CURRENT STANDARD OF CARE OF COLORECTAL CANCER: THE EVOLUTION OF ESMO CLINICAL PRACTICE GUIDELINES

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Melanie McDonald
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1 CURRENT STANDARD OF CARE OF COLORECTAL CANCER: THE EVOLUTION OF ESMO CLINICAL PRACTICE GUIDELINES Fortunato Ciardiello ESMO Past-President Dipartimento di Medicina di Precisione Università degli Studi della Campania Luigi Vanvitelli

2 CONFLICT OF INTEREST DISCLOSURE Advisory Boards: Roche, Amgen, Lilly, Merck, Servier, Bayer, Symphogen Institutional Research Funding: Roche, Amgen, Bayer, Merck

Drivers for first line treatment choices in metastatic colorectal cancer *Tumour Characteristics Clinical presentation (tumour burden, primary tumour

8 Drivers for first line treatment choices in metastatic colorectal cancer *Tumour Characteristics Clinical presentation (tumour burden, primary tumour localisation) Tumour biology RAS mutation status BRAF mutation status Patient characteristics Age Performance status Organ function Comorbidities Patient attitude, expextations, preference Treatment characteristics Toxicity profile Flexibility of treatment admnistration Socioeconomic factors Quality of life *Additional tumour characteristics: HER2 amplification; MSI-H status Adapted from Van Cutsem et al, ESMO Consensus Conference, Annals of Oncology 2016

9 The results of the Consensus Conference on metastatic colorectal cancer were summarized in: 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.

10 Molecular Pathology and Biomarkers 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.

11 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]

12 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].

13 ESMO consensus guidelines for the management of patients with metastatic colorectal cancer

15 ESMO Special Symposia manuscript for submission to Annals of Oncology Final submission draft Table 1. Source of patients for the analyses Trial characteristics Trial name CRYSTAL [28, 42, 43] FIRE-3 [28, 36] Phase of trial Chemotherapy backbone Bevacizumab in control arm? Anti-EGFR therapy Treatment line Randomised With KRAS evaluable With KRAS Wt* With all RAS wt III FOLFIRI No Cetuximab 1 st % 364 III FOLFIRI Yes Cetuximab 1 st 752 NA %% 394 PEAK [35] II FOLFOX6 Yes Panitumumab 1 st $ 143 PRIME III FOLFOX4 No Panitumumab 1 st [40, 41] III FOLFIRI No Panitumumab 2 nd [45] CALGB [27, 38] III FOLFIRI/ FOLFOX6 Yes Cetuximab 1 st $$ 474 With all RAS wt and tumour side confirmed *Not always easy to determine, taken from publication or slide presentation. Sometimes refers to all ITT population (PRIME, PEAK, AMGEN181) sometimes from the KRAS wt exon 2 (CRYSTAL, FIRE-3) sometimes from available tissue to test (CALGB 80405). % Only 430 patients were evaluable for other RAS mutations; %% 475 patients were tested successfully for the other KRAS mutations; $ Extended RAS analysis was performed in 250 patients with 233 patients with KRAS or RAS results. Out of the 221 patients with KRAS exon 2 wt at this stage, 170 were RAS wt; $$ 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

16 Final submission draft Figure 1.

17 Prognostic effect on OS ESMO Special Symposia manuscript for submission to Annals of Oncology Final submission draft Figure 2. in the CT + Anti-EGFR Arm A

18 Prognostic effect on PFS in the CT + Anti-EGFR Arm ESMO Special Symposia manuscript for submission to Annals of Oncology Final submission draft B

19 Prognostic effect on RR ESMO Special Symposia manuscript for submission to Annals of Oncology in the CT Final submission + Anti-EGFR draft Arm C

20 ESMO Special Symposia manuscript for submission to Annals of Oncology Final submission draft Prognostic effect on OS Figure 3. in the CT +/- Bevacizumab Arm A

21 Prognostic effect on PFS ESMO Special Symposia manuscript for submission to Annals of Oncology Final submission draft in the CT +/- Bevacizumab Arm B

22 Prognostic effect on RR ESMO Special Symposia manuscript for submission to Annals of Oncology Final submission draft in the CT +/- Bevacizumab Arm C

23 Figure 4. A Predictive effect on OS

24 Final submission draft B Predictive effect on PFS

25 Final submission draft C Predictive effect on RR

26 Final submission draft are strong negative prognostic markers but might be (non-significant) predictive markers for intensive therapy [54]. Therefore, with all of the caveats resulting from this analysis, which was performed retrospectively, and involved a limited number of patients from the individual trials, a relatively small number of rightsided patients, and most importantly did not consider a preference for distinct treatment sequences, as only the randomization to the respective treatment line was analysed, it provides evidence in the first-line treatment setting to: i. Reinforce the use of EGFR antibody therapy in patients with mcrc and left-sided RAS wt tumours. ii. Promote the idea that patients with right-sided RAS wt tumours might be better treated with chemotherapy alone or chemotherapy plus bevacizumab - except maybe if the goal is tumour size reduction as the ORRs were higher (but not PFS and OS). iii. Emphasise that in the absence of data on specific treatment sequences, there is no reason that EGFR-antibody therapy should be avoided in cases of disease progression or treatment intolerance independent of primary tumour location. iv. Promote the concept of a continuum of care and the sequential use of all therapies, including bevacizumab where appropriate, in the treatment of patients with mcrc. However the developmental, genetic, physiological and biological differences associated with the different locations in the colon and rectum are clearly more complex than simple right- and left-

27 iii. iv. tumour size reduction as the ORRs were higher (but not PFS and OS). Emphasise that in the absence of data on specific treatment sequences, there is no reason that EGFR-antibody therapy should be avoided in cases of disease progression or treatment intolerance independent of primary tumour location. Promote the concept of a continuum of care and the sequential use of all therapies, including bevacizumab where appropriate, in the treatment of patients with mcrc. However the developmental, genetic, physiological and biological differences associated with the different locations in the colon and rectum are clearly more complex than simple right- and leftsidedness and one might predict that a comprehensive evaluation of molecular features in left- and right-sided CRCs will contribute to improvements in treatment outcomes in the future. Going forward, new randomised controlled trials should have to stratify patients according to primary tumour location and if the sequence in which the currently available therapies are delivered matters we need more trials based on tumour location and molecular characteristics. acknowledgements Anne Kinsella (Cancer Communications and Consultancy Ltd, Knutsford, Cheshire UK) is acknowledged for her assistance in the preparation of the manuscript, funded by ESMO. funding All expenses relating to the special symposia were covered by ESMO.

28 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

My first line treatment choices in April 2018 (in fit patients) Goal Mutation Preferred first line option Cytoreduction RAS and BRAF WT Left: Right: DOUBLET + anti-egfr FOLFOXIRI + bevacizumab

33 My first line treatment choices in April 2018 (in fit patients) Goal Mutation Preferred first line option Cytoreduction RAS and BRAF WT Left: Right: DOUBLET + anti-egfr FOLFOXIRI + bevacizumab (DOUBLET + anti-egfr?) RAS mut FOLFOXIRI + bevacizumab BRAF mut FOLFOXIRI + bevacizumab Disease stabilization RAS and BRAF WT Left: Right: DOUBLET + anti-egfr FOLFOXIRI or DOUBLET + bevacizumab RAS mut FOLFOXIRI or DOUBLET + bevacizumab BRAF mut FOLFOXIRI + bevacizumab

REVIEW ON THE ESMO CONSENSUS CONFERENCE ON ADVANCED COLORECTAL CANCER

ESMO Preceptorship Programme Colorectal Cancer Barcelona November, 25-26, 2016 REVIEW ON THE ESMO CONSENSUS CONFERENCE ON ADVANCED COLORECTAL CANCER Andrés Cervantes Professor of Medicine Strategic changes