Validated and promising predictive factors in mcrc: Recent updates on RAS testing Fotios Loupakis, MD PhD

Transcription

1 Validated and promising predictive factors in mcrc: Recent updates on RAS testing Fotios Loupakis, MD PhD U.O. Oncologia 2 Universitaria Azienda Ospedaliero-Universitaria Pisana Pisa, Italy

2 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

3 The beginning of KRAS story Phase III CA trial: Cet vs. BSC in advanced lines Phase III trial: Pan vs. BSC in advanced lines 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 15/06/ Jonker DJ et al. N Engl J Med 2007;357(20): 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): Reprinted with permission. (2007) American Society of Clinical Oncology. All rights reserved

4 The first clinical report In a small retrospective cohort, KRAS exon 2 mutations seemed to predict resistance to anti-egfrs 15/06/ Reprinted from Lièvre A et al. Cancer Res 2006;66(8): , with permission from AACR

5 Post-hoc analyses of phase III trials KRAS exon 2 wt Jonker DJ et al. N Engl J Med 2007 KRAS exon 2 mut Karapetis CS et al. N Engl J Med 2008 Benefit from cetuximab was restricted to KRAS exon 2 wt population 15/06/ Jonker DJ et al. N Engl J Med 2007;357(20): 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): Reproduced with permission of Massachusetts Medical Society in the format Use in an ecoursepack via Copyright Clearance Center

6 Post-hoc analyses of phase III trials KRAS exon 2 wt Van Cutsem E et al. J Clin Oncol 2007 Amado RG et al. J Clin Oncol 2008 KRAS exon 2 mut Benefit from panitumumab was restricted to KRAS exon 2 wt population 15/06/ Van Cutsem E et al. J Clin Oncol 2007;25(13): Reprinted with permission. (2007) American Society of Clinical Oncology. All rights reserved; Amado RG et al. J Clin Oncol 2008;26(10): Reprinted with permission. (2008) American Society of Clinical Oncology. All rights reserved

7 Benefit from anti-egfrs in the «KRAS exon 2-selected» population mpfs (mos) N Cet BSC HR p Unselected <0.001 KRAS exon 2 wt <0.001 KRAS exon 2 mut NS Jonker DJ et al. N Engl J Med 2007;357(20): ; Karapetis CS et al. N Engl J Med 2008;359(17): mpfs (mos) N Pan BSC HR p Unselected KRAS exon 2 wt <0.001 KRAS exon 2 mut NS Van Cutsem E et al. J Clin Oncol 2007;25(13): ; Amado RG et al. J Clin Oncol 2008;26(10): The magnitude of benefit from anti-egfr moabs is amplified 15/06/ in KRAS exon 2 wt population

8 KRAS exon 2: evidences in the 1 st line setting Phase III CRYSTAL trial: FOLFIRI +/- Cetuximab in 1 st line mpfs (mos) N FOLFIRI+Cet FOLFIRI HR p Unselected KRAS exon 2 wt KRAS exon 2 mut The magnitude of benefit from the addition of cetuximab to 1 st line FOLFIRI is amplified in KRAS exon 2 wt population Van Cutsem E et al. J Clin Oncol 2007;25(13):

9 EMA Indications for anti-egfrs June By permission of the European Medicines Agency

10 KRAS mutations: the size of the problem KRAS exon 2 mutations affect about 40-45% of mcrc 15/06/ Data from the COSMIC database

11 Beyond KRAS exon 2 15/06/ Edkins S et al. Cancer Biol Ther 2006;5(8): ; Buhrman G et al. Structure 2007;15(12):

12 Beyond KRAS exon 2 10% KRAS exon 3 and 4 mutations: constitutively activate RAS/RAF/MAPKs pathway occur in about 10% of mcrcs 15/06/ Edkins S et al. Cancer Biol Ther 2006;5(8): ; Buhrman G et al. Structure 2007;15(12):

13 Beyond KRAS exon 2 10% 10% Other RAS mut: 20% NRAS exon mutations: constitutively activate RAS/RAF/MAPKs pathway occur in about 10% of mcrcs Irahara N et al. Diagn Mol Pathol 2010;19(3): ; Vaughn CP et al. Genes Chromosomes Cancer 2011;50(5):

14 Metastatic tumuor N= 107 pairs Primary tumuor RAS status: concordance between primary and metastases Prevalence of mutations tested* in 107 paired primary and metastatic tumour samples KRAS 89% NRAS 83% HIGH prim-mets CONCORDANCE for RAS status 15/06/ * 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 KRAS «rare» mutations: data from retrospective series Retrospective cohort of KRAS exon 2 wt pts treated with cetuximab plus irinotecan 15/06/ Reprinted by permission from Macmillan Publishers Ltd on behalf of Cancer Research UK: Loupakis F et al. Br J Cancer 2009;101(4):

16 KRAS «rare» mutations: data from retrospective series Retrospective Consortium analysis in chemorefractory mcrc pts receiving cetuximab Responders Non Responders KRAS cod 61 ORR: 0% mut vs. 35.7% wt p= KRAS codon 61 wt 0 13 KRAS codon 61 mut KRAS cod 146 ORR: 18.2% mut vs. 36.9% wt p= /06/ KRAS codon 146 wt 2 9 KRAS codon 146 mut Responders Non Responders Adapted from De Roock W et al. Lancet Oncol 2010;11(8): (2010), with permission from Elsevier

17 NRAS mutations: data from retrospective series Retrospective Consortium analysis in chemorefractory mcrc pts receiving cetuximab Responders Non Responders NRAS wt 1 12 NRAS mut NRAS ORR: 7.7% mut vs. 38.1% wt OR 0.14, 95% CI ; p= /06/ Adapted from De Roock W et al. Lancet Oncol 2010;11(8): (2010), with permission from Elsevier

18 NRAS mutations: evidences from phase III trials Panitumumab vs. BSC in advanced lines PICCOLO trial: Irinotecan +/- Panitumumab in 2 nd line 15/06/2015 NRAS mutations may be potentially predictive of resistance to panitumumab Reprinted from Peeters M et al. Clin Can Res 2013;19(7): , with permission from AACR; Seymour MT et al. Lancet Oncol 2013;14(8): , by permission of Elsevier

19 The beginning of RAS story Phase III PRIME trial: FOLFOX +/- Panitumumab in 1 st 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 1 st line FOLFOX, but may even derive a detrimental effect 15/06/ Douillard JY et al. N Eng J Med 2013;369(11): Reproduced with permission of Massachusetts Medical Society in the format Use in an e-coursepack via Copyright Clearance Center

20 PRIME trial: OS in RAS* wt * KRAS exon 2,3,4 and NRAS exon 2,3,4 wt The magnitude of benefit from panitumumab is amplified by the extended molecular selection 15/06/ Douillard JY et al. N Eng J Med 2013;369(11): Reproduced with permission of Massachusetts Medical Society in the format Use in an e-coursepack via Copyright Clearance Center

21 OPUS trial: PFS according to RAS status Phase II OPUS trial: FOLFOX +/- Cetuximab in 1 st line RAS* wt HR: 0.43 [ ] p=0.018 RAS* mut HR: 1.59 [ ] p=0.018 The addition of cetuximab to 1 st line FOLFOX might be detrimental in patients with RAS mutations * KRAS 15/06/2015 exon 2,3,4 and NRAS exon 2,3,4 By permission of Tejpar S et al. J Clin Oncol ASCO GI 2014;32(3_suppl):LBA444

22 Benefit from anti-egfrs in the «RAS-selected» population in 1 st line setting (PFS) Phase III PRIME trial N FOLFOX+Pan FOLFOX HR p KRAS exon 2 wt RAS wt Phase II OPUS trial N FOLFOX+Cet FOLFOX HR p KRAS exon 2 wt RAS wt Phase III CRYSTAL trial N FOLFIRI+Cet FOLFIRI HR p KRAS exon 2 wt RAS wt The magnitude of benefit from the addition of an anti-egfr moab to 1 st line chemotherapy is amplified in RAS wt population 15/06/ Douillard JY et al. N Eng J Med 2013;369(11): ; 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

23 Benefit from anti-egfrs in the «RAS-selected» population in 1 st line setting (OS) Phase III PRIME trial N FOLFOX+Pan FOLFOX HR p KRAS exon 2 wt RAS wt Phase II OPUS trial N FOLFOX+Cet FOLFOX HR p KRAS exon 2 wt RAS wt Phase III CRYSTAL trial N FOLFIRI+Cet FOLFIRI HR p KRAS exon 2 wt RAS wt The magnitude of benefit from the addition of an anti-egfr moab to 1 st line chemotherapy is amplified in RAS wt population 15/06/ Douillard JY et al. N Eng J Med 2013;369(11): ; 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

24 New EMA indication for Panitumumab and Cetuximab August 2013 January /06/ By permission of the European Medicines Agency

25 RAS: evidences from head-to-head trials Phase II PEAK trial: FOLFOX+Pan vs. FOLFOX+Bev in 1 st line mpfs (mos) N FOLFOX+Pan FOLFOX+Bev HR p KRAS exon 2 wt RAS wt KRAS exon 2 wt RAS wt 15/06/ Schwartzberg LS et al. J Clin Oncol 2014;32(21): Reprinted with permission. (2014) American Society of Clinical Oncology. All rights reserved

26 RAS: evidences from head-to-head trials Phase III FIRE-3 trial: FOLFIRI+Cet vs. FOLFIRI+Bev in 1 st line mpfs (mos) N FOLFIRI+Cet FOLFIRI+Bev HR p KRAS exon 2 wt RAS wt /06/ By permission of Stintzing S et al. J Clin Oncol ASCO GI 2014;32(3_suppl):445

27 RAS: evidences from head-to-head trials Phase III CALGB/SWOG trial: Chemo+Cet vs. Chemo+Bev in 1 st line mpfs (mos) N Chemo+Cet Chemo+Bev HR p KRAS exon 2 wt RAS wt KRAS exon 2 wt RAS wt 15/06/2015 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 trial: Chemo+Cet vs. Chemo+Bev in 1 st line mos (mos) N Chemo+Cet Chemo+Bev HR p KRAS exon 2 wt RAS wt 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

29 RAS: evidences in the 2 nd line setting Phase III trial: FOLFIRI +/- Panitumumab in 2 nd line mpfs (mos) N FOLFIRI+Pan FOLFIRI HR p KRAS exon 2 wt RAS wt /06/2015 By permission of Peeters M et al. J Clin Oncol ASCO GI 2014;32(3_suppl):LBA387

30 RAS: evidences in advanced lines Phase III trial: Panitumumab vs. BSC in advanced lines mpfs (mos) N Pan BSC HR p KRAS exon 2 wt <0.001 RAS wt <0.001 KRAS exon 2 wt RAS wt 15/06/ By permission of Patterson SD et al. J Clin Oncol ASCO 2013;31(15_suppl):3617

31 What s next? BRAF! BRAF mutations affect 8-10% of mcrcs and about 15-20% of RAS wt tumours RAS mut all RAS wt BRAF mut 15/06/

32 BRAF mutation: prognostic impact Richman SD et al. J Clin Oncol 2009;27(35): Reprinted with permission. (2009) American Society of Clinical Oncology. All rights reserved Reprinted by permission from Macmillan Publishers Ltd on behalf of Cancer Research UK: Souglakos J et al. Br J Cancer 2009;101(3): 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): /06/ Strong negative prognostic marker in mts setting

33 BRAF and anti-egfrs: evidences from retrospective series Retrospective analysis of BRAF mutation in mcrc KRAS wt pts treated with cetuximab or panitumumab 15/06/ Di Nicolantonio F et al. J Clin Oncol 2008;26(35): Reprinted with permission. (2008) American Society of Clinical Oncology. All rights reserved

34 BRAF and anti-egfrs: evidences from retrospective series Retrospective Consortium analysis in chemorefractory mcrc pts receiving cetuximab Responders BRAF wt 2 22 BRAF mut Non Responders BRAF ORR: 8.3% mut vs. 38.0% wt OR 0.17, 95% CI p= Adapted from De Roock W et al. Lancet Oncol 2010;11(8): (2010), with permission from Elsevier

35 BRAF and anti-egfrs: evidences from phase III trials PICCOLO trial: Irinotecan +/- Panitumumab in 2 nd line 15/06/ Seymour MT et al. Lancet Oncol 2013;14(8): (2013), with permission from Elsevier

36 BRAF and anti-egfrs: evidences from phase III trials CRYSTAL trial: FOLFIRI +/- Cetuximab in 1 st line Van Cutsem E et al. J Clin Oncol 2011;29(15): Reprinted with permission. (2011) American Society of Clinical Oncology. All rights reserved 36

37 BRAF and anti-egfrs: evidences from phase III trials PRIME trial: FOLFOX +/- Panitumumab in 1 st line Douillard JY et al. N Eng J Med 2013;369(11): Reproduced with permission of Massachusetts Medical Society in the format Use in an e-coursepack via Copyright Clearance Center 37

38 PRIME trial: RAS and BRAF selection mpfs (mos) N FOLFOX+Pan FOLFOX HR p KRAS exon 2 wt RAS wt RAS/BRAF wt mos (mos) N FOLFOX+Pan FOLFOX HR p KRAS exon 2 wt RAS wt RAS/BRAF wt Douillard JY et al. N Eng J Med 2013;369(11):

39 The open issue: BRAF testing in daily clinical practice 15/06/

40 Acquired resistance to anti-egfrs Acquired resistance Drug Response 15/06/

41 A new perspective: Liquid biopsy 15/06/ Crowley E et al. Nat Rev Clin Oncol 2013;10(8): ; From Bettegowda C et al. Sci Transl Med 2014;6(224):224ra24. Reprinted with permission from AAAS

42 Acquired resistance: a common experience 15/06/ Diaz LA Jr and Bardelli A. J Clin Oncol 2014;32(6): Reprinted with permission. (2014) American Society of Clinical Oncology. All rights reserved

43 Acquired resistance: what really happens 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. 15/06/ Reprinted by permission from Macmillan Publishers Ltd: Misale S et al. Nature 2013;486(7404): ; From Bettegowda C et al. Sci Transl Med 2014;6(224):224ra24. Reprinted with permission from AAAS

44 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/

45 Conclusions - 2 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/

46 Thank you! 15/06/