progress and challenges in colorectal treatment: towards...
TRANSCRIPT
Progress and challenges in colorectal treatment:
towards personalized treatment
Prof Eric Van Cutsem, MD, PhDGastroenterology / Digestive Oncology
Leuven, [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)
Circulating cell-free DNA
ctDNA in the metastatic setting: PROSPECT-C Study
Circulating cell-free DNA
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
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
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
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
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
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
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)
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
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%
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
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