Validated and promising predictive factors in …...Validated and promising predictive factors in...
Transcript of Validated and promising predictive factors in …...Validated and promising predictive factors in...
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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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August 2013
January 2014
By permission of the European Medicines Agency
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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
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Acquired resistance to anti-EGFRs
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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.
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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.
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Conclusions - 2
Thank you!
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