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]
Molecular Pathology and Biomarkers
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].
Molecular Pathology and Biomarkers
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
ESMO Special Symposia manuscript for submission to Annals of Oncology 06.02.17
Final submission draft
37#
Figure 4.
A
Predictive effect on OS
ESMO Special Symposia manuscript for submission to Annals of Oncology 06.02.17
Final submission draft
38#
B
Predictive effect on PFS
ESMO Special Symposia manuscript for submission to Annals of Oncology 06.02.17
Final submission draft
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.*
S Kopetz et al. N Engl J Med 2019;381:1632-1643.
Adverse Events and Selected Laboratory Abnormalities.*
S Kopetz et al. N Engl J Med 2019;381:1632-1643.
Tumor Response in Patients with Metastatic Colorectal Cancer
with the BRAF V600E Mutation.*
S Kopetz et al. N Engl J Med 2019;381:1632-1643.
Best Percentage Change in Size of Target Lesions.
S Kopetz et al. N Engl J Med 2019;381:1632-1643.
Overall Survival.