12th ESO Colorectal Cancer Observatory:Innovation and care in the next 12 months

Wednesday 1st July 2015, 18:45 – 20:15

Panellists:Nadir Arber, IL

Roberto Labianca, ITEric Van Cutsem, BEJosep Tabernero, ES

Bernard Nordlinger, FRNeil Howie, UK/RS

Chair: Mario Dicato, LUCo-Chair: Jola Gore-Booth, UK

12th ESO Colorectal Cancer Observatory:Innovation and care in the next 12 months

Nadir Arber

The Tel-Aviv Sourasky Medical Center

Tel Aviv, Israel

View of a Gastroenterologist

ESO Observatory:Screening of CRC

Retired American Major League Baseball

catcher, manager, and coach and

Integrated Cancer Prevention Center, Tel Aviv

It's tough to make predictions, especially about the future."

"Yogi" Berra and Nadir Arber

My Financial Disclosures:Bayer

GI ViewTakeda

Bio ViewCheck-Cap

Bio-ExplorerNawe-Pharma

Ideal CRC Screening Test• Organized program

• High Uptake

• Test accuracy (NPV, PPV, Spec, Sens)

• Quality (FIT, colonoscopy, polypectomy)

• Costs

• Adherence to surveillance

• Reduced incidence of CR neoplasia

• Reduced specific morbidity

• Reduced specific mortality

• Reduced overall mortality

Blood tests (Septin9, Medial, CD24)

Stool Tests (FOBT, FIT, Cologuard, M2-PK)

Sigmoidoscopy

Colonoscopy

CT-colonography

Capsule endoscopy (Covidian, Check-Cap)

Different ScreeningModalities

Any Screening Modality is Better

than NothingBut colonoscopy is the

best option….in 2016…..as well

In 2015

• Before (referral practices, consent, anticoagulants,

bowel prep quality)

• During (sedation, technique, difficult polyps,

safety issues, documentation)

• After (recovery, post-procedure questionnaire,

surveillance recommendations)

European Guidelines for Quality Assurance in CRC Screening

Ed. J. Patnick, N Segnan, L. Von Karsa

NordICC trial – Polish arm

Kaminski MF, Regula J et al.N Engl J Med, 2010; 362: 1795-803

Colonoscopy Quality Parameters

• Mean withdrawal time (> 6

minutes)

• Adenoma detection rate

• Cecal intubation rate

• Number of adenomas/colonoscopy

• Bowel prep quality

• Photodocumentation of the cecum

• Adverse events (24 hours – 30 days)

Optimizing Colonoscopy Efficacy:

New/Current Technologies• Endocuff

• G-Eye

• Full Spectrum Endoscopy

• Extra Wide Angle View Endoscope

• Third Eye Retroscope

• Third Eye Panoramic

• Aer-O-scope

• Colon Capsule

• Prepless Colonic Capsule (Check-Cap)

Improving Polyps Detection

“Inspection Behind Folds”

Optical Approach

The third eye FUSE full spectrum

endoscopy

Omnivision

330°Field of View

Extra Wide Angle View Endoscope(EWAVE)

Improving Polyps Detection

“Inspection Behind Folds”

Mechanical Fold Flattening Approach

Cap assisted colonoscopy

Endocuff/Endoings

Endoscopic Over tube

G-EYETM

Colonoscope

Capsule Endoscopy

Prepless Colonoscopy: Ultra Low Dose X-ray-Based Imaging Technology (Check-Cap, Israel)

19

• Ultra-low dose (0.03 mSv)

• Low energy (56 – 70 Kev)

11.5mm

34mm

Moshkowitz, Gluk, Arber, Gut (submitted)

Single Use Colonoscope

20

Aeroscope (GI View, Israel):

Self Propelling Self Navigating

New Technologies – Improve Imaging

• Autofluorescence

• Chromoendoscopy

• HD

• NBI

HD Endoscopy & NBI

HD 1280×1024-pixel frame

NBI

Virtual Chromoendoscopy:i-Scan and FICE

23

Does it look like anattractive screening test?

Stool Testing

• Methylated Septin 9, Church et al. Gut 2014 ;63:317-25

• CD24, Kraus and Arber. Disease Markers, 2015

• Meidal

Highest Compliance with Blood Tests

• MedialICS (Israel)

Approach

• Looking into

standard CBC

• Identifying trends

and variations

within the normal

ranges in millions

of CBC26

MeScore: Computed Indicator for CRC Findings

MeScore

CD24 is Overexpressed in PBLs from CRC Patients

a-CD24

a-CD24

Kraus & Arber: Disease Markers, 2015

Conclusions

-Two stages approach

- Non invasive test as the initial step

Blood test

Stool test/capsule/virtual colonoscopy/prepless cap?

- Quality parameters for colonoscopy

ADR

Withdrawal time

“A test is better than none, and the best test is the one that is done”

Conclusions- Monitoring of quality (The big brother)

- Improvement in teaching methods

- Advanced technologies are available,

but are time and money consuming

- Public demands

- Legal issues

12th ESO Colorectal Cancer Observatory :Innovation and care in the next 12 months

Roberto Labianca

Hospital Giovanni XXIII

Bergamo, Italy

View of a Medical Oncologist

Adjuvant therapy of colorectal cancerColon Cancer

Colon cancer stage II patients will receive adjuvant CT only if“high-risk”, according to clinico-pathological criteria(biological criteria: still experimental)

Colon cancer stage III: FOLFOX or XELOX for 6 months willremain the standard treatment in patients up to 70 (75) years

In stage III elderly patient: fluoropyrimidine alone is still anacceptable choice

Duration could decrease to 3 months (Kumar, CCC 2015) ifthe ongoing IDEA collaboration will be positive (but dataexpected only in 2017-2018)

Avenues for progress

The interventions on lifestyle (diet, physical exercise,smoking habits…) will gain an increased roleNew independent studies will evaluate aspirin (or COX-2inhibitors) +/- chemotherapyAlso immunotherapy could be evaluated in this setting(e.g.: vaccine in Stage IV R0)Anti-PD1/PDL-1 in MSI patients???The opportunities for translational (BRAF, MSI…) orepidemiological (e.g.: BMI, metformin, L/N,thromboembolism…) research linked to adjuvant trialswill increase

Colon Cancer

Rectal Cancer

In preoperative setting: fluoropyrimidine alone(capecitabine or 5FU) will remain the standard, without arole for oxaliplatinIn postoperative setting: adjuvant chemotherapy(fluoropyrimidine + oxaliplatin) will be more frequentlyused in clinical practice (see also: EXPERT DISCUSSIONHERE TODAY)Through better neoadjuvant treatment: more sphinctersaving surgeryBiological/genomic characterization: not ready for use

12th ESO Colorectal Cancer Observatory :Innovation and care in the next 12 months

Eric Van Cutsem

University Hospital Gasthuisberg

Leuven, Belgium

View of a Medical Oncologist

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 ramucirimab early: rilotumumab, Sym004,

dabrafenib, trametenib, nivolumumab, nintedanib, …

Median Survival; 5-Year Survival Rate for Stage IV CRC Remains Only 6%

*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.

29 – 29.9*

28.4**

31

28.1 – 33.1**

26**

25.0 – 25.8*

23.9*

23.5*

21.3

22.6

20.3

19.5

17.4

14.8

14.1

12.6

0 5 10 15 20 25 30 35

Venook

Van Cutsem

Falcone

Heinemann

Douillard

Falcone/Heinemann

Douillard

Van Cutsem

Bokemeyer

Saltz

Falcone

Hurwitz

Goldberg

Douillard

Saltz

Douillard

Saltz

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

OS30 months

2015: A classical case of mCRC

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

Metastatic colorectal cancer (mCRC) is not one disease

Patient and tumor characteristics vary widely

Tumor cell heterogeneity is what makes tumors challenging to treat:

– Multiple molecular alterations occur during tumor progression

– Various molecular signaling pathways are involved

Development of drugs which target and inhibit key molecular pathways is an essential step towards personalized cancer care

Colorectal cancer subtyping consortium : CRCSC –Results

Summary

CMS1 13%Females, older age, right colon, MSI, hypermutation, BRAF

mut, immune activationBetter RFS, intermediate OS, worse

SaR

CMS2 35% Left colon, epithelial, MSS, high CIN, TP53 mut,

WNT/MYC pathway activationIntermediate RFS, better OS, better

SaR

CMS3 11%Epithelial, CIN/MSI, KRAS mut, MYC ampl, IGFBP2

overexpressionIntermediate

RFS, OS and SaR

CMS4 20%Younger age, stage III/IV, mesenchymal, CIN/MSI, TGFβ/VEGF activation, NOTCH3 overexpression

Worse RFS, worse OS Intermediate SaR

Unclassified 21%Mixed subtype with variable epithelial-

mesenchymal activation?Intermediate

RFS, OS and SaR

CMS: Consensus Molecular Subtype

Presented by R Dienstmann, ASCO 2014: SAGE consortium

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

Treatment decisions should take into account patient preference

1L

treatment

• Expectations

• Toxicity profile

• Flexibility

• Socio-economic factors

• Quality of life• Age

• Performance status

• Prior adjuvant treatment

• Comorbidities

Tumour

characteristics

Patient

preference

Patient

characteristics

• Clinical presentation

• Tumour biology

• RAS mutation status

• BRAF mutation status

Treatment choice: more than efficacy

The continuum of care of mCRC

1st line cytotoxic 3rd line cytotoxic2nd line cytotoxic

1st line biologic 2nd line biologic

At progression

change chemo,

biologic or both?

Independent

sequences?

FluoropyrimidinesOxaliplatinIrinotecan

BevacizumabCetuximab/panitumumabAfliberceptRegorafenib

How to start?

What is best

strategy?

What to do for

liver metastases?

Locoregional therapy: SIRSSurgery

3nd line biologic

Schmoll H, Van Cutsem E et al, ESMO consensus guidelines ,Ann Onc 2012

Josep TaberneroVall d’Hebron University Hospital

Vall d’Hebron Institute of OncologyBarcelona

New Therapies

Advances in the treatment in mCRC

Acquired capacities of cancer: phenotype

Targeting the EGFR pathway in CRC

BRAF mutation 5-10%

KRAS mutation 45–50%NRAS mutation 5-8%

EGFR expression 27–95%

EGFR mutation 1-2%

MAPK

MEK

BRAF

KRAS

EGFTGF-α

AmphiregulinEpiregulin

Grb2

SosEGFR

Anti-EGFR MoAbs:CetuximabPanitumumab

(RAS inh.)

RAF inh.

MEK inh.

ERK inh.

Inhibitors

• More efficient anti-EGFR MoAbs:

– Sym004, MM-151

• MoAbs directed to other members of the EGFR/HER family:

– HER-2: trastuzumab, trastuzumab + pertuzumab, trastuzumab + lapatinib

– HER-3: Duligotuzumab (MEHD7945A)

• MoAbs directed to other receptors:

– cMET: rilotumab, ficlatuzumab, omartuzumab

• Combination with downstream effector inhibitors:

– BRAF mt: Anti-EGFR MoAb + BRAFi / MEKi

Beyond EGFR inhibition

HERACLES study: trastuzumab + lapatinib

Dienstmann R & Tabernero J. Ed Book ASCO 2015

EGFRi + BRAFi / MEKi in BRAF mt mCRC

Modified from Acevedo, et al. Cell Cycle 2009

Ang = angiopoietin; FGF = fibroblast growth factor MMPs = matrix metalloproteinasesTNF = tumour necrosis factor; VEGFR = VEGF receptorPlGF = placental growth factor

Tumourcell

FGF2

IL-8IL-8IL-8

IL-8IL-8

IL-8

ECM MMPs

VEGF release

Inflammatory cell

Cell adhesionproteins

VEGFsAng-2

TNFα

TNFαR

NF-kB

Ang-1

Stabilised mature

blood vessel

Tie-2

VEGFR

Endothelial cellproliferation

Blood vessel/endothelial cells

PlGFs

Integrins

Angiogenesis: a multiple signaling process

No established predictive biomarker so far

Tyrosine kinase inhibitors (TKIs)(Regorafenib, Nintedanib, Sunitinib, Vatalanib, Sorafenib, Cediranib)

Anti-VEGFR MAbs(IMC-1C11, Ramucirumab)

Signal Transduction

R R

K K

LigandsAnti-VEGF MAbs(Bevacizumab)

Soluble receptors(VEGF Trap, Aflibercept)

Ribozymes

Anti-PlGF Mabs(TB-403)

Anti-VEGF pathway therapies

Anti-VEGF-A/Ang2(Vanucizumab)

Opportunities for Immunotherapy

Segal N. Proc ASCO 2015

Pembrolizumab in MMRd/MSI mCRC

• Target discovery has resulted in numerous novel drugs in clinical development

• Median survival of patients with mCRC has reached a new benchmark of ≈30 months

• Different CRC subtypes: genomic signatures• Tumor heterogenity and clonal selection/evolution• Several examples of treatment benefit in small populations• Need for molecular profile and selection• Combinations: mechanistic interactions, rationale-based• Need to balance pricing/reimbursement for accesibility

Summary and challenges

12th ESO Colorectal Cancer Observatory:Innovation and care in the next 12 months

Bernard Nordlinger

Hôpital Amboise Paré

Boulogne-Billancourt, France

View of a Surgical Oncologist

Surgical progress in the treatment of rectal cancer

- Laparoscopic vs Open- One port: NOTES- Robot

COLOR II Study

• International trial in 30 hospitals,

• 1044 patients with adenocarcinoma of the rectum

• 15 cm of the anal verge, not invading adjacent tissues, no T4 and T3 with CRM less than 2mm and without distant metastases

• Non inferiority margin 5%

• laparoscopic n= 699

• open surgery n= 345, 2:1 ratio.

• End points: primary: 3y locoregional recurrence

secondary: DFS,OS.

COLOR II Study:Results

3 years:

- Locoregional recurrence: 5.0% in the 2 groups

- DFS :74.8% laparoscopic and 70.8% open.

- OS : 86.7% laparoscopic, 83.6% open.

COLOR II Study:Conclusions

• Laparoscopic surgery in patients with rectal cancer was associated with rates of

- locoregional recurrence

- disease-free

- overall survival

• Similar to those for open surgery

COREAN TRIAL• Open versus laparoscopic surgery for mid or low rectal

cancer cT3N0–2M0 after neoadjuvantchemoradiotherapy

• Randomised controlled trial; non inferiority, margin 15%

• From April 2006, to Aug 2009, 3 centers in Korea. 340 patients to receive either open surgery (n=170) or laparoscopic surgery (n=170).

• Stratification by sex and preoperative chemotherapy regimen.

• Primary endpoint: 3 y DFS, with a non-inferiority margin of 15%.

• 3 year disease-free survival was 72·5% (95% CI 65·0–78·6) for the open surgery group and 79·2% (72·3–84·6) for the laparoscopic surgery group

• Difference was lower than the prespecified non-inferiority margin (–6·7%,95% CI –15·8 to 2·4; p<0·0001).

• 25 (15%) patients died in the open group and 20 (12%) died in the laparoscopicgroup. No deaths were treatment related.

COREAN TRIAL: RESULTS

COREAN TRIAL: INTERPRETATION

• Laparoscopic resection for locally advanced rectal cancer after preoperative chemoradiotherapy provides similar outcomes for disease-free survival as open resection.

ENDOSCOPIC TRANSANAL PROCTECTOMY

• NOTES: natural orifice transluminal endoscopic surgery

• The aim of this study was to evaluate the technical feasibility of ENDOSCOPIC TRANSANAL PROCTECTOMY, with a particular focus on postoperative and oncological results and on functional outcomes.

• Hybrid technique

ENDOSCOPIC TRANSANAL PROCTECTOMY

• 56 consecutive patients (41 M/ 15 F) Feb 2010 to Jun 2012. • Median age was 65 years (39–83), median BMI was 27 (20-42). • No intraoperative complications; no postoperative mortality,• Postoperative morbidity rate was 26%. • Pathologic examination:

- intact mesorectum( 84%) or almost intact(16%).- median number of lymph nodes retrieved was 12 - median margins: CRM 8 mm (0–20), distal 10 mm (3–40),- R0 resection was achieved in 94.6%).

• Function: (28%)patients reported stool fragmentation and difficult evacuation.

CONCLUSIONS

• ENDOSCOPIC TRANSANAL PROCTECTOMY is feasible for rectal resection and may represent a step toward rectal natural orifice transluminal endoscopic surgery (NOTES).

ROBOTIC RESECTION OF RECTAL CANCER

• 217 patients; April 2006 to August 2011

• Rectal cancer with stage I–III disease

• Prospectively assigned to surgery either with robot ( n = 133) or laparoscopy ( n = 84).

• Median follow-up 58 months ( 4–80 )

• Evaluated for early outcome, morbidity,

5-y survival, prognostic factors, cost

ROBOTIC RESECTION OF RECTAL CANCER Results:

• Early outcome: no significant differences except higher conversion rate and longer hospital stay for robot.

• 5-year OS: 92.8% (robot), and 93.5% (laparoscopic) (ns)• The 5-year DFS 81.9% (robot)and 78.7%, (laparoscopic).• Local recurrence rates: 2.3% and 1.2% • Surgical approach was not a prognostic factor for long-

term survival. • The patient’s• Mean cost for patient was more than double for robotic

surgery

ROBOTIC RESECTION OF RECTAL CANCERConclusions

Robotic surgery for rectal cancer failed to offer any oncologic or clinical benefits as compared with laparoscopy despite at higher cost

LAPAROSCOPIC, TRANSANAL,ROBOTIC… RESECTION OF RECTAL CANCER

DO NOT FORGET

• TOTAL MESORECTUM EXCISION IS THE STANDARD

• THIS IS DIFFICULT SURGERY

• THE AIM IS TO CURE CANCER WITH ACCEPTABLE FUNCTION

Neil HowiePatient Advocate

Charity Runner Neil

”The patient’s perspective”

View of an Advocate Representative

12th ESO Colorectal Cancer Observatory:Innovation and care in the next 12 months

April 2014

On FOLOFOX4 asDiagnosed with T3N2aM0 Stage 3 cancer

April 2015

London Marathon

September 2015

Motivation

• Cancer is not JUST about the ACTUAL treatment

• Life goes on after cancer

• Treatment MUST also focus on the motivation to get through it

• Positive reinforcement of a goal/challenge can help– Can come via family / friends / health professionals

Drug guidance - Future

• What are the drugs

– Clear guidance on the differences

– Simplify the options

• E.g. Europacolon new guide “Colorectal Cancer Prevention and Screening: What YOU Need to Know”

– Clear guide on what is being recommended

– And why

Testing - Future

• Testing kits available– Where are they, and do people know

– For all those Over 50

– Plus for those with family history (http://www.knowyourrisk.org.au/)

• More encouragement to Over 50s to use– Through clearer, simple posters

– But related to all cancers to reduce information overload

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