Progress and challenges in colorectal treatment: towards personalized treatment

Transcription

1 Progress and challenges in colorectal treatment: towards personalized treatment Prof Eric Van Cutsem, MD, PhD Gastroenterology / Digestive Oncology Leuven, Belgium Eric.VanCutsem@uzleuven.be

2 Agenda: Cancer (focus on colon cancer) A. General aspects B. Overview of therapeutic modalities and progress

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4 Leuven city hall and University

5 Leuven: capital of beer AnheuserBusch-InBev Some important AB-Inbev brands are Stella Artois, Beck s, Jupiler, Budweiser, Leffe, Labatt, Hoegaerden, Bass and Corona.

6 1994 Desperate for anything No/limited treatment options All cancers the same Dose intensity for all Some cancers cured by surgery Minor cost impact Everbody or nobody can treat patients Changing perspectives in Colon Cancer Care 2016 Screening is implemented Treatment for many cancer patients All patients and cancers are different Right drug, dose, patient Cancer as a chronic disease Clear impact on survival Major cost impact Starting to realize that expertise is crucial Patient is central However, still many unmet needs

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8 A. General aspects What is cancer? Genetic disorder in which cells are not controlled anymore by normal growth regulating mechanisms: with as a consequence abnormal cell growth causes a tumor

9 A. General aspects What is cancer? CANCER is a disease of: GROWTH DIFFERENTIATION TISSUE-INTEGRITY 3 essential properties of the development and maintenance of multicellular organisms

10 BASAL LAYER STROMA TUMOR- CELLS HEALTHY CELLS TUMOR- CELLS DYSPLASIE INTERVASATIE METASTASIZE HYPERPLASIE CARCINOMA ADHESION TRANSPORT INVASION EXTRAVASATIE EXTRAVASATIE IN SITU TRANSPORT ORGAN 2 BLOODVESSEL ORGAN 1 CAPILLARIES

11 CANCER: a genetic disorder

12 CANCER: Complex genetic disorder Can be caused by environmental factors, named carcinogens Cancer occurs in tissue where oncogenes are activated and/or tumor suppressorgenes are inactivated Accumulation of mutations is multistep proces Cancer cells inside the blood vessels of a mouse s lung (Couzin, 2003 Science)

13 Benign tumors are frequent, but cause usually little risk intact basal membrane Non-invasive No metastases Frequently encapsulated Slow growth Expansive

14 Malignant tumors invade often surrounding tissues and spread through the body metastases Invasive Metastases No capsule Fast growing Infiltrative

15 Pathology and molecular analysis! Tissue is the issue. Biopsy/ histology Fine needle aspiration/ cytology Resection specimen Liquid biopsies Histology, genetic and molecular analysis (NGS, proteomics.)

16 What will inform future clinical practice in colon cancer? Circulating cell-free DNA

17 Source circulating cell-free DNA Bone Marrow GI Tract Skin Tumor DNA Pool of Cell-free DNA

18 Liquid Biopsy: circulating tumour DNA (ctdna) Circulating cell-free DNA

19 ctdna in the metastatic setting: PROSPECT-C Study Circulating cell-free DNA

20 How does cancer develop

21 Tumor incidence and growth increases with time

22 Epidemiology of human cancers suggests that the development of cancer requires many mutations

23 Cancer: changes in the cell and metastases

24 Cancer=genetic disorder: Abnormal genetic material in the cell Sometimes hereditary (e.g. breast cancer BRCA 1-2; colon cancer: MMR mutations or APC mutation in Lynch syndrome or in FAP) Often acquired

25 Carcinogens Chemical carcinogens Asbest, nicotine Physical causes UV light, Biological causes Hepatitis-B & C-virus, EBV, HPV,

26 Multiple hit theory

27 Genes and growth factors who stimulate the progression till cancer Adenoma Carcinoma sequence

28 example : breast cancer and BRCA Frequent BRCA 1 and 2 gene on chromosome 17 and 13 resp. Risk for breast cancer: 12% of all women, 70-90% of woman with mutation Also increased risk for ovarian cancer: BRCA 1 mutations increases risk to 40-60% - and also some other tumors (e.g. pancreatic cancer)

29 illustration: HNPCC, mutation MLH1

30 Immune Mechanisms in Cancer

31 Role of the Immune System: Limited to Immuno-Surveillance? TUMOR HOST NKs Cancer Cells DCs CD4+ T-cells CD8+ T-cells Adapted from Colombo MP, et al. Nat Rev Cancer

32 Paradigm Shift in Cancer Therapy Historical Paradigm: Targeting Tumor Cells New Paradigm: Targeting Immune Cells Lymphocyte Tumor Cell

33 The Future of Oncology? Tumor

34 Principles of tumor growth Abnormal tumor growth, independent of signals in environment Tumor cells also produce growth factors, that stimulate tumor growth If the time of doubling remains constant, the growth will be exponential

35 Tumor growth: constant rate = explosion on linear scale 5 10 Cell number (Bi l l i ons) "s ile nt" pe riod Tumor v olume (c m 3 ) Number of doublings

36 Growth rates of human tumors Tumor volume (cm 3 ) Intervals of 100 days

37 Signal transduction and cancer Extracellular signals regulate cel proliferation, migration, differentiation, survival, apoptosis E.g. wound: cell must receive a signal that she is present at the wound and she must devide to close the defect. If the defect is closed, the signal disappears and cellproliferation stops Cancer: cell does not recognize when she has to stop dividing and continues to divide An extracellular signal produces a change in the intracellular status

38 Signaling Networks in Cancer Hanahan and Weinberg Cell 100:57

39 Cel signalling and cancer Dysregulation of signal cascade with growth stimulating effect Overexpression of receptor PTK: constitutive activation of downstream pathways E.g. EGFr and c-erbb2: overexpression in 30% of breast and ovarian cancer Mutations in genes who code for intracellular signal molecules E.g. bcr-abl in CML and ALL E.g. ras oncoges

40 Therapeutic possibilities

41 Cancer treatment Surgery Chemotherapy Radiotherapy Hormonal Local ablative therapy Immunotherapy Radioembolisation PRRT Targeted therapy

42 Importance/Sequence is determined by tumor type and tumor stage

43 Bowel Cancer Incidence

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45 Global trends in colon cancer survival

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47 Diagnosis of colorectal cancer Clinical examination Bloodtests Tumor markers: CEA not always trustfull Endoscopy and imaging Endoscopy: colosconospy Biopsies for miscoscopic examination (Radiography of lungs) (Ultrasonography of the abdomen) CAT-scan of thorax and abdomen NMR = MRI (IRM, KST), certainly of the rectum PET/CT scan Others only on indication

48 Colon cancer staging STAGE I II III IV TNM Limited to the wall T1 & T2 Through the wall T3 & T4 Node involvement N0, N1 & N2 Metastases M0 & M1

49 Endoscopic or intraluminal rectal ultrasonography

50 MRI NMR of the pelvis

51 MRI : major impact on decision making

52 Diffusion-weighted MRI Microstructural biomarker (ADC) for tumour viability (predictive technique) Allows direct tissue characterization **viable tumour versus necrosis Post-processing and quantification straightforward Facilitated diffusion Restricted diffusion

53 DWI helps detect nodes Up to 26% more nodes found with DWI Lambregts et al. Eur Rad 2010

54 Right hemicolectomy Sigmoid resection

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56 Low rectal cancer through the wall

57 Preoperative chemoradiotherapy for rectal cancer Goal: shrinking of the tumor increase the chance to preserve the sphincter decrease the chance of relapse improve the survival

58 Total mesorectal excision (TME) Lymphenode tumor

59 TME : complete resection of the rectum

60 Positive margins Has the tumor been removed completely?

61 Radiotherapy for rectal cancer

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63 MRI Adequate planning of radiotherapy FDG-PET CT FUSION-images

64 RT dose escalation: how? EBRT boost Contact RT HDR brachy

65 Tools to reduce toxicity MRI-guided radiotherapy Jaffray et al., Nat Rev Clin Oncol 2012

66 Tools to reduce toxicity Proton therapy Wolff et al, Radiother Oncol 2012

67 Organ preservation Preop CRT + TME is the standard treatment for LARC But sometimes complete respons In the past: Accidental Now: Wanted Still to operate?

68 Colo-anal Anastomosis

69 Surgery for rectal cancer difficult and requires expertise Pouch construction Anterior resection

70 5 years survival of colorectal cancer Colon cancer: EU: 57.0% Belgium: 61.7% (3 rd ) Rectal cancer: EU: 55.8% Belgium: 62.9% (2 nd ) De Angelis R et al, Eurocare 5; Lancet Oncology 2014 Procare project in rectal cancer (BE): adjusted 5y survival for pts with radical resection Procare: 69.46%; %

71 Colonic reservoir : Colon J pouch

72 Damaged innervation after radical rectumresection Risk mainly with large T small pelvis ventral and lower 1/3

73 SURGERY FOR RECTAL CANCER LOCAL EXCISION TEMS transanal endoscopic microsurgery

74 Transanal Endoscopic Microsurgery (TEMS)

75 TEMS: Only for very early superficial cancers depth n n (%)N+ Sm (3%) Sm (8%) Sm (23%) SM = submucosa Nascimbeni R et al. Dis Colon Rectum 2002, 45,

76 Ultralow (Intersphincteric) Anastomosis

77 Intersphincteric Mucosal sleeve Colo-anal manual anastomosis

78 abdominoperineal rectum amputation APRA APRA

79 Significant decrease in APRA rate in Belgium % 22 %

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81 Canard Enchainé R-TME medico-economic study (S Colasse H Mathieu Daude) The way for improved profitability! Today: Extra cost of H30 for OR 13 d HL (daily charge 264 E) If we save 2 H for the OR (- 2H => saving 800 ) 5 D for HL ( 5d => saving 1790 ) We obtain a Return On Investissement if we increase the number of patients But with stable means (depreciation/consumables) +++

82 Treatment of rectal cancer Early rectal cancer (T1,T2,N0) Advanced rectal cancer T3, TxN1 T1sm1 < 3 cm good-moderate differentiation absence LV-invasion non-ulcerated Neoadjuvant CRT or RT TEM/TAE Radical Surgery (TME/APRA) Adjuvant CT (or CRT)

83 Potential future personalized treatment strategy of rectal cancer: evolving concepts Proximal tumors Very Low risk Proximal tumors Moderate risk Distal tumors Low to moderate risk High-risk tumors T1, T2, N0 T3 or N+ Surgery CT + Surgery CT CRT RT CT CT Surg CRT Surg CT CRT (or RT) RT only if high risk of local failure CT: molecular driven combinations Observation Surgery if no CR Surg CT CT CT Surg CT

84 Marginally resectable/ unresectable Definitely unresectable Easily resectable Number Surgery ± FOLFOX Size Optimal therapy + surgery Palliative therapy

85 Increasing resectability with Chemotherapy Downstaging after Chemotherapy: A role for Surgery?

86 CRC liver metastases Before chemotherapy After chemotherapy Surgery to be planned

87 Figure 1: toolbox of ablative treatments Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016 Online Ann Oncol, July 2016

88 Radioembolisation Morgan, Kennedy, Lewington et al. Nature Reviews in Clinical Oncology October micron 90 Y micron micron TACE 88

89 Radioembolization/SIRT Yttrium 90 resin SIR-Spheres

90 Y90 resin SIR-Spheres Yttrium 90 layer Tumour cells Beta radiation median 2.5 mm max. 11 mm Normal hepatocytes

91 HIPEC Hyperthermic Intra Peritoneal Chemotherapy Intravenous Administration Intraperitoneal Administration Pestieau SR, J Surg Oncol 2001 Temperature: 42.5 Mean flow: 700ml/min; Duration : min

92 Patients with unresectable liver metastases: OS is the primary treatment goal Classification Upfront resectable Borderline resectable Unresectable 10% 20% 70% Treatment strategy Resection 8% 1 CT ± biologic 12% 1 CT ± biologic 14% 2 Relapse Required outcome Curative surgery Overall survival / long-term disease control 4% 96% 1. Wong, et al. Ann Oncol 2011; 2. Zakaria, et al. Ann Surg Van Cutsem E et al. Ann Oncol 2014; 4. Adam R Van Cutsem E et al. Cancer Treat Rev 2015

93 The continuum of care of mcrc Fluoropyrimidines: 5FU, capecitabine, TAS102 Oxaliplatin Irinotecan Surgery (RFA) Locoregional therapy: SIRS 1st line cytotoxic 2nd line cytotoxic 3rd line cytotoxic How to start? What is best strategy? What to do for liver metastases? Maintenance strategy At progression change chemo, biologic or both? Independent sequences? 1st line biologic Bevacizumab Cetuximab/panitumumab Aflibercept Ramucirumab Regorafenib 2 nd line biologic 3 nd line biologic

94 A classical case of mcrc in 2016 CONTINUUM OF CARE 3 months preterminal phase 3 months rechallenge 5 months first-line induction 3 months third line 3 months break 4 months second line OS 30 months 6 months maintenance 3 months reintroduction (or treatment beyond progression) 1991: OS 6 months

95 Metastatic colorectal cancer CHEMOTHERAPY: combinaton of cytotoxic and biological targeted drugs Cytotoxic agents 5-FU/capecitabine (S1) irinotecan oxaliplatin raltitrexed (mitomycine) TAS-102 Biological agents bevacizumab cetuximab panitumumab aflibercept regorafenib ramucirumab early: Sym004, dabrafenib, trametenib,nintedanib, nivolumumab, pembrozulimab, atezolizumab, cobimetinib, MABp1, BBI.. Other contributing factors to improved outcome: surgery,.

96 Treatment Approaches to First-Line mcrc FU/LV bolus 5-FU/LV infusion IFL LVFU2/irinotecan FOLFOX IFL + bevacizumab FOLFOX/FOLFIRI XELOX/FOLFOX + bevacizumab FOLFOX + cetuximab FOLFIRI + cetuximab FOLFOX + panitumumab FOLFIRI + bevacizumab FOLFOX + panitumumab FOLFIRI + cetuximab FOLFOXIRI + bevacizumab FOLFIRI + cetuximab FOLFOX/FOLFIRI + cetuximab or bevacizumab 22.8* Overall Survival (months) *KRAS wild type tumors; **Extended RAS wild type population. Note: Informal comparison as these are not head-to-head clinical trials. 1. Saltz. N Engl J Med. 2000; 2. Douilliard. Lancet. 2000; 3. Goldberg. J Clin Oncol. 2004; 4. Hurwitz. N Engl J Med. 2004; 5. Saltz. J Clin Oncol. 2008; 6. Falcone. J Clin Oncol. 2007; 7. Bokemeyer. Ann Oncol. 2011; 8. Van Cutsem. J Clin Oncol. 2011; 9. Douilliard. ASCO Abstract 3510; 10. Heinemann. ASCO Abstract LBA3506; 11. Stintzing and Heinemann. ESMO Abstract LBA17; 12. Falcone. ASCO Abstract 3505; 13. Douillard JY, et al. New Engl J Med. 2013;369(11): ;14. Van Cutsem et al. Ann Oncology ESMO GI 2014 A. 15. Venook P, et al. ASCO Abstract LBA3; Plenary presentation.

97 Treatment of metastatic disease Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016; Online Ann Oncol, July 2016

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100 Progress and personalized health care in colorectal cancer Changing perspectives in colorectal cancer care Integration of clinical algorithms and molecular knowledge Adjuvant treatment of colon cancer Rectal cancer Metastatic colorectal cancer Future: Models of new trials

101 The dream of every physician may become true Towards individualized and personalized therapy

102 Progress and personalized health care in colorectal cancer Changing perspectives in colorectal cancer care Integration of clinical algorithms and molecular knowledge Adjuvant treatment of colon cancer Rectal cancer Metastatic colorectal cancer Future: Models of new trials

103 Outcome of colon cancer: based on TNM classification: pathology 93 p < Stage II colon cancer +/- adj 5FU : 5-yr risk of death = 17.5% overall 17% had T4 tumors (stage IIB) with 27.8% risk of death 83% had T3 tumors (stage IIA) with 15.3% risk of death (near average risk for all stage II) T4 = high risk; T3 = average risk (not necessarily low risk) O Connell JB et al. J Natl Cancer Inst. 2004

104 Adjuvant therapy for stage III colon cancer: Which benefit? % Disease Free Survival Surgery alone Surgery plus Chemotherapy 15-20% 20% 15-20% 60% No benefit of chemotherapy Cured by chemotherapy: fluoropyrimidine + oxaliplatin Cured by surgery already exposed to toxicity Years

105 Adjuvant therapy for Stage II colon cancer: Which benefit? 100 Surgery plus chemotherapy 15% Chemotherapy without benefit Overall Survival Surgery alone ~5 % ~5% 80% Cured by chemotherapy allready cured by surgery T O X I C I T Y Years

106 Factors influencing prognosis in stage II Concept of high risk stage II Molecular markers: To be validated MSS-MSI Tumor invasion (T4) T3N0 without favorable prognostic factors and or MSI : prognosis close to Stage I Perforation Occlusion Age T 3-4 N0 with unfavorable prognositic factors : prognosis close to Stage III No. of nodes examined Less to 8-12 Lymphatic Venous Perineural invasion CEA increase Poor Differentiation

107 PETACC-3 in stage II patients overall survival Roth A,.. Van Cutsem E. Journal National Cancer Institute 2012

108 Multigene platforms in Colon Cancer Genomic Health Agendia Almac Veridex Are prognostic, but are not proven to be predictive (info on benefit of treatment)

109 Colorectal Cancer adjuvant: ColoPrint ColoPrint : an independent prognostic factor RFS 5 y (all stages, n=206) : Low risk 87,6% High risk 67,2% (HR) 2,5 (95%CI : 1,33 4,73 ; p<0,005) RFS 5 y (stage II, n=114) : Low risk 90,9% High risk 73,9% (95%CI : 59,2% 88,6% ; p=0,017) RFS 5 y (stade III, n=62) : Low risk 78,2% high risk 47,2% Salazar R. et al. JCO 2011

110 Progress and personalized health care in colorectal cancer Changing perspectives in colorectal cancer care Integration of clinical algorithms and molecular knowledge Adjuvant treatment of colon cancer Rectal cancer Metastatic colorectal cancer Future: Models of new trials

111 Metastatic colorectal cancer (mcrc) not one disease: different biological behaviour various treatment options Tumor cell heterogeneity is one of important factors that makes tumors challenging to treat: Multiple molecular alterations occur during tumor progression Various molecular signaling pathways are involved

112 Treatment choice: more than efficacy Tumour characteristics Clinical presentation Tumour biology RAS mutation status BRAF mutation status Expectations Patient preference Toxicity profile 1L treatment Flexibility Socio-economic factors Quality of life Patient preference Patient characteristics Age Performance status Prior adjuvant treatment Comorbidities

113 The hallmarks of cancer Hanahan D & Weinberg B. Cell 2011

114 Cellular targets for antitumoral agents

115 Ongoing advances in personalized treatment of mcrc Targeting multiple signaling pathways involved in tumorigenesis RAS pathway Anti-EGFR antibodies BRAF pathway combination therapy e.g.: anti-egfr, BRAF and MEK inhibitors or PI3K inhibitors or chemotherapy HER2 Trastuzumab + lapatinib Induction of immune responses to target tumor cells MSI tumors: Anti-PD(L) antibodies * Pembrolizumab, Nivolumab MSS tumors: Innovative combination treatment Further molecular definition of individual patient subgroups CMS 1-4 tumors

116 Crystal study in mcrc no biomarker Overall patient population 1.0 CRYSTAL Cetuximab + CT (FOLFIRI) (n=599) CT (FOLFIRI) (n=599) 0.8 OS estimate months 19.9 months HR=0.878 p= Time (months) Van Cutsem E et al, New England Journal Medicine 2009; Van Cutsem E et al. J Clin Oncol 2011

117 Oncogenic activation of the EGFR signaling pathway in mcrc Antibodies (cetuximab, panitumumab) Ciardiello F, Tortora G. N Engl J Med 2008;358:

118 Hotspots of Mutations in KRAS and NRAS Initially: KRAS testing identifies mutations in codons 12 and 13 of exon 2 KRAS EXON 2 EXON 3 EXON % ~8% NRAS EXON % 6 7% EXON 3 EXON 4 RAS % 4 6% 0-1% KRAS/NRAS mutations outside KRAS exon 2 are now tested before using cetuximab and panitumumab

119 Crystal study in mcrc: KRAS (exon 2) status as a biomarker KRAS wt (exon 2) population 1.0 CRYSTAL Cetuximab + CT (FOLFIRI) (n=316) CT (FOLFIRI) (n=350) 0.8 OS estimate months 23.5 months 60% of overall population HR=0.796 p= Time (months) Van Cutsem E et al, New England Journal Medicine 2009; Van Cutsem E et al. J Clin Oncol 2011

120 KRAS wt or mt status: validated predictive biomarker for anti-egfr antibodies in mcrc Some KRAS wt tumors are resistant to EGFR mabs KRAS wt Non-responders KRAS mt Most KRAS mutant tumors are resistant to EGFR mabs Many KRAS wt tumors are responsive to EGFR mabs KRAS wt Responders

121 CRYSTAL: RAS wt selection extended the benefit with cetuximab + FOLFIRI KRAS exon 2 wt population 1 Probability of OS FOLFIRI + cetuximab FOLFIRI No. of events Median, months 95% CI HR (95% CI) 0.80 ( ) Months RAS wt population (85%) 2 367/430 patients with KRAS exon 2 wt tumors evaluated for RAS status were RAS wt Probability of OS FOLFIRI + cetuximab FOLFIRI Months No. of events Median, months 95% CI HR (95% CI) 0.69 ( ) Van Cutsem E, et al. J Clin Oncol Van Cutsem E, et al. J Clin Oncol 2015

122 Excluding additional mutant tumors increases the relative proportion of responsive wt tumors Increasing relative proportion of wt population responsive to EGFR mabs Resistant wt Other mts KRAS 12/13 mt Detection of additional mutant tumors that are resistant to EGFR mabs Enhanced benefit profile for EGFR inhibitors in the more selected population Responsive wt

123 Primary resistance to anti-egfr therapy in colorectal cancer Responder (15%) KRAS/PIK3CA/PTEN KRAS amplification (1%) KRAS-NRAS (35-45%) BRAF/PIK3CA/PTEN MET amplification (2%) BRAF (5-10%) PIK3CA and/or PTEN (15%) HER2 amplification (3%) Non responder (16%) Modified from Bardelli, J Clin Oncol 2010

124 Ongoing advances in personalized treatment of mcrc Targeting multiple signaling pathways involved in tumorigenesis RAS pathway Anti-EGFR antibodies BRAF pathway combination therapy e.g.: anti-egfr, BRAF and MEK inhibitors or PI3K inhibitors or chemotherapy HER2 Trastuzumab + lapatinib Induction of immune responses to target tumor cells MSI tumors: Anti-PD(L) antibodies * Pembrolizumab, Nivolumab MSS tumors: Innovative combination treatment Further molecular definition of individual patient subgroups CMS 1-4 tumors

125 Targeting the RAF pathway in mcrc Signaling in BRAF mt CRC Reactivation of EGFR signaling upon BRAF inhibition Bendell JC, et al. ASCO 2014 (Abstract No. 3515)

126 BRAF inhibitors for BRAF mt mcrc: Triple combinations BRAF inhibitor + EGFR inhibitor MEK inhibitor PI3K/AKT inhibitor + or or Chemotherapy BRAF inhibitor-containing combination (n) ORR, % SD, % Median PFS, months Cetuximab + vemurafenib + irinotecan (n=17) Cetuximab + encorafenib + alpelisib (n=28) Panitumumab + dabrafenib + trametinib (n=35) Hong DS, et al. ASCO 2015 (Abstract No. 3511); 2. Elez E, et al. WCGC 2015 (Abstract No. LBA08); 3. Van Cutsem E, et al. WCGC 2015 (Abstract No. LBA07)

127 Ongoing advances in personalized treatment of mcrc Targeting multiple signaling pathways involved in tumorigenesis RAS pathway Anti-EGFR antibodies BRAF pathway combination therapy e.g.: anti-egfr, BRAF and MEK inhibitors or PI3K inhibitors or chemotherapy HER2 Trastuzumab + lapatinib Induction of immune responses to target tumor cells MSI tumors: Anti-PD(L) antibodies * Pembrolizumab, Nivolumab MSS tumors: Innovative combination treatment Further molecular definition of individual patient subgroups CMS 1-4 tumors

128 Immune checkpoint mechanisms assisting in immune evasion of tumor cells Schultheis AM, et al. ASCO 2013 (Abstract no. 3567)

129 Le DT, et al. N Engl J Med Mismatch-repair status predicted clinical benefit of immune checkpoint blockade in CRC Treatment with pembrolizumab (anti-pd-1 antibody) (n=11 mismatch repair-deficient CRC, n=21 mismatch-repair proficient CRC, n=9 mismatch-repair deficient non-crc) Radiographic responses* OS in CRC Immune-related ORR in mismatchrepair deficient vs proficient CRC: 40% vs 0% Adjusted OS HR for mismatch-repair deficient vs proficient CRC: 0.18, p=0.05

130 Ongoing advances in personalized treatment of mcrc Targeting multiple signaling pathways involved in tumorigenesis RAS pathway Anti-EGFR antibodies BRAF pathway combination therapy e.g.: anti-egfr, BRAF and MEK inhibitors or PI3K inhibitors or chemotherapy HER2 Trastuzumab + lapatinib Induction of immune responses to target tumor cells MSI tumors: Anti-PD(L) antibodies * Pembrolizumab, Nivolumab MSS tumors: Innovative combination treatment Further molecular definition of individual patient subgroups CMS 1-4 tumors

131 The Colorectal Cancer Subtyping Consortium (CRCSC) identifies a network of molecular subtypes CMS, CRC molecular subtypes Guinney J et al, Nature Medicine 2015

132 Clinical and molecular correlates WNT and MYC inhibitors? Metabolic inhibitors? Canonical Metabolic MSI - Immune Mesenchymal Immune checkpoint inhibitors Immune regulators BRAF strategies TGFb inhibitors New antiangiogenics Matrix inhibitors Dienstmann R. J Clin Oncol 2014

133 Molecular subtyping has the potential to drive treatment decisions in mcrc Molecular subtypes Subtype A Therapy A Biomarker profiling Subtype B Therapy B Subtype C Therapy C In the future, molecular subtyping with validated biomarkers (gene signatures or individual biomarkers) may increase the likelihood that specific treatments will provide a direct benefit to individual patients Adapted from Mallmann MR, et al. EPMA J 2010;1:

134 Maintaining a balance of costs and benefits for patients with mcrc Costs Benefits/ savings Frank M, Mittendorf T. Pharmacoeconomics 2013;31:

135 Clinical cancer trials of the future Basic Research Scientists Clinical Scientists Governments Regulatory Agencies Bioinformatics Pharma Industry Transforming the dream of tailored cancer therapy into reality

136 Are we making progress in personalized health care in oncology? Yes The dream. The reality...

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138 Months Prognosis of metastatic colon cancer Median survival Still unmet needs 0 BSC 1980s 1990s 2000s FU 1. Cunningham, et al. Lancet 1998; 2. Van Cutsem, et al. BJC Rothenberg, et al. JCO 2003; 4. Hurwitz, et al. NEJM 2004; 5. Cunningham, et al. NEJM 2004; 6. Van Cutsem et al, NEJM 2009; 7. Van Cutsem, et al. JCO 2007 ; 8. Van Cutsem E et al, JCO 2012 ; 9 Grothey A, Van Cutsem E et al, Lancet 2012; 10. Mayer R, Van Cutsem E et al NEJM 2015 Irinotecan 1 capecitabine 2 Oxaliplatin 3 Bevacizumab 4 Cetuximab 5,6 Panitumumab 7 Aflibercept 8 Regorafenib 9 TAS102 10

139 Leuven Towards prevention and cure of cancer with the help of personalized health care sagalassos