 146) and NRAS exons 2, 3 and 4 (codons 12, 13, 59, 61 and 117).

◆ Turnaround time for RAS testing (expanded RAS analysis) should be ≤7 working

days from the time of receipt of the specimen by the testing laboratory to the time of

issuing of the final report, for >90% of specimens.

Molecular Pathology and Biomarkers

Recommendation 5: BRAF testing

◆ Tumour BRAF mutation status should be assessed alongside the assessment of

tumour RAS mutational status for prognostic assessment (and/or potential selection

for clinical trials) [I, B]

Recommendation 6: MSI testing

◼ MSI testing in the metastatic disease setting can assist clinicians in genetic

counselling [II, B]

◼ MSI testing has strong predictive value for the use of immune check-point inhibitors

in the treatment of patients with mCRC [II, B]


Recommendation 9: emerging technologies

◆ Although CTC number correlates with prognosis in patients with mCRC, the clinical

utility of CTC assessments is not yet clear and therefore cannot be recommended

[IV, D].

◆ The utility of liquid ctDNA biopsies to guide treatment decisions is currently under

investigation in clinical trials, but cannot yet be recommended in routine practice [V,

D].

◆ Whole genome, whole exome and whole transcriptome analysis should be carried

out only in a research setting [V, D].


ESMO consensus guidelines for the management ofpatients with metastatic colorectal cancer

13

There are multiple differences between the

right and left colon and their associated

tumors

Embryologic origin

Midgut Hindgut

Function

Almost inactive

metabolically

Waste reservoir

MetabolismFermentationProteolysisDegradationProcessing

Microbiome

Biofilm negative

Biofilm positive

Epigenetic Genetic

MethylationMSI-HighBRAF mt

Female Male

Higher TNM stage

Larger tumors

More mucinous type

Lower TNM stage

Smaller tumors

Lower crypt-like and

mixed subtypes

MUTYH-associated

polyposis

Familial adenomatous

polyposis

More active immune cells,

promoting immunogenicity

Inflammatory/CIMP-H-like subtype

Immunologically less active,

promoting tolerogenesis

CIMP/MSI/BRAF positive

tumors predominate

Serrated pathway

Activation of MAPK cascade

Chromosomal instability

tumors predominate

HER1 and HER2 amplification

EGF/Wnt signaling

14

Right- and left-sided primary colon tumors

have distinct biology1–3

Rectum

Right (proximal/midgut) colon

Left (distal/hindgut) colon

Descending

colon

Transverse

colon†

Ascending

colon

*Percentage of patients; left-sided includes patients with rectal cancer; †Classification of the transverse colon as right- or left-sided colon differs between studies; BRAF, v-raf murine sarcoma viral oncogene homolog B1; CIMP, cytosine-guanosine (CpG) island methylation phenotype; MSI, microsatellite instability; TNM, American Joint Committee on Cancer tumor–node–metastasis stage

1. Maus MK, et al. Pharmacogenomics J 2015;15:354–362;2. Lee GH, et al. Eur J Surg Oncol 2015;41:300–308;3. Missiaglia E, et al. Ann Oncol 2014;25:1995–2001.

20–40%*1,2 60–80%*1,2

ESMO Special Symposia manuscript for submission to Annals of Oncology 06.02.17

Final submission draft

18#

Table 1. Source of patients for the analyses

Trial name

Trial characteristics

Phase of trial

Chemo-therapy

backbone

Bevacizumab in control

arm?

Anti-EGFR therapy

Treatment line

Randomised With KRAS

evaluable

With KRAS

Wt*

With all RAS

wt

With all RAS wt and

tumour side confirmed

CRYSTAL [28, 42, 43]

III FOLFIRI No Cetuximab 1st

1217 1063 666 367%

364

FIRE-3

[28, 36]

III FOLFIRI Yes Cetuximab 1st

752 NA 609£ 400

%% 394

PEAK [35] II FOLFOX6 Yes Panitumumab 1st

285 285 285 170$

143

PRIME [40, 41]

III FOLFOX4 No Panitumumab 1st

1183 1096 656 512 416

20050181

[45]

III FOLFIRI No Panitumumab 2nd

1186 1083 597 421 368

CALGB

80405 [27, 38]

III FOLFIRI/

FOLFOX6

Yes Cetuximab 1st 1137 1137 1137 526

$$ 474

*Not always easy to determine, taken from publication or slide presentation. Sometimes refers to all ITT population (PRIME, PEAK, AMGEN181) sometimes from the KRAS wt exon 2 (CRYSTAL, FIRE-3) sometimes from available tissue to test (CALGB 80405). %

Only 430 patients were evaluable for other RAS mutations; %%

475 patients were tested successfully for the other KRAS mutations; $

Extended RAS analysis was performed in

250 patients with 233 patients with KRAS or RAS results. Out of the 221 patients with KRAS exon 2 wt at this stage, 170 were RAS wt; $$

Out of 670 patients tested for all RAS; £592 patients if only those receiving study treatment are considered and 493 patients if only those receiving study treatment and had assessable CT-scan are considered.

EGFR, epidermal growth factor receptor; NA, not available; wt, wild-type



37#

Figure 4.

A

Predictive effect on OS



38#

B

Predictive effect on PFS



39#

C

Predictive effect on RR

Pan-Asia adapted ESMO consensus guidelines

for the management of patients with metastatic

colorectal cancer

JSMO/ESMO joint initiative endorsed by CSCO, KACO,

MOS, SSO and TOS

Expert Face-to-Face Meeting

Kobe, July 30, 2017

Which therapy after second line?In unselected, chemorefractory mCRC patients, after progression to two lines of allavailable chemotherapies and biologic agents, both TAS-102 and regorafenib are validtherapeutic options:

▪ Comparable efficacy (although no direct formal comparison)

▪ Both drugs are mainly cytostatic rather than cytotoxic

▪ More effective in PS0 patients with a long history of metastatic disease

▪ Approximately 20% of treated patients benefit for relatively long term treatments

▪ Different toxicity profiles

▪ No preference in the sequence of the two drugs in third and fourth line

HER2 gene amplification occurs in approximately 5% of RAS wild type patients and isgenerally associated with resistance to anti-EGFR therapies:

▪ More often found in left side primary tumors

▪ Evidence for relevant antitumor activity of combined anti-HER2 therapies (trastuzumab plus lapatinib;trastuzumab plus pertuzumab) in chemorefractory disease

MSI-H cancer is so far the only subgroup of mCRC in which immune checkpointinhibitors have shown clinical efficacy:

▪ In which line of treatment (first line or after conventional treatment failure)?

▪ Montherapy (pembrolizumab or nivolumab) or combined therapy (nivolumab plus ipilimumab)?

Rechallenge with first line treatments in subsequent lines of therapy remains anexperimental approach that should be validated by appropiately designed clinical studies.

IMMUNOTHERAPY FOR COLORECTAL CANCER:

CHALLENGES FOR CLINICAL EFFICACY

◆ Colorectal cancer is a highly heterogenous disease.

◆ The presence of a potential active immune response is limited to

subgroup(s) of patients.

◆ Currently, the only effective immunotherapies are obtained in

molecularly selected MSI-H or dMMR tumours.

◆ Is it possible to activate immune competence in MSS tumours?

CMS subtypes – clinical and molecular

correlates

CMS1 - MSI – Immune 14%

CMS2 – Canonical

37% CMS3 – Metabolic

13%

CMS4–

Mesenchymal 23%

Guinney J, Dienstmann R et al. Nat Med 2015

Becht E et al, Clin Cancer Res 2016

Immune vs Transcriptomic subtypes of CRC

Supervised immune infiltration analysis

Immune vs Transcriptomic subtypes of CRC

dMMR – MSI

Hypermutation

Immune-activated

Th1 cells

PDL1

MacrophagesNK cells

Cytotoxic

T cells

Th1 cells IFNγIFNγ

CXCL9/10/13

Cancer cell

Cancer cell

Immune-ignorant

Inflammation

Cancer cell

TGFβ

Complement

Stromal cellsTh17 cells

MDSC

Stromal cells

MacrophagesNK cells

Cytotoxic

T cells

CCL2

CCL2TGFβ IL-23

IL-17

Immune-tolerantInflamed

Monocytes

Durable Clinical Benefit With Nivolumab Plus Low-Dose Ipilimumab as First-Line Therapy in Microsatellite Instability-High/Mismatch Repair

Deficient Metastatic Colorectal Cancer

Heinz-Josef Lenz,1 Eric Van Cutsem,2 Maria Luisa Limon,3 Ka Yeung Mark Wong,4 Alain Hendlisz,5

Massimo Aglietta,6 Pilar García-Alfonso,7 Bart Neyns,8 Gabriele Luppi,9 Dana B. Cardin,10

Tomislav Dragovich,11 Usman Shah,12 Ajlan Atasoy,13 Roelien Postema,13 Zachary Boyd,13 Jean-

Marie Ledeine,13 Michael James Overman,14 Sara Lonardi15

1USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA; 2University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium; 3Hospital Universitario Virgen del Rocio, Sevilla, Spain; 4Westmead Hospital, Sydney, Australia; 5Institut Jules Bordet, Brussels, Belgium; 6Candiolo

Cancer Institute and University of Torino Medical School, Candiolo, Italy; 7Hospital Gral Universitario Gregorio Marañon, Madrid, Spain; 8University

Hospital Brussels, Brussels, Belgium; 9University Hospital of Modena, Modena, Italy; 10Vanderbilt – Ingram Cancer Center, Nashville, TN, USA; 11Banner MD Anderson Cancer Center, Gilbert, AZ, USA; 12Lehigh Valley Hospital, Allentown, PA, USA; 13Bristol-Myers Squibb, Princeton, NJ, USA;

14The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 15Istituto Oncologico Vento IOV-IRCSS, Padova, Italy

Presentation number: LBA18_PR

HIGHLY CONFIDENTIAL

Introduction: CheckMate 142

• In CheckMate 142, nivolumab plus low-dose (1 mg/kg) ipilimumab provided improved clinical benefit relative to nivolumab monotherapy, with a favorable benefit-risk profile, in previously treated patients with MSI-H/dMMR mCRCa,1

– ORR, 55% vs. 31%; 12-month OS rate, 85% vs. 73%, respectively

– Grade 3–4 TRAEs, 32% vs. 20%; discontinuation due to any grade TRAEs, 13% vs. 7%, respectively

• Based on these results, nivolumab received accelerated FDA approval as a single agent or in combination with ipilimumab in patients with MSI-H/dMMR mCRC who progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan2

• Here we report the first results of the efficacy and safety of nivolumab plus low-dose ipilimumab as a 1L therapy for patients with MSI-H/dMMR mCRC from CheckMate 142

4

CheckMate 142

aIndirect comparisons; CheckMate 142 monotherapy and combination therapy cohorts were not randomized or designed for a formal comparison

FDA = Food and Drug Administration; ORR = objective response rate; OS = overall survival; TRAEs = treatment-related adverse events

1. Overman MJ, et al. J Clin Oncol 2018;8:773–779; 2. OPDIVO® (nivolumab) [prescribing information]. Bristol-Myers Squibb Co., 2018.

CheckMate 142 Study Design

•CheckMate 142 is an ongoing, multi-cohort, nonrandomized phase 2 study evaluating the efficacy and safety of nivolumab-based therapies in patients with mCRC (NCT02060188)

•Median follow-up for the 1L nivolumab plus low-dose ipilimumab cohort was 13.8 months (range, 9–19)c

5

CheckMate 142

aUntil disease progression or discontinuation in patients receiving study therapy beyond progression, discontinuation due to toxicity, withdrawal of consent, or the study end; bPatients with a CR, PR, or SD for ≥12 weeks

divided by the number of treated patients; cTime from first dose to data cutoff

BICR = blinded independent central review; CR = complete response; CRC = colorectal cancer; DCR = disease control rate; DOR = duration of response; IPI1 = ipilimumab 1 mg/kg; NIVO3 = nivolumab 3 mg/kg; PFS =

progression-free survival; PR = partial response; Q2W = once every 2 weeks; Q3W = once every 3 weeks; Q6W = once every 6 weeks; RECIST = Response Evaluation Criteria in Solid Tumors; SD = stable disease

• Histologically

confirmed

metastatic or

recurrent CRC

•MSI-H/dMMR per

local laboratory 1L

NIVO3 Q2WaPreviously treated

Previously treated NIVO3 + IPI1 Q3W

(4 doses and then

NIVO3 Q2W)a

NIVO3 Q2W +

IPI1 Q6Wa

Primary endpoint:

• ORR per investigator

assessment (RECIST v1.1)

Other key endpoints:

• ORR per BICR, DCR,b

DOR, PFS, OS, and safety

Baseline CharacteristicsNIVO3 (Q2W) + IPI1 (Q6W)

N = 45

Median age (range), years 66 (21–85)

Male, n (%) 23 (51)

ECOG performance status, n (%)

0

1

25 (56)

20 (44)

Disease stage at diagnosis, n (%)a

I–III

IV

28 (62)

17 (38)

Tumor PD-L1 expression at baseline, n (%)*

≥ 1%

< 1%

Unknown

12 (27)

26 (58)

7 (16)

Mutation status, n (%)

BRAF/KRAS wild type

BRAF mutation

KRAS mutation

Unknown

13 (29)

17 (38)

10 (22)

5 (11)

Lynch syndrome,b n (%)

Yes

No

Unknown

8 (18)

11 (24)

26 (58)

6

CheckMate 142

*Percentages may not add up to 100% because of roundingaAll patients had stage IV disease at study entry; bBased on clinical records of patients at sites in countries where this reporting was permitted (excluded Italy)BRAF = V-Raf murine sarcoma viral oncogene homolog B1; ECOG = Eastern Cooperative Oncology Group; KRAS = Kirsten rat sarcoma viral oncogene homolog

Response and Disease Control

Investigator-assessed

NIVO3 (Q2W) + IPI1 (Q6W)

N = 45

ORRa, n (%)

[95% CI]

27 (60)

[44.3–74.3]

Best overall response, n (%)*

CR

PR

SD

PD

Not determined

3 (7)

24 (53)

11 (24)

6 (13)

1 (2)

DCRb, n (%)

[95% CI]

38 (84)

[70.5–93.5]

9

CheckMate 142

*Percentages may not add up to 100% because of roundingaPatients with CR or PR divided by the number of treated patients; bPatients with a CR, PR, or SD for ≥12 weeks divided by the ◼◆mber of treated patie◼tsCI = confidence interval; PD = progressive disease

•Responses were observed regardless of tumor PD-L1 expression, BRAF or KRAS mutation status, or diagnosis of Lynch syndrome

– The ORR and DCR in patients with a BRAF mutation (n = 17) were 71% and 88%, respectively

Best Reduction in Target Lesions

10

CheckMate 142

*Confirmed response per investigator assessmentaEvaluable patients per investigator assessment

• 84% of patients had a reduction in tumor burden from baseline

Be

st re

du

ction

fro

m b

ase

line

in t

arg

et le

sio

n (

%)

Patientsa

75

100

50

*****

***

************

*******

25

0

–25

–50

–75

–100

–30%

Progression-Free and Overall Survival

13

CheckMate 142

aPer investigator assessment.mo = month; NE = not estimable; NR = not reached

Nivolumab + ipilimumab

90

80

70

60

50

40

30

20

10

0

0 3 6 9 12 15 18

Pro

gre

ss

ion

-fre

e s

urv

ival

(%)

Months

No. at risk 45 37 34 24 15 7 7

0 3 6 9 12 15 18 21

Ove

rall

su

rviv

al

(%)

Months

45 42 40 38 24 13 1 0

100

90

80

70

60

50

40

30

20

10

0

PFSaNIVO3 (Q2W) + IPI1 (Q6W)

N = 45

Median PFS, months (95% CI) NR (14.1–NE)

9-mo rate (95% CI), % 77 (62.0–87.2)

12-mo rate (95% CI), % 77 (62.0–87.2)

OSaNIVO3 (Q2W) + IPI1 (Q6W)

N = 45

Median OS, months (95% CI) NR (NE)

9-mo rate (95% CI), % 89 (74.9–95.1)

12-mo rate (95% CI), % 83 (67.6–91.7)

100

Summary and Conclusions

•Nivolumab (Q2W) plus low-dose ipilimumab (Q6W) demonstrated robust and durable clinical benefit as a 1L treatment for MSI-H/dMMR mCRC

– High ORR (60%, with 7% CR)

– Durable responses (median DOR not reached)

– High rate of disease co◼trol for ≥12 weeks (84%)

– Most patients had a reduction in tumor burden from baseline (84%)

– Median PFS and OS not reached with a median follow-up of 14 months

– 12-month PFS and OS rates were 77% and 83%, respectively

•Nivolumab plus low-dose ipilimumab was well-tolerated (grade 3–4 TRAEs, 16%) with a low rate of discontinuation due to TRAEs (7%)

•Nivolumab plus low-dose ipilimumab may represent a new 1L treatment option for patients with MSI-H/dMMR mCRC

15

CheckMate 142

But wait for the results of: “KEYNOTE-177, a phase 3, open-label, randomized study of

first-line pembrolizumab versus investigator-choice chemotherapy for mismatch repair-

deficient (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal

carcinoma (mCRC)”.

WHAT IS NEXT AS PRACTICE CHANGING THERAPEUTIC

OPTION IN METASTATIC COLORECTAL CANCER?

First phase III evidence for rational combinations of targeted

drugs in molecularly selected metastatic colorectal cancer:

The BRAF V600E mutation as a disease driver

BRAFV600E mutation in mCRC

1. Loupakis F, et al. Br J Cancer. 2009;101:715. 2. Tie J, et al. Int J Cancer. 2011;128:2075. 3. De Roock W, et al. Lancet Oncol. 2010;11(8):753. 4. Mitani S, et al. Ann Oncol. 2017;28(5s). 5. Ulivi P, et al. J Transl

Med. 2012;10:87. 6. Kopetz S, et al. J Clin Oncol. 2017;35(15):3505. 7. Corcoran RB, et al. Cancer Disc. 2012;2(3):227. 8. Prahallad A, et al. Nature 2012;100:100. 9. Tabernero J, et al. J Clin Oncol. 2016;34:3544.

10. Adapted From: Strickler JH. Cancer Treatment Reviews. 2017; 60:109.

CETUX=cetuximab; EGFR=epidermal growth factor receptor; ENCO=encorafenib; MAPK=mitogen-activated protein kinase; mCRC=metastatic colorectal

cancer; PFS=progression-free survival; ORR=objective response rate; OS=overall survival; VIC=vemurafenib + irinotecan + cetuximab.

MAPK Signaling in Colorectal Cancer10

* Data cut-off January 2018; last patient enrolled 14 April 2015. Full updated data to be presented at future meeting.

▪ Occurs in 10%–15% of patients and confers a poor prognosis1,2

▪ Standard therapies have limited benefits after ≥1 line of treatment:

▪ Median OS 4–6 mo, median PFS ~2 mo and ORR <10%1,3-5

▪ SWOG S1406 results with vemurafenib, irinotecan, cetuximab (VIC):

Median OS of 9.6 mo, median PFS of 4.3 mo, and ORR in 16%

(confirmed + unconfirmed)6

▪ BRAF inhibitors cause feedback activation of EGFR in BRAF-mutant

CRC, leading to continued cell proliferation7,8

▪ Feedback may be overcome by targeting multiple nodes in the pathway

▪ Updated mature phase 2 results with doublet of ENCO + CETUX*:

Median OS of 9.3 mo, median PFS of 4.2 mo and ORR in 24%9

BEACON CRC Phase 3 Study Design

Safety Lead-in Phase 3

ENCO 300 mg QD

+

BINI 45 mg BID

+

CETUX 400 mg/m2 (initial) then

250 mg/m2 QW

N=30

Triplet therapy

ENCO + BINI + CETUX

n=205

Doublet Therapy

ENCO + CETUX

n=205

Control Arm

FOLFIRI + CETUX, or

IR + CETUX

n=205

Disease

progression

Disease

progression

Disease

progression

Continued

follow-up

for

evaluation

of OS

R

1:1:1

Journal of Clinical Oncology, 37: 1460-69, 2019

S Kopetz et al. N Engl J Med 2019;381:1632-1643.

Baseline Characteristics of the Patients Who Underwent

Randomization.*


Adverse Events and Selected Laboratory Abnormalities.*


Tumor Response in Patients with Metastatic Colorectal Cancer

with the BRAF V600E Mutation.*


Best Percentage Change in Size of Target Lesions.


Overall Survival.

review of the esmo consensus conference on metastatic …

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