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Validated and promising predictive factors
in mCRC: Recent updates on RAS testing
Fotios Loupakis, MD PhDU.O. Oncologia 2 Universitaria
Azienda Ospedaliero-Universitaria Pisana
Pisa, Italy
Learning Objectives
Why and how did molecular testing in mCRC change?
Implications for RAS testing in clinical practice?
New perspectives for RAS testing?
15/06/2015 2
The beginning of KRAS story
15/06/2015 3
Jonker et al. N Engl J Med 2007 Van Cutsem et al. J Clin Oncol 2007
Phase III trials comparing anti-EGFR monotherapy vs. BSC suggested
a «subgroup effect» with regard to the benefit from Cet and Pan
Phase III CA225025 trial:
Cet vs. BSC in advanced linesPhase III 20020408 trial:
Pan vs. BSC in advanced lines
Jonker DJ et al. N Engl J Med 2007;357(20):2040-2048. Reproduced with permission of Massachusetts Medical Society in the format Use in an e-
coursepack via Copyright Clearance Center; Van Cutsem E et al. J Clin Oncol 2007;25(13):1658-1664.
Reprinted with permission. © (2007) American Society of Clinical Oncology. All rights reserved
The first clinical report
15/06/2015 4
In a small retrospective cohort , KRAS exon 2 mutations
seemed to predict resistance to anti-EGFRs
Reprinted from Lièvre A et al. Cancer Res 2006;66(8):3992-3995, with permission from AACR
Post-hoc analyses of phase III trials
15/06/2015 5
Jonker DJ et al. N Engl J Med 2007
KRAS exon 2 wt
KRAS exon 2 mut
Karapetis CS et al. N Engl J Med 2008
Benefit from cetuximab was restricted to KRAS exon 2 wt population
Jonker DJ et al. N Engl J Med 2007;357(20):2040-2048. Reproduced with permission of Massachusetts Medical Society in the
format Use in an ecoursepack via Copyright Clearance Center; Karapetis CS et al. N Engl J Med 2008;359(17):1757-1765.
Reproduced with permission of Massachusetts Medical Society in the format Use in an ecoursepack via Copyright Clearance Center
15/06/2015 6
Van Cutsem E et al. J Clin Oncol 2007
Amado RG et al. J Clin Oncol 2008
Post-hoc analyses of phase III trials
KRAS exon 2 wt
KRAS exon 2 mut
Benefit from panitumumab was restricted to KRAS exon 2 wt population
Van Cutsem E et al. J Clin Oncol 2007;25(13):1658-1664. Reprinted with permission. © (2007) American Society of Clinical Oncology.
All rights reserved; Amado RG et al. J Clin Oncol 2008;26(10):1626-1634.
Reprinted with permission. © (2008) American Society of Clinical Oncology. All rights reserved
Benefit from anti-EGFRs
in the «KRAS exon 2-selected» population
mPFS (mos)
N Cet BSC HR p
Unselected 572 1.9 1.8 0.68 <0.001
KRAS exon 2 wt 215 3.7 1.9 0.40 <0.001
KRAS exon 2 mut 151 1.8 1.8 0.99 NS
15/06/2015 7The magnitude of benefit from anti-EGFR moAbs is amplified
in KRAS exon 2 wt population
mPFS (mos)
N Pan BSC HR p
Unselected 463 1.8 1.7 0.54 0.66
KRAS exon 2 wt 243 2.8 1.7 0.45 <0.001
KRAS exon 2 mut 184 1.7 1.7 0.99 NS
Jonker DJ et al. N Engl J Med 2007;357(20):2040-2048;
Karapetis CS et al. N Engl J Med 2008;359(17):1757-1765
Van Cutsem E et al. J Clin Oncol 2007;25(13):1658-1664;
Amado RG et al. J Clin Oncol 2008;26(10):1626-1634
KRAS exon 2:evidences in the 1st line setting
mPFS (mos)
N FOLFIRI+Cet FOLFIRI HR p
Unselected 1198 8.9 8.0 0.85 0.05
KRAS exon 2 wt 666 9.9 8.4 0.70 0.001
KRAS exon 2 mut 397 7.4 7.7 1.17 0.26
The magnitude of benefit from the addition of cetuximab
to 1st line FOLFIRI is amplified in KRAS exon 2 wt population
Phase III CRYSTAL trial: FOLFIRI +/- Cetuximab in 1st line
Van Cutsem E et al. J Clin Oncol 2007;25(13):1658-1664
EMA Indications for anti-EGFRs
9
June 2008
By permission of the European Medicines Agency
15/06/2015 10
KRAS mutations: the size of the problem
KRAS exon 2 mutations affect about
40-45% of mCRC
Data from the COSMIC database
Beyond KRAS exon 2
15/06/2015 11Edkins S et al. Cancer Biol Ther 2006;5(8):928-932;
Buhrman G et al. Structure 2007;15(12):1618-1629
Beyond KRAS exon 2
15/06/2015 12
10%
KRAS exon 3 and 4 mutations: constitutively activate RAS/RAF/MAPKs pathway
occur in about 10% of mCRCs
Edkins S et al. Cancer Biol Ther 2006;5(8):928-932;
Buhrman G et al. Structure 2007;15(12):1618-1629
Other RAS mut: 20%
Beyond KRAS exon 2
10%10%
NRAS exon 2-3-4 mutations: constitutively activate RAS/RAF/MAPKs pathway
occur in about 10% of mCRCsIrahara N et al. Diagn Mol Pathol 2010;19(3):157-163;
Vaughn CP et al. Genes Chromosomes Cancer 2011;50(5):307-312
15/06/2015 14
RAS status:concordance between primary and metastases
Pri
ma
ry t
um
uo
rM
eta
sta
tic
tu
mu
or
N=
10
7 p
air
s
Prevalence of mutations tested* in 107 paired
primary and metastatic tumour samples
KRAS
NRAS
89%
83%
HIGH prim-mets CONCORDANCE
for RAS status
* Ion Torrent AmpliSeq Cancer Panel Adapted from and by permission of Kopetz S et al. J Clin Oncol ASCO 2014;32(15_suppl):3509
15/06/2015 15
KRAS «rare» mutations: data from retrospective series
Retrospective cohort of KRAS exon 2 wt pts treated with cetuximab plus irinotecan
Reprinted by permission from Macmillan Publishers Ltd on behalf of Cancer Research UK:
Loupakis F et al. Br J Cancer 2009;101(4):715-721
KRAS «rare» mutations: data from retrospective series
15/06/2015 16
123
0
222
13
0
50
100
150
200
250
KRAS codon 61 wt KRAS codon 61 mut
Responders
Non Responders
101
2
173
9
0
50
100
150
200
KRAS codon 146 wt KRAS codon 146 mut
Responders
Non Responders
KRAS cod 61
ORR: 0% mut vs. 35.7% wtp=0.006
KRAS cod 146
ORR: 18.2% mut vs. 36.9% wtp=0.34
Retrospective Consortium analysis in chemorefractory mCRC pts receiving cetuximab
Adapted from De Roock W et al. Lancet Oncol 2010;11(8):753-762 © (2010), with permission from Elsevier
NRAS mutations:data from retrospective series
15/06/2015 17
110
1
179
12
0
20
40
60
80
100
120
140
160
180
200
NRAS wt NRAS mut
Responders
Non Responders
NRASORR: 7.7% mut vs. 38.1% wtOR 0.14, 95% CI 0.007-0.70; p=0.013
Retrospective Consortium analysis in chemorefractory mCRC pts receiving cetuximab
Adapted from De Roock W et al. Lancet Oncol 2010;11(8):753-762 © (2010), with permission from Elsevier
NRAS mutations:evidences from phase III trials
15/06/2015
Panitumumab vs. BSC in advanced lines
PICCOLO trial: Irinotecan +/- Panitumumab in 2nd line
NRAS mutations may be potentially predictive
of resistance to panitumumabReprinted from Peeters M et al. Clin Can Res 2013;19(7):1902-1912, with permission from AACR;
Seymour MT et al. Lancet Oncol 2013;14(8):749-759, by permission of Elsevier
The beginning of RAS story
15/06/2015 19
Phase III PRIME trial: FOLFOX +/- Panitumumab in 1st line
*KRAS exon 2,3,4 and NRAS exon 2,3,4
*
Not only RAS mutant patients do not benefit
from the addition of panitumumab to 1st line FOLFOX,
but may even derive a detrimental effect
Douillard JY et al. N Eng J Med 2013;369(11):1023-1034. Reproduced with permission of Massachusetts Medical Society in the format Use in an
e-coursepack via Copyright Clearance Center
PRIME trial: OS in RAS* wt
15/06/2015 20
20.2 26.0
* KRAS exon 2,3,4 and NRAS exon 2,3,4 wt
The magnitude of benefit from panitumumab is amplified by the
extended molecular selectionDouillard JY et al. N Eng J Med 2013;369(11):1023-1034. Reproduced with permission of Massachusetts Medical Society in the format Use in an
e-coursepack via Copyright Clearance Center
OPUS trial: PFS according to RAS status
15/06/2015* KRAS exon 2,3,4 and NRAS exon 2,3,4
RAS* wt RAS* mut
Phase II OPUS trial: FOLFOX +/- Cetuximab in 1st line
The addition of cetuximab to 1st line FOLFOX
might be detrimental in patients with RAS mutations
HR: 0.43 [0.21-0.88]
p=0.018
HR: 1.59 [1.08-2.36]
p=0.018
By permission of Tejpar S et al. J Clin Oncol ASCO GI 2014;32(3_suppl):LBA444
15/06/2015 22
The magnitude of benefit from the addition of an anti-EGFR moAb to
1st line chemotherapy is amplified in RAS wt population
Benefit from anti-EGFRs in the «RAS-selected»
population in 1st line setting (PFS)
Phase III PRIME trial
N FOLFOX+Pan FOLFOX HR p
KRAS exon 2 wt 656 9.6 8.0 0.80 0.02
RAS wt 512 10.1 7.9 0.72 0.004
Phase II OPUS trial
N FOLFOX+Cet FOLFOX HR p
KRAS exon 2 wt 179 8.3 7.2 0.57 0.006
RAS wt 82 12.0 5.8 0.43 0.018
Phase III CRYSTAL trial
N FOLFIRI+Cet FOLFIRI HR p
KRAS exon 2 wt 666 9.9 8.4 0.70 0.0012
RAS wt 367 11.4 8.4 0.56 0.0002
Douillard JY et al. N Eng J Med 2013;369(11):1023-1034; Tejpar S et al. J Clin Oncol ASCO GI 2014;32(3_suppl):LBA444;
Ciardiello F et al. J Clin Oncol ASCO 2014;32(3_suppl):LBA443; Ciardiello F et al. J Clin Oncol ASCO 2014;32(15_suppl):3506
15/06/2015 23
The magnitude of benefit from the addition of an anti-EGFR moAb to
1st line chemotherapy is amplified in RAS wt population
Phase III PRIME trial
N FOLFOX+Pan FOLFOX HR p
KRAS exon 2 wt 656 23.8 19.4 0.83 0.03
RAS wt 512 26.0 20.2 0.78 0.04
Phase II OPUS trial
N FOLFOX+Cet FOLFOX HR p
KRAS exon 2 wt 179 22.8 18.5 0.86 0.39
RAS wt 82 20.7 17.8 0.83 0.50
Phase III CRYSTAL trial
N FOLFIRI+Cet FOLFIRI HR p
KRAS exon 2 wt 666 23.5 20.0 0.80 0.0093
RAS wt 367 28.4 20.2 0.69 0.0024
Benefit from anti-EGFRs in the «RAS-selected»
population in 1st line setting (OS)
Douillard JY et al. N Eng J Med 2013;369(11):1023-1034; Tejpar S et al. J Clin Oncol ASCO GI 2014;32(3_suppl):LBA444;
Ciardiello F et al. J Clin Oncol ASCO 2014;32(3_suppl):LBA443; Ciardiello F et al. J Clin Oncol ASCO 2014;32(15_suppl):3506
New EMA indication for
Panitumumab and Cetuximab
15/06/2015 24
August 2013
January 2014
By permission of the European Medicines Agency
15/06/2015 25
Phase II PEAK trial: FOLFOX+Pan vs. FOLFOX+Bev in 1st line
RAS: evidences from head-to-head trials
mPFS (mos)
N FOLFOX+Pan FOLFOX+Bev HR p
KRAS exon 2 wt 285 10.9 10.1 0.87 0.353
RAS wt 170 13.0 9.5 0.65 0.029
KRAS exon 2 wt RAS wt
Schwartzberg LS et al. J Clin Oncol 2014;32(21):2240-2247. Reprinted with permission. © (2014) American Society of Clinical Oncology.
All rights reserved
15/06/2015 26
Phase III FIRE-3 trial: FOLFIRI+Cet vs. FOLFIRI+Bev in 1st line
mPFS (mos)
N FOLFIRI+Cet FOLFIRI+Bev HR p
KRAS exon 2 wt 592 10.0 10.3 1.06 0.55
RAS wt 342 10.4 10.2 0.93 0.54
RAS: evidences from head-to-head trials
By permission of Stintzing S et al. J Clin Oncol ASCO GI 2014;32(3_suppl):445
15/06/2015
Phase III CALGB/SWOG 80405 trial: Chemo+Cet vs. Chemo+Bev in 1st line
RAS: evidences from head-to-head trials
mPFS (mos)
N Chemo+Cet Chemo+Bev HR p
KRAS exon 2 wt 1137 10.4 10.8 1.04 0.55
RAS wt 526 11.4 11.3 1.10 0.31
KRAS exon 2 wt RAS wt
By permission of Venook AP et al. J Clin Oncol ASCO 2014;32(3_suppl):LBA3;
By permission of Lenz HJ et al. ESMO 2014
28
RAS: evidences from head-to-head trials
Phase III CALGB/SWOG 80405 trial: Chemo+Cet vs. Chemo+Bev in 1st line
mOS (mos)
N Chemo+Cet Chemo+Bev HR p
KRAS exon 2 wt 1137 29.9 29.0 0.93 0.34
RAS wt 526 32.0 31.2 0.90 0.40
KRAS exon 2 wt RAS wt
By permission of Venook AP et al. J Clin Oncol ASCO 2014;32(3_suppl):LBA3;
By permission of Lenz HJ et al. ESMO 2014
15/06/2015
Phase III 20050181 trial: FOLFIRI +/- Panitumumab in 2nd line
RAS: evidences in the 2nd line setting
mPFS (mos)
N FOLFIRI+Pan FOLFIRI HR p
KRAS exon 2 wt 597 5.9 3.9 0.73 0.004
RAS wt 415 6.4 4.4 0.70 0.006
By permission of Peeters M et al. J Clin Oncol ASCO GI 2014;32(3_suppl):LBA387
15/06/2015 30
Phase III 20020408 trial: Panitumumab vs. BSC in advanced lines
KRAS exon 2 wt RAS wt
RAS: evidences in advanced lines
mPFS (mos)
N Pan BSC HR p
KRAS exon 2 wt 243 2.8 1.7 0.45 <0.001
RAS wt 136 3.2 1.6 0.36 <0.001
By permission of Patterson SD et al. J Clin Oncol ASCO 2013;31(15_suppl):3617
15/06/2015 31
BRAF mutations affect 8-10% of mCRCs
and about 15-20% of RAS wt tumours
What’s next? …BRAF!
RAS mut
all RAS wt
BRAF mut
Richman SD et al. J Clin Oncol 2009;27(35):5931-5937. Reprinted with permission.
© (2009) American Society of Clinical Oncology. All rights reserved
15/06/2015 3215/06/2015 32
Strong negative prognostic marker in mts setting
BRAF mutation: prognostic impact
Reprinted by permission from Macmillan Publishers Ltd on behalf of Cancer
Research UK: Souglakos J et al. Br J Cancer 2009;101(3):465-472 © 2009
By permission of Koopman M. ESMO 2009
Reprinted by permission from Macmillan Publishers Ltd
on behalf of Cancer Research UK: Yokota T et al.
Br J Cancer 2011;104(5):856-862 © 2011
15/06/2015 33
BRAF and anti-EGFRs:evidences from retrospective series
Retrospective analysis of BRAF mutation in mCRC KRAS wt pts treated with cetuximab or panitumumab
Di Nicolantonio F et al. J Clin Oncol 2008;26(35):5705-5712. Reprinted with permission. © (2008) American Society of Clinical Oncology.
All rights reserved
124
2
202
22
0
50
100
150
200
250
BRAF wt BRAF mut
Responders
Non Responders
BRAFORR: 8.3% mut vs. 38.0% wtOR 0.17, 95% CI 0.02–0.51 p=0.0012
Retrospective Consortium analysis in chemorefractory mCRC pts receiving cetuximab
BRAF and anti-EGFRs:evidences from retrospective series
Adapted from De Roock W et al. Lancet Oncol 2010;11(8):753-762 © (2010), with permission from Elsevier
BRAF and anti-EGFRs:evidences from phase III trials
15/06/2015 35
PICCOLO trial: Irinotecan +/- Panitumumab in 2nd line
Seymour MT et al. Lancet Oncol 2013;14(8):749-759 © (2013), with permission from Elsevier
BRAF and anti-EGFRs:evidences from phase III trials
36
CRYSTAL trial: FOLFIRI +/- Cetuximab in 1st line
Van Cutsem E et al. J Clin Oncol 2011;29(15):2011-2019. Reprinted with permission. © (2011) American Society of Clinical Oncology.
All rights reserved
BRAF and anti-EGFRs:evidences from phase III trials
37
PRIME trial: FOLFOX +/- Panitumumab in 1st line
Douillard JY et al. N Eng J Med 2013;369(11):1023-1034. Reproduced with permission of Massachusetts Medical Society in the format Use in an
e-coursepack via Copyright Clearance Center
PRIME trial: RAS and BRAF selection
38
mPFS (mos)
N FOLFOX+Pan FOLFOX HR p
KRAS exon 2 wt 656 9.6 8.0 0.80 0.02
RAS wt 512 10.1 7.9 0.72 0.004
RAS/BRAF wt 446 10.8 9.2 0.68 0.002
mOS (mos)
N FOLFOX+Pan FOLFOX HR p
KRAS exon 2 wt 656 23.8 19.4 0.83 0.03
RAS wt 512 26.0 20.2 0.78 0.04
RAS/BRAF wt 446 28.3 20.9 0.74 0.02
Douillard JY et al. N Eng J Med 2013;369(11):1023-1034
The open issue: BRAF testing in daily clinical practice
15/06/2015 39
Acquired resistance to anti-EGFRs
15/06/2015 40
Drug
Response
Acquired resistance
A new perspective: Liquid biopsy
15/06/2015 41Crowley E et al. Nat Rev Clin Oncol 2013;10(8):472-484;
From Bettegowda C et al. Sci Transl Med 2014;6(224):224ra24. Reprinted with permission from AAAS
Acquired resistance: a common experience
15/06/2015 42Diaz LA Jr and Bardelli A. J Clin Oncol 2014;32(6):579-586. Reprinted with permission. © (2014) American Society of Clinical Oncology.
All rights reserved
Acquired resistance: what really happens
15/06/2015 43
The continuous monitoring of
circulating cell-free DNA shows the
emergence of mutations in RAS
pathway as a potential mechanism of
acquired resistance to anti-EGFRs.
Reprinted by permission from Macmillan Publishers Ltd: Misale S et al. Nature 2013;486(7404):532-536 © 2013;
From Bettegowda C et al. Sci Transl Med 2014;6(224):224ra24. Reprinted with permission from AAAS
Conclusions - 1
RAS testing is mandatory in patients candidate to anti-EGFR
therapy.
An extended molecular selection, including KRAS and NRAS (exon
2-3-4) mutational status, allows to identify:
a population of patients (RAS mut) that do not benefit from the anti-
EGFR and may even derive a detrimental effect;
a population of patients (RAS wt) in which the benefit from anti-EGFR is
significantly amplified.
15/06/2015 44
Also BRAF testing may be useful in clinical choices:
The impact of anti-EGFRs is minimal if not absent in BRAF mutant
patients.
An intensive treatment might be a promising strategy to contrast the
aggressiveness of BRAF mutant disease (FOLFOXIRI plus Bev may be
a valid option).
BRAF is a compelling druggable target. Waiting for data from new
therapeutic strategies (i.e. BRAFi±MEKi±anti-EGFR).
Liquid biopsies may be a new reliable tool to track the dynamism of
tumour progression and to clarify mechanisms of acquired
resistance.
15/06/2015 45
Conclusions - 2
Thank you!
15/06/2015 46