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

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



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


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


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


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


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


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


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


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


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


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


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


BRAF and anti-EGFRs:evidences from retrospective series


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


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


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


PRIME trial: RAS and BRAF selection

38

mPFS (mos)


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)


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

Validated and promising predictive factors in …...Validated and promising predictive factors in...

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