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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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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
mColoRectal Cancer – continuum of care Malvezzi M et al. Ann Oncol 2018;29:1016–22
mColoRectal Cancer – continuum of care Malvezzi M et al. Ann Oncol 2018;29:1016–22
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
mColorectal Cancer (mCRC)– continuum of care, multi-optional
GERCOR study – chemotherapy sequence Tournigand C et al. J ClinOncol 2004;22:229–37
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
Efficacy Safety Histopathology Tumor characteristics Patient characteristics Previous treatment Patient preference Goals of therapy Biomarkers
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
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
mCRC – biomarkers & choice of treatment CT=chemotherapy; Beva=bevacizumab; Cetu=cetuximab; Pmab=panitumumab; Afli=aflibercept; Regoraf=regorafenib; Ram=Ramucirumab
Sinicrope FA et al. Clin Cancer Res2015;21:5294-304 Sinicrope FA et al. ClinGastroenterolHepatol 2016;14:651-658
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
…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
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).
Nivolumab+Ipilimumab Andre T et al, ASCO GI 2018; 553 Nivolumab Overman J et al, ASCO GI 2018; 554
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
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
Primrose JN et al. Lancet Oncol 2014;15:601-11 Ye L-Ch et al. J ClinOncol 2013:31;1931-38
F. Petrelli & S. Barni in Int J Colorectal Dis (2012) 27:997–1004
mCRC – treatment intensification Geissler M et al. ESMO2017; Madrid
AIO: Arnold, et al. ASCO 2014; Hegewisch-Becker et al., Lancet Oncol2015 DCCG: Koopman, et al., ASCO 2014; Simkens et al., Lancet 2015
AIO: Arnold, et al. ASCO 2014; Hegewisch-Becker et al., Lancet Oncol2015 DCCG: Koopman, et al., ASCO 2014; Simkens et al., Lancet 2015
First lineMetastaticTherapy AdjuvantTherapy < 6 months Ind. Therapy Surgery 1° Therapy 1° Therapy 1° Therapy Maintenance QOL PFS, OS OR 1° Therapy
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.
Later line treatment in mCRC – focus on Trifluridine/Tipiracil Mayer RJ et al. N Engl J Med. 2015;372:1909-1919
Later line treatment in mCRC– focus on Regorafenib, efficacy ECOG PS 0 or 1 and ≥2 Prior lines of therapy
Later line treatment in mCRC– anti-EGFR therapy Price T, Peeters M et al. Lancet Oncol. 2014;15:569-579
mCRCancer – rechallenge in full wt Courtesyto F. Loupakis
mCRCancer – rechallenge in full wt Courtesyto F. Loupakis