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Marc Peeters MD, PhD Coordinator Multidisciplinary Oncological Center Antwerpen (MOCA)

Sequencing of S ystemic treatment in mCRC – According to the International Guidelines. Marc Peeters MD, PhD Coordinator Multidisciplinary Oncological Center Antwerpen (MOCA) Head of the Oncology Department UZA, Full Professor in Oncology UA, Assistant Professor Ghent University.

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Marc Peeters MD, PhD Coordinator Multidisciplinary Oncological Center Antwerpen (MOCA)

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  1. Sequencing of Systemic treatment in mCRC – According tothe International Guidelines Marc Peeters MD, PhD CoordinatorMultidisciplinaryOncological Center Antwerpen (MOCA) Head of the Oncology Department UZA, Full Professor in Oncology UA, Assistant Professor Ghent University

  2. Disclosures

  3. mColoRectal Cancer – continuum of care Malvezzi M et al. Ann Oncol 2018;29:1016–22

  4. mColoRectal Cancer – continuum of care Malvezzi M et al. Ann Oncol 2018;29:1016–22

  5. mColoRectal Cancer – more patients, more benefit 100% (420) 74.3% (277/373) 63.3% (143/226) Probability of clinical benefit† Proportion of patients submittedto each line of therapy 45.9% (56/122) 71.5% 48.6% 35.2% 1st-line 2nd-line 3rd-line 4th-line 25.0% Tampellini M et al. Clin Colorectal Cancer 2017; 16(4):372-376

  6. mColorectal Cancer (mCRC)– continuum of care, multi-optional

  7. GERCOR study – chemotherapy sequence Tournigand C et al. J ClinOncol 2004;22:229–37

  8. mCRC– how to decide in a given patient? • I usemy standard regimens in different lines • I take intoconsiderationfollowingtumoural factors: • Biomarker profile – RAS, BRAF and MSI • Location of theprimarytumour • Aim of the treatment – control vs.cytoreduction

  9. Efficacy Safety Histopathology Tumor characteristics Patient characteristics Previous treatment Patient preference Goals of therapy Biomarkers

  10. Yoshino T et al. Ann Oncol 2018;29:44-70

  11. Diagnosis of rectal adenocarcinoma • Lung and liver metastasis • PD • PD • PD • PD • PD (bone mets) Cape Study FOLFIRI/Pmab TAS-102 Regorafenib CapOX + Bevacizumab RT TAS-102 Panitumumab Regorafenib FOLFOX + Cetuximab FOLFIRI/Aflibercept 2015 2016 2017 2018 • TME

  12. BIOMARKERS

  13. Establishedbiomarkers – RAS & anti-EGFR Combination: FOLFOX or FOLFIRI (1st line); FOLFIRI (2nd line¥); monotherapy (CTxR) (WT RAS)2 Unselected WT KRAS exon 2 WT RAS Monotherapy (CTxR) (WT KRAS)2 Combination: FOLFOX (1st line); FOLFIRI (2nd-line); monotherapy (CTxR) (WT KRAS)2 Label variation(WT RAS)2 EU label variations* Combination: IRI-based CTx or FOLFOX4; monotherapy (CTxR†)(WT KRAS)1 Combination: IRI-based CTx; FOLFOX (1st line); monotherapy (CTxR†)(WT KRAS)1 Combination: CTx; Monotherapy(CTxR†) (WT KRAS)1 Combination: IRI (CTxR)1 Label variation(WT RAS)1 2004 2007 2008 2009 2010 2011 2012 2013 2014 2015 Panitumumab Cetuximab

  14. mCRC – biomarkers & choice of treatment CT=chemotherapy; Beva=bevacizumab; Cetu=cetuximab; Pmab=panitumumab; Afli=aflibercept; Regoraf=regorafenib; Ram=Ramucirumab

  15. Sinicrope FA et al. Clin Cancer Res2015;21:5294-304 Sinicrope FA et al. ClinGastroenterolHepatol 2016;14:651-658

  16. Incidence of BRAF mutations 4% 30% Boeckx N et al. Ann Oncol 2017;28:1862-68; Boeckx N et al. Clin Colorectal Cancer 2018;17:170-178

  17. …molecular subgroup analyses of the open-label, phase 3 TRIBE study Between July 17, 2008, and May 31, 2011, 508 patients were randomly assigned. At a median follow-up of 48·1 months (IQR 41·7–55·6), median overall survival was 29·8 months (95% CI 26·0–34·3) in the FOLFOXIRI plus bevacizumab group compared with 25·8 months (22·5–29·1) in the FOLFIRI plus bevacizumab group (hazard ratio [HR] 0·80, 95% CI 0·65–0·98; p=0·03). Median overall survival was 37·1 months (95% CI 29·7–42·7) in the RAS and BRAF wild-type subgroup compared with 25·6 months (22·4–28·6) in the RAS-mutation-positive subgroup (HR 1·49, 95% CI 1·11–1·99) and 13·4 months (8·2–24·1) in the BRAF-mutation-positive subgroup (HR 2·79, 95% CI 1·75–4·46; likelihood-ratio test p<0·0001). Treatment effect was not significantly different across molecular subgroups (p interaction=0·52). Cremolini C et al. Lancet 2015;16:1306-1315

  18. Geissler M et al. ESMO2017; Madrid

  19. FOCUS 4 study programme (MRC)Molecularly stratified therapy in inoperable advanced or metastatic CRC GI0016 Master protocol:1 • Eligible patients: • Advanced or metastatic CRC • Fit for 1st-line treatment • Consent to biomarker analysis Patient selection • Biomarker panel analysis during1st-line treatment:† • On FFPE tumour block • BRAF, PIK3CA, KRAS, NRAS mutation; mRNA EREG; IHC MMR, PTEN Registration period Standard 1st-line treatment for  16 weeks  Stable or responding disease Molecular selection† BRAF mutation2 KRAS or NRAS mutation Non-stratified (unclassified orwhen other stratifications are refused or unavailable) All wild type with PTEN expression PIK3CA mutation A B C D N Primary outcomes:PFS and/or OS from randomisation R R R R R NoRx P Aspirin P P HER 1,2,3inhibitor No Rx Capecitabine BRAF + EGFR ± MEK inhibitors* AKT+ MEK inhibitors Trial period On progression restart 1st-line chemotherapy *Dabrafenib + panitumumab ± trametinib.†The molecular cohorts are arranged in a hierarchy from left to right. For example, a patient with both a PIK3CA mutation and a KRAS mutation will be assigned the PIK3CA mutation cohort.MRC, Medical Research Council; No Rx, active monitoring only; P, placebo. EUDRACT #: 2012-005111-12;1. FOCUS 4 Master Protocol v3.0 (Accessed 09-10-15);2. FOCUS 4A Trial Protocol v1.0 (Accessed 09-10-15).

  20. Kopetz S et al. ASCO2017; 3505

  21. Nivolumab+Ipilimumab Andre T et al, ASCO GI 2018; 553 Nivolumab Overman J et al, ASCO GI 2018; 554

  22. SIDENESS

  23. Holch JW et al. Eur J Cancer 2017;70:87-98

  24. Primary tumor sidedness has an impact on prognosis and treatment outcome in metastatic colorectal cancer: results from two randomized first-line panitumumab studies • Boeckx N, Koukakis R, Op de Beeck K, Rolfo C, Van Camp G, Siena S, Tabernero J, Douillard JY, André T & Peeters M. Ann Oncol2017;28:1862-1868 • Effect of primary tumor sidedness on second-or later-line treatment outcome in patients with RAS wild-type metastatic colorectal cancer and in all lines of treatment in patients with RAS mutations in four randomized panitumumab studies • Boeckx N, Koukakis R, Op de Beeck K, Rolfo C, Van Camp G, Siena S, Tabernero J, Douillard JY, André T & Peeters M. ClinColorectal Cancer 2018;17:170-178 Pmab + FOLFOX PRIME(NCT00364013) First-line Phase III FOLFOX Pmab + FOLFOX PEAK(NCT00819780) First-line Phase II Bmab + FOLFOX Pmab + FOLFIRI 200501813(NCT00339183) 20050181(NCT00339183) Second-line Phase III FOLFIRI Pmab + BSC 20020408(NCT00113763) Later-line Phase III BSC

  25. Tumor location, Left vs. Right % 75% 25% Boeckx N et al. Ann Oncol 2017;28:1862-68; Boeckx N et al. Clin Colorectal Cancer 2018;17:170-178

  26. Arnold D et al. Ann Oncol 2017;28:1713-1729

  27. Arnold D et al. Ann Oncol 2017;28:1713-1729

  28. Geissler M et al. ESMO2017; Madrid

  29. INDICATION

  30. Primrose JN et al. Lancet Oncol 2014;15:601-11 Ye L-Ch et al. J ClinOncol 2013:31;1931-38

  31. F. Petrelli & S. Barni in Int J Colorectal Dis (2012) 27:997–1004

  32. mCRC – treatment intensification Geissler M et al. ESMO2017; Madrid

  33. AIO: Arnold, et al. ASCO 2014; Hegewisch-Becker et al., Lancet Oncol2015 DCCG: Koopman, et al., ASCO 2014; Simkens et al., Lancet 2015

  34. AIO: Arnold, et al. ASCO 2014; Hegewisch-Becker et al., Lancet Oncol2015 DCCG: Koopman, et al., ASCO 2014; Simkens et al., Lancet 2015

  35. Courtesyto F. Loupakis

  36. LATER LINES

  37. First lineMetastaticTherapy AdjuvantTherapy < 6 months Ind. Therapy Surgery 1° Therapy 1° Therapy 1° Therapy Maintenance QOL PFS, OS OR 1° Therapy

  38. Bennouna J et al., ESMO 2017 Madrid

  39. Bennouna J et al., ESMO 2017 Madrid

  40. ESMO guidelines for third-line therapy in mCRC BRAF, B-Rapidly Accelerated Fibrosarcoma; EGFR, epidermal growth factor receptor; ESMO, European Society for Medical Oncology; mCRC, metastatic colorectal cancer; OS, overall survival; QoL, quality of life; RAS, rat sarcoma; wt, wild type. 1. Van Cutsem E et al. Ann Oncol 2016;27:1386–422.

  41. Later line treatment in mCRC – focus on Trifluridine/Tipiracil Mayer RJ et al. N Engl J Med. 2015;372:1909-1919

  42. Later line treatment in mCRC– focus on Regorafenib, efficacy ECOG PS 0 or 1 and ≥2 Prior lines of therapy

  43. Later line treatment in mCRC– focus on Regorafenib, dosing

  44. Later line treatment in mCRC– anti-EGFR therapy Price T, Peeters M et al. Lancet Oncol. 2014;15:569-579

  45. mCRCancer – rechallenge in full wt Courtesyto F. Loupakis

  46. mCRCancer – rechallenge in full wt Courtesyto F. Loupakis

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