Progress and challenges in colorectal treatment: towards...

Progress and challenges in colorectal treatment:

towards personalized treatment

Prof Eric Van Cutsem, MD, PhDGastroenterology / Digestive Oncology

Leuven, [email protected]

mailto:[email protected]

Agenda:

Cancer (focus on colon cancer) A. General aspects B. Overview of therapeutic modalities

and progress

Leuven city hall and University

Leuven: capital of beerAnheuserBusch-InBev

Some important AB-Inbev brands are Stella Artois, Beck’s, Jupiler, Budweiser, Leffe, Labatt, Hoegaerden, Bass and Corona.

Changing perspectives in Colon Cancer Care

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

2016 Screening is implemented Treatment for many cancer

patients All patients and cancers are

differentRight drug, dose, patient

Cancer as a chronic diseaseClear impact on survival

Major cost impact Starting to realize that expertise is

crucial Patient is central However, still many unmet needs

A. General aspectsWhat 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

CANCER is a disease of:

3 essential properties of the development and maintenance of multicellular organisms

• GROWTH

• DIFFERENTIATION

• TISSUE-INTEGRITY

A. General aspectsWhat is cancer?

HYPERPLASIE

HEALTHY CELLS

DYSPLASIEINTERVASATIE

STROMA

BASAL LAYER

BLOODVESSEL

ORGAN 1

ORGAN 2

CAPILLARIES

TUMOR-CELLS

CARCINOMAIN SITU

TUMOR-CELLS

INVASIONTRANSPORTTRANSPORTTRANSPORTADHESION

EXTRAVASATIEEXTRAVASATIEMETASTASIZE

CANCER: a genetic disorder

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)

Benign tumors are frequent, but cause usually little risk

intact basal membrane

• Non-invasive• No metastases• Frequently encapsulated• Slow growth• Expansive

Malignant tumors invade often surrounding tissues and spread through the body

metastases

• Invasive• Metastases• No capsule• Fast growing• Infiltrative

Pathology and molecular analysis!

Tissue is the issue…. Biopsy/ histology Fine needle aspiration/ cytologyResection specimen… Liquid biopsies

Histology, genetic and molecular analysis (NGS, proteomics….)

What will inform future clinical practice in colon cancer?

Circulating cell-free DNA

Source circulating cell-free DNA

Bone Marrow GI Tract Skin

Pool of Cell-free DNA

Tumor DNA

Liquid Biopsy: circulating tumour DNA (ctDNA)


ctDNA in the metastatic setting: PROSPECT-C Study


How does cancer develop

Tumor incidence and growth increases with time

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

Cancer: changes in the cell and metastases

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

Carcinogens

• Chemical carcinogens

– Asbest, nicotine…• Physical causes

– UV light,…• Biological causes

– Hepatitis-B & C-virus, EBV, HPV, …

Multiple hit theory

Genes and growth factors who stimulate the progression till cancer

Adenoma – Carcinoma sequence

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)

illustration: HNPCC, mutation MLH1

Immune Mechanisms in Cancer

Adapted from Colombo MP, et al. Nat Rev Cancer. 2007.

Role of the Immune System:Limited to Immuno-Surveillance ?

TUMOR HOST

Cancer Cells

NKs

CD8+ T-cells

CD4+ T-cells

DCs

Paradigm Shift in Cancer Therapy

Tumor Cell

Historical Paradigm:Targeting Tumor Cells

Lymphocyte

New Paradigm:Targeting Immune Cells

The Future of Oncology?

Tumor

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

2 4 8 16 32 64

0 1 0 2 0 3 0 4 0 5 0

Number of doublings

0

1

2

3

4

5

(Bil

lion

s)

Ce

ll n

um

be

r

0

2

4

6

8

1 0

Tu

mo

r v

olu

me

(c

m3 )

"s ilent" pe riod

Tumor growth: constant rate = “explosion” on linear scale

Intervals of 100 days

Tum

or v

olum

e (c

m3 )

0.1

1

10

100

1000

10000

Growth rates of human tumors

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

Hanahan and Weinberg Cell 100:57

Signaling Networks in Cancer

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

Therapeutic possibilities

Cancer treatment

RadiotherapySurgery Chemotherapy

Hormonal

Immunotherapy

Targeted therapy

Local ablative therapy Radioembolisation

PRRT

Importance/Sequence is determined by tumor type and tumor stage

Bowel Cancer Incidence

Global trends in colon cancer survival

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

Colon cancer staging

I II III IV

Limited to the wallT1 & T2

Through the wall

T3 & T4

Node involvementN0, N1 & N2

MetastasesM0 & M1

STAGE

TNM

Endoscopic or intraluminal rectal ultrasonography

MRI – NMR of the pelvis

MRI : major impact on decision making

Diffusion-weighted MRI

Facilitated diffusion Restricted diffusion

Microstructural biomarker (ADC) for tumour viability (predictive technique)

Allows direct tissue characterization

**viable tumour versus necrosis

Post-processing and quantification straightforward

DWI helps detect nodes

Lambregts et al. Eur Rad 2010

Up to 26% more nodes found with DWI

Right hemicolectomy Sigmoid resection

Low rectal cancer through the wall

Preoperative chemoradiotherapy for rectal cancer

Goal:

• shrinking of the tumor

• increase the chance to preserve the sphincter

• decrease the chance ofrelapse

• improve the survival

tumorLymphenode

Total mesorectal excision (TME)

TME : complete resection of the rectum

Positive marginsHas the tumor been removed completely?

Radiotherapy for rectal cancer

Adequate planning of radiotherapyFDG-PET

CTMRI

FUSION-images

EBRT boost Contact RT HDR brachy

RT dose escalation: how?

Jaffray et al., Nat Rev Clin Oncol 2012

MRI-guided radiotherapy

Tools to reduce toxicity

Proton therapy

Wolff et al, Radiother Oncol 2012

Tools to reduce toxicity

• Preop CRT + TME is the standard treatment for LARC• But sometimes complete respons

– In the past: Accidental– Now: Wanted

• Still to operate?

Organ preservation

Colo-anal Anastomosis

Surgery for rectal cancerdifficult and requires expertise

Pouch construction Anterior resection

Colon cancer: EU: 57.0% Belgium: 61.7% (3rd )

Rectal cancer: EU: 55.8% Belgium: 62.9% (2nd)

Procare project in rectal cancer (BE): adjusted 5y survival for

pts with radical resection

Procare: 69.46%; 78.33 %

De Angelis R et al, Eurocare 5; Lancet Oncology 2014

5 years survival of colorectal cancer

Colonic reservoir : Colon – J pouch

Damaged innervation after radical rectumresection

Risk mainly with

• large T • small pelvis• ventral and lower 1/3

TEMStransanal endoscopic

microsurgery

LOCAL EXCISION

SURGERY FOR RECTAL CANCER

Transanal Endoscopic Microsurgery(TEMS)

Nascimbeni R et al. Dis Colon Rectum 2002, 45, 200-206

depth n n (%)N+

Sm1 70 2 (3%)

Sm2 120 9 (8%)

Sm3 154 35 (23%)

TEMS: Only for very early superficial cancers

SM = submucosa

Ultralow (Intersphincteric) Anastomosis

Intersphincteric Mucosal sleeve

Colo-anal manual anastomosis

abdominoperineal rectum amputation APRA

APRA

Significant decrease in APRA rate in Belgium

1995 – 1997

50 %

2006 – 2009

22 %

Canard Enchainé 4.2014

R-TME medico-economic study (S Colasse – H Mathieu Daude)

The way for improved profitability!– Today: Extra cost of 2000 €

• 6H30 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 patientsBut with stable means (depreciation/consumables) +++

Radical Surgery(TME/APRA)

Treatment of rectal cancer

Early rectal cancer(T1,T2,N0)

Advanced rectal cancer≥ T3, TxN1

NeoadjuvantCRT or RT

TEM/TAE

T1sm1 < 3 cmgood-moderate differentiationabsence LV-invasionnon-ulcerated

Adjuvant CT (or CRT)

Potential future personalized treatment strategy of rectal cancer: evolving concepts

Proximal tumorsVery Low risk

Surgery

T1, T2, N0

Proximal tumorsModerate risk

CT +Surgery

RT only if high risk of local

failure

T3 or N+

Distal tumors Low to moderate risk High-risk tumors

CT

CRT

Observation

Surgery if no CR

CRT

Surg

CT

CT

CRT (or RT)

Surg

CT

CT

Surg

CT

CT: molecular driven combinations

RT

CT

Surg

CT

Easily resectable

Marginally resectable/unresectable

Number

Size

Definitelyunresectable

Surgery± FOLFOX

Optimal therapy + surgery Palliative therapy…

Downstaging after Chemotherapy: A role for Surgery ?

Increasing resectability with Chemotherapy

Before chemotherapy After chemotherapy

CRC liver metastases

Surgery to be planned

Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016Online Ann Oncol, July 2016

Figure 1: toolbox of ablative treatments

88

Morgan, Kennedy, Lewington et al. Nature Reviews in Clinical Oncology October 2010

300 – 800 micron

100 – 300micron

20 - 40 micron

90Y

TACE

Radioembolisation

Radioembolization/SIRTYttrium 90 resin SIR-Spheres

Yttrium 90 layer

Y90 resin SIR-Spheres®

Beta radiationmedian 2.5 mm

max. 11 mm

Tumour cells

Normal hepatocytes

Intravenous Administration Intraperitoneal Administration

HIPEC Hyperthermic Intra Peritoneal Chemotherapy

Pestieau SR, J Surg Oncol 2001

Temperature: 42.5 °Mean flow: 700ml/min; Duration : 60-90 min

Patients with unresectable liver metastases: OS is the primary treatment goal

Resection

Overall survival / long-term disease control

Treatment strategy

Requiredoutcome Curative surgery

10% 20% 70%

Classification Upfront resectable Borderline resectable Unresectable

CT ±biologic

CT ±biologic

≈12%1≈8%1

Relapse14%2

4% 96%1. Wong, et al. Ann Oncol 2011; 2. Zakaria, et al. Ann Surg 2007

3. Van Cutsem E et al. Ann Oncol 2014; 4. Adam R … Van Cutsem E et al. Cancer Treat Rev 2015

The continuum of care of mCRC

1st line cytotoxic 3rd line cytotoxic2nd line cytotoxic

1st line biologic 2nd line biologic

Maintenance strategy

At progressionchange chemo,biologic or both?

Independentsequences?

Fluoropyrimidines: 5FU, capecitabine, TAS102OxaliplatinIrinotecan

BevacizumabCetuximab/panitumumabAfliberceptRamucirumabRegorafenib

How to start?What is best strategy?What to do for liver metastases?

Locoregional therapy: SIRSSurgery (RFA)

3nd line biologic

OS30 months

A classical case of mCRC in 2016CONTINUUM OF CARE

5 monthsfirst-line induction

3 monthsreintroduction (or treatment beyond

progression)

3 months“rechallenge”

3 monthsbreak

6 monthsmaintenance

4 monthssecond line

3 monthsthird line

3 monthspreterminal phase

1991: OS 6 months

Metastatic colorectal cancer

CHEMOTHERAPY: combinaton of cytotoxic and biological targeted drugs

Cytotoxic agents Biological agents

5-FU/capecitabine (S1) irinotecan oxaliplatin raltitrexed (mitomycine) TAS-102

bevacizumab cetuximab panitumumab aflibercept regorafenib ramucirumab early: Sym004, dabrafenib,

trametenib,nintedanib, nivolumumab, pembrozulimab, atezolizumab, cobimetinib, MABp1 , BBI …..

Other contributing factors to improved outcome: surgery,….

*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 2011. Abstract 3510; 10. Heinemann. ASCO 2013. Abstract LBA3506; 11. Stintzing and

Heinemann. ESMO 2013. Abstract LBA17; 12. Falcone. ASCO 2013. Abstract 3505; 13. Douillard JY, et al. New Engl J Med. 2013;369(11):1023-1034;14. Van Cutsem et al. Ann Oncology ESMO GI 2014 A. 15. Venook P, et al. ASCO 2014. Abstract LBA3; Plenary presentation.

Overall Survival (months)

5-FU/LV bolus

5-FU/LV infusion

IFL

LVFU2/irinotecan

FOLFOX

IFL + bevacizumab

FOLFOX/FOLFIRI

XELOX/FOLFOX + bevacizumab

FOLFOX + cetuximab

FOLFIRI + cetuximab

FOLFOX + panitumumab

Treatment Approaches to First-Line mCRC

FOLFIRI + bevacizumab

2013

2000

2012

2011

2011

2008

2007

2004

2004

2000

2000

2000

2011

2013

2014FOLFOX/FOLFIRI + cetuximab or bevacizumab

2013

22.8*

FOLFOXIRI + bevacizumab

FOLFIRI + cetuximab

FOLFOX + panitumumab

FOLFIRI + cetuximab

2014

Treatment of metastatic disease

Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016; Online Ann Oncol, July 2016

Progress and personalized health care in colorectal cancer

Changing perspectives in colorectal cancer care

Integration of clinical algorithms and molecularknowledge Adjuvant treatment of colon cancer Rectal cancer Metastatic colorectal cancer Future: Models of new trials

The dream of every physician may become true…

Towards individualized and personalized therapy

Outcome of colon cancer: based on TNM classification: pathology

O’Connell JB et al. J Natl Cancer Inst. 2004

8372

p < .001

8593

64

44

8

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)

Years

No benefit of chemotherapy

Cured bychemotherapy: fluoropyrimidine + oxaliplatin

Cured by surgery already

Adjuvant therapy for stage III colon cancer:Which benefit ?

0

20

40

60

80

100

0 1 2 3 4 5

exposed to toxicity

Surgery alone

Surgery plus Chemotherapy

15-20%

%

Dis

ease

Fre

e Su

rviv

al

60%

15-20%

20%

Years

Chemotherapy without benefit

Cured bychemotherapy

allready cured by surgery

Adjuvant therapy for Stage II colon cancer:Which benefit ?

0

20

40

60

80

100

0 1 2 3 4 5

T O X IC

I T Y

Surgery alone

Surgery plus chemotherapy

~5 %

80%

~5%

15%

Ove

rall

Surv

ival

Factors influencing prognosis in stage IIConcept of high risk stage II

LymphaticVenous

Perineuralinvasion

Poor Differentiation

Tumor invasion (T4)

No. of nodes examined

Less to 8-12

PerforationOcclusionMSS-MSI

T3N0 without favorable prognostic factors and or MSI : prognosis close to Stage I

T 3-4 N0 with unfavorable prognositic factors : prognosis close to Stage IIIAge

CEA increase

Molecular markers:To be validated

PETACC-3 in stage II patientsoverall survival

Roth A, ….. Van Cutsem E. Journal National Cancer Institute 2012

Multigene platforms in Colon Cancer

Genomic Health Agendia Almac Veridex

Are prognostic, but are not proven to bepredictive (info on benefit of treatment)

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

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

1Ltreatment

• Expectations • Patient preference• Toxicity profile• Flexibility• Socio-economic factors• Quality of life

• Age• Performance status• Prior adjuvant treatment• Comorbidities

Tumourcharacteristics

Patientpreference

Patientcharacteristics

• Clinical presentation• Tumour biology• RAS mutation status• BRAF mutation status

Treatment choice: more than efficacy

Hanahan D & Weinberg B. Cell 2011

The hallmarks of cancer

Cellular targets for antitumoral agents

Targeting multiple signaling pathways

involved in tumorigenesis

Induction of immune responses to target

tumor cells

Further molecular definition of individual

patient subgroups

RAS pathwayAnti-EGFR antibodies

BRAF pathwaycombination therapy e.g.: anti-EGFR, BRAF and MEK inhibitors or

PI3K inhibitors or chemotherapy

HER2Trastuzumab + lapatinib

MSI tumors:Anti-PD(L) antibodies

* Pembrolizumab, Nivolumab

Ongoing advances in personalized treatment of mCRC

MSS tumors:Innovative combination

treatment

CMS 1-4 tumors

Overall patient population

CRYSTAL

Time (months)5442 48

Cetuximab + CT (FOLFIRI) (n=599)CT (FOLFIRI) (n=599)

0.0

0.2

0.4

0.6

0.8

1.0

180 6 12 24 30 36

OS

estim

ate

HR=0.878p=0.0419

19.9 months

18.6months

Crystal study in mCRCno biomarker

Van Cutsem E et al, New England Journal Medicine 2009; Van Cutsem E et al. J Clin Oncol 2011

Oncogenic activation of the EGFR signaling pathway in mCRC

Ciardiello F, Tortora G. N Engl J Med 2008;358:1160–1174.

Antibodies (cetuximab, panitumumab)

Initially: KRAS testing identifies mutations in codons 12 and 13 of exon 2

KRAS EXON 2

12 13

KRAS

KRAS/NRAS mutations outside KRAS exon 2 are now tested before using cetuximab and panitumumab

EXON 3 EXON 4

61 117 146

4% 6–7%

EXON 3 EXON 4NRAS EXON 2

12 13 61 117 146

4–6% 0-1%3–5%

Hotspots of Mutations in KRAS and NRAS

RAS~8%30-35%

CRYSTALKRAS wt (exon 2)population

OS

estim

ate

Crystal study in mCRC:KRAS (exon 2) status as a biomarker

Time (months)5442 48

23.5 months

20.0months

0.0

0.2

0.4

0.6

0.8

1.0

180 6 12 24 30 36

HR=0.796p=0.0093

Cetuximab + CT (FOLFIRI) (n=316)CT (FOLFIRI) (n=350)

60% of overall population

Van Cutsem E et al, New England Journal Medicine 2009; Van Cutsem E et al. J Clin Oncol 2011

KRAS wt or mt status: validated predictive biomarker for anti-EGFR antibodies in mCRC

KRAS wtResponders

KRAS mt

KRAS wtNon-responders

Most KRAS mutant tumors are resistant

to EGFR mAbs

Many KRAS wt tumors are responsive to

EGFR mAbs

Some KRAS wt tumors are resistant to EGFR mAbs

CRYSTAL: RAS wt selection extended the benefit with cetuximab + FOLFIRI

KRAS exon 2 wt population1

RAS wt population (85%) 2

367/430 patients with KRAS exon 2 wt tumors evaluated for RAS status were RAS wt

1. Van Cutsem E, et al. J Clin Oncol 20112. Van Cutsem E, et al. J Clin Oncol 2015

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Prob

abili

ty o

f OS

Months

HR (95% CI) 0.80 (0.67–0.95)

No. of eventsMedian, months95% CI

24223.521.2–26.3

28820.017.4–21.7

0 6 12 18 24 30 36 42 48 54

FOLFIRI + cetuximabFOLFIRI

Prob

abili

ty o

f OS

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 570.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months

FOLFIRI + cetuximabFOLFIRI

HR (95% CI) 0.69 (0.54–0.88)

No. of eventsMedian, months95% CI

13028.424.7–31.6

15420.217.0–24.5

Excluding additional mutant tumors increases the relative proportion of responsive wt tumors

Responsive wt

KRAS 12/13 mt

Resistant wt

Detection of additional mutant tumors that are

resistant to EGFR mAbs

Increasing relative proportion of wt

population responsive to EGFR mAbs

Othermts

Enhanced benefit profile for EGFR inhibitors in the more selected population

Responder (15%)

PIK3CA and/or PTEN (15%)

BRAF (5-10%)

KRAS/PIK3CA/PTEN

BRAF/PIK3CA/PTENKRAS-NRAS (35-45%)

Non responder (16%)

Primary resistance to anti-EGFR therapy in colorectal cancer

HER2 amplification (3%)

MET amplification (2%)

KRAS amplification (1%)

Modified from Bardelli, J Clin Oncol 2010




tumor cells


patient subgroups









treatment

CMS 1-4 tumors

Signaling in BRAF mt CRCReactivation of EGFR signaling

upon BRAF inhibition

Bendell JC, et al. ASCO 2014 (Abstract No. 3515)

Targeting the RAF pathway in mCRC

BRAF inhibitors for BRAF mt mCRC: Triple combinations

BRAF inhibitor-containingcombination (n) ORR, % SD, % Median PFS,

months

Cetuximab + vemurafenib + irinotecan (n=17)1 35 59 7.7

Cetuximab + encorafenib + alpelisib (n=28)2 32 61 4.3

Panitumumab + dabrafenib+ trametinib (n=35)3 26 57 4.1

BRAF inhibitor

EGFR inhibitor+ MEK

inhibitorPI3K/AKT inhibitor

Chemo-therapy+ or or

1. 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)




tumor cells


patient subgroups









treatment

CMS 1-4 tumors

Immune checkpoint mechanisms assisting in immune evasion of tumor cells

Schultheis AM, et al. ASCO 2013 (Abstract no. 3567)

Mismatch-repair status predicted clinical benefit of immune checkpoint blockade in CRC

Le DT, et al. N Engl J Med 2015.

Radiographic responses*

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)

OS in CRC

Adjusted OS HR for mismatch-repair deficient vs proficient CRC: 0.18,p=0.05

Immune-related ORR in mismatch-repair deficient vs proficient CRC: 40% vs 0%




tumor cells


patient subgroups









treatment

CMS 1-4 tumors

The Colorectal Cancer Subtyping Consortium (CRCSC) identifies a network of molecular subtypes

Guinney J et al, Nature Medicine 2015CMS, CRC molecular subtypes

Clinical and molecular correlates

Dienstmann R. J Clin Oncol 2014

MSI - Immune

Canonical Metabolic

Mesenchymal

WNT and MYC inhibitors? Metabolic inhibitors?

TGFb inhibitorsNew antiangiogenicsMatrix inhibitors

Immune checkpoint inhibitorsImmune regulatorsBRAF strategies

Molecular subtyping has the potential to drive treatment decisions in mCRC

Adapted from Mallmann MR, et al. EPMA J 2010;1:421–437

Molecular subtypes

Subtype A Therapy A

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

Biomarkerprofiling

Maintaining a balance of costs and benefits for patients with mCRC

Costs Benefits/savings

Frank M, Mittendorf T. Pharmacoeconomics 2013;31:215–228

Clinical cancer trials of the future

Basic Research Scientists

Bioinformatics

Clinical Scientists

Pharma Industry

Governments Regulatory Agencies

Transforming the dream of tailored cancer therapy into reality

Are we making progress in personalized health care in oncology? Yes

The dream….

The reality ...

Median survivalMonths

1980s 1990s 2000s 2016

Cetuximab5,6

BSC

Irinotecan1

capecitabine2

Oxaliplatin3

Bevacizumab4

5-FU

Panitumumab7

15

10

5

0

20

25

30

1. Cunningham, et al. Lancet 1998; 2. Van Cutsem, et al. BJC 2004 3. 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

Aflibercept8

Regorafenib9

Prognosis of metastatic colon cancer

TAS10210

Still unmet needs

Towards prevention and cure of cancerwith the help of personalized health care

sagalassos

Xian @ Leuven

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