Kolorektalni karcinom- novosti u liječenju. PANEL: Maja Banjin, Janja Ocvirk, Borislav Belev, Ivan Nikolić, Anes Pašić

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1 Kolorektalni karcinom- novosti u liječenju PANEL: Maja Banjin, Janja Ocvirk, Borislav Belev, Ivan Nikolić, Anes Pašić

2 Kolorektalni karcinomnovosti u liječenju PANEL : Maja Banjin, Janja Ocvirk, Borislav Belev, Ivan Nikolić, Anes Pašić

3 Pozicija primarnog tumora, prognostička i prediktivna vrednost za KRAS wt ( sidedness )? Nove terapijske opcije sa dopunom smernica Imunoterapija Biomarkeri i terapija

4 Pozicija primarnog tumora, prognostička i prediktivna vrednost za KRAS wt ( sidedness ) Nove terapijske opcije i dopune smernice Imunoterapija Biomarkeri i terapija

5 Jahorina Olimpijski ski centar Vučko 1984 Jure Franko-srebro Source: education.lego.com

6 Personalising treatment: what is state of the art? How many ways can these six eight-stud building bricks be combined? 915,103,765

7 Personalising treatment: what is state of the art? Multiple factors influence treatment choice Patient characteristics Molecular characteristics Patient preference Choice of targeted therapy Tumour characteristics Choice of chemotherapy

8 Definition of heterogeneity: clinical relevance Molecular characteristics RAS Tumour characteristics Tumour location BRAF HER2 MSI status Gene expression

9 Definition of heterogeneity: clinical relevance Molecular characteristics RAS Tumour characteristics Tumour location BRAF HER2 MSI status Gene expression

10 Distal and proximal colon cancers differ in terms of molecular, pathological and clinical features Right Right Left Left BRAF MT MSI KRAS PIK3CA Mucinous differentiation EREG expression 18q loss 20q gain EGFR gain HER2 gain Missiaglia et al. Ann Oncol 2014

11 Enrichment of molecular characteristics by side Right-sided tumours Incidence: ~40% (increasing) Older patients Microsatellite instability BRAF mutations KRAS mutations Left-sided tumours Incidence: ~60% Younger patients Predominantly WT EGFR gain HER2 gain Better prognosis Bufill. Ann Intern Med 1990; Missiaglia et al. Ann Oncol 2014; Brule. ASCO 2013 Cancer Genome Atlas Network. Nature 2012; Bendardaf. Anticancer Res 2008

12 NCIC CO.17 trial: effect of tumour location on PFS in KRAS WT patients Phase III trial of cetuximab plus best supportive care (BSC) vs BSC alone in patients with EGFR+ refractory advanced CRC Proportion alive Right-sided tumour (n=56) Cetuximab + BSC BSC only Cetuximab + BSC: 1.9 months BSC only: 1.9 months HR=0.73 ( ) p=0.26 Proportion alive Left-sided tumour (n=105) Cetuximab + BSC BSC only Cetuximab + BSC: 5.4 months BSC only: 1.8 months HR: 0.28 ( ) p< Time (months) Time (months) Brulé et al. Eur J Cancer 2015

13 CALGB/SWOG Substudy: Tumor Location in KRAS wt mcrc CALGB/SWOG found no significant difference in OS or PFS between cetuximab and bevacizumab when added to first-line FOLFIRI or FOLFOX in pts with RAS wt mcrc [1] Primary tumor location may affect outcome in mcrc Study N Molecular Selection Treatment Outcome Mos Right Tumor Side O Dwyer 2001 [2] 1120 None 5-FU variations OS Brulé 2015 [3] 399 KRAS wt Loupakis 2015 [4] 2027 None BSC BSC + CET FOLFIRI/BEV FOLFOX4/XELOX/BEV IFL/BEV Retrospective analysis of data from CALGB/SWOG evaluated to determine effect of primary tumor location on outcomes in KRAS wt mcrc [5] PFS OS Left Clin Oncol. 2001;19: Brulé SY, et al. Eur J Cancer. 2015;51: Loupakis F, et al. J Natl Cancer Inst. 2015;107:dju Venook AP, et al. ASCO Abstract 3504.

14 CALGB/SWOG Substudy: Baseline Population Characteristic Overall* (N = 1137) Right (n = 293) Tumor Side Left (n = 732) P Value Mean age, yrs <.0001 Male, % Synchronous stage IV, % Previous adjuvant therapy, % FOLFOX/FOLFIRI, % 73.4/ / / Primary in place, % Metastases pattern, % Liver only Liver metastases Extrahepatic *Side totals excluding 66 pts with tumor in transverse colon and 46 pts with unknown location. Any liver metastases vs extrahepatic..02 Venook AP, et al. ASCO Abstract 3504.

15 CALGB/SWOG Substudy: Tumor Sidedness Prognostic for PFS Median PFS, Mos (n = 1025) Primary Tumor Side Right (n = 293) Left (n = 732) All pts Cetuximab Bevacizumab HR (95% CI) 1.03 ( ) 1.56 ( ) 1.06 ( ) P Value*.0006 < *Adjusted for biologic, protocol chemotherapy, previous adjuvant therapy, previous radiotherapy, age, sex, synchronous disease, in place primary, liver metastases. Venook AP, et al. ASCO Abstract 3504.

16 CALGB/SWOG Substudy: Tumor Sidedness Prognostic for overall survival OS prolonged for left-sided vs right-sided tumors OS (%) Right Side Left Right Left N (Events) 732 (550) 293 (242) Median (95% CI) 33.3 ( ) 19.4 ( ) HR (95% CI) P Value 1.55 ( ) < Mos Venook AP, et al. ASCO Abstract 3504.

17 CALGB 80405: effect of tumour location on OS in all RAS WT patients Bevacizumab Left: 32.7 months Right: 29.2 months Cetuximab Left: 39.3 months Right: 13.7 months Event free (%) HR=0.88 (95% CI: ) Adjusted p=0.50 Event free (%) HR=0.55 (95% CI: ) Adjusted p= Months from study entry Months from study entry Lenz et al. ESMO 2016

18 CALGB/SWOG Substudy: Conclusions Location of primary tumor prognostic in KRAS wt mcrc PFS, OS longer in pts with left- vs right-sided tumors Tumor sidedness predictive of response to biologics Markedly longer OS in pts with left-sided tumors treated with first-line chemotherapy + cetuximab vs bevacizumab Pts with right-sided tumors showed greater benefit with first-line chemotherapy + bevacizumab vs cetuximab Investigator conclusions: Sidedness is a surrogate marker for tumor biology Identification of other biomarkers may replace sidedness, help individualize care Pts should be stratified by sidedness in clinical trials Venook AP, et al. ASCO Abstract 3504.

19 PRIME/PEAK/181 Significant increase in OS only shown in PRIME! Different level of evidence to Erbitux: No Phase III data with pani versus bev No significant difference in OS Differences in CT backbone used: No Phase III trial with 1st line pani + FOLFIRI

20 FIRE-3 study Erbitux + FOLFIRI > 38 months mos in LS tumors 10 month benefit vs bev in LS tumors!

21 CRYSTAL-study Erbitux + FOLFIRI > 28 months OS in LS tumors 7 month benefit vs CT alone in LS tumors!

22 Current insight from meta-analysis: overall survival Clear OS benefit of anti- EGFR + CT therapy over bev + CT or CT alone in LS tumors

23 Summary: implementing biomarker knowledge into clinical decisions Primary tumour location is a surrogate marker of molecular alterations; it has prognostic and possibly predictive implications 1 BRAF mutations are more frequent in right-sided tumours, 2 as is MSI-high status 3 HER2: new emerging target in mcrc, predominantly in leftsided tumours 3 Compelling evidence for pertuzumab + trastuzumab; 4 other HER2-targeted combinations are being explored 5,6 1. Loupakis et al. J Natl Cancer Inst Barras. Biomark Cancer Missiaglia et al. Ann Oncol Hainsworth et al. ASCO Sartore-Bianchi et al. Lancet Oncol Siena. ESMO 2016

24 Pozicija primarnog tumora, prognostička i prediktivna vrijednost za KRAS wt ( sidedness ) Nove terapijske opcije i dopune smjernice Imunoterapija Biomarkeri i terapija

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