11st ESO Colorectal Cancer Observatory:Innovation and care in the next 12 months

Wednesday 25th June 2014, 19:00 – 20:30

Panellists:Felix Leung, US

Josep Tabernero, ESRoberto Labianca, IT

Bernard Nordlinger, FRMario Dicato, LU

Jolien Pon, NL

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

11st ESO Colorectal Cancer Observatory:Innovation and care in the next 12 months

Felix W. Leung

David Geffen School of Medicine at UCLA

Chief of GI, Sepulveda Ambulatory Care Center

VAGLAHS

Los Angeles, USA

View of a Gastroenterologist

ADR and interval cancer• Colon ADR

– proportion with 1 adenoma– indicator of colonoscopy quality

• Interval cancer– after screening colonoscopy– challenge– high ADR - fewer interval cancer†

• 1% in ADR– 3.0%* in risk of interval cancer– 5%** in risk of fatal interval cancer††

†Kaminski NEJM 2010; ††Corley NEJM 2014.

*hazard ratio, 0.97; 95% CI, 0.96 to 0.98; **hazard ratio, 0.95; 95% CI, 0.94 to 0.97.

Interventions RS OS RCTs

Impact on ADR +ve -ve +ve -ve +ve -ve

Poor bowel preparation

Telephone re-education

Split dose preparation

Same day preparation

Sedated vs. unsedated

Deep vs. conscious sedation

Insertion polypectomy

Dynamic position change

Retroflex examination

Withdrawal time >6 min

Withdrawal technique vs. time

3rd eye retroscope

Cap assisted

Dye spray chromoendoscopy

Narrow band imaging

and indicates report exists for the reference category

QJM 2013; 106(2):117

White light NBI

Hyperplastic polyp

Adenoma

Other recent reports

• Confocal laser colonoscopy

– In vivo diagnosis of tissue type

– Impact on ADR – not described

• Full spectrum endoscope (FUSE)

– 330○ view

– significant miss rate (12%)

– no impact on ADR• standard (28%), FUSE (34%), p=0.3482

– incomplete insertion (2%)

– poor prep (1%)

http://www.brighamandwomens.org

DOI: 10.5772/55959

Normal Normal

Adenoma Adenoma

Hyperplastic polyp

2014 DDW Topic Forum Novel Methods for Polyps Detection

• L-Menthol ADR, 43-60% (p=0.008, 2) (Inoue).

• EndoCuff PDR, 42-56% (p=0.001) (Floer).

• Polyp, adenoma, HP, and SSA detection rates variedamong colonoscopists; their classification rates varied among pathologists (Flores).

• Capsule colonoscopy: safe & effective, detects lesions, high accuracy and acceptability (Oka); detects neoplasia, high specificity & sensitivity in screening population (Suchanek).

Water exchange (WE)

Impact on ADR

Positive

RS RCTs

Water exchange 3 6

Leung FW. Water-aided methods for colonoscopy. In: Gastroenterology Clinics Edited

by Charles J. Kahi. Saunders-Elsevier, Philadelphia. 2013;42:506-519.

• Water exchange - modified from WI

– air pump off - avoid colon elongation

– residual air suctioned - minimize angulations

– water infusion - confirm correct tip orientation

– infused water is suctioned during insertion to remove feces; reduce distension and looping

RS, retrospective study; RCT, randomized controlled trial

Water exchange + new methods

1Hsieh, AJG, 2014, in press; 2Cadoni, Endoscopy 2014; 3Leung J, JIG 2013; 4Leung J, JIG, 2014, in press; 5Yen, GIE 2013.

New methods

ADR (%)

RefOverall Proximal [right]

C WE p C WE p

High Definition (RCT) 43 57 0.10 [11] [27] 0.02 1

High Definition (RCT) 19 26 0.03 5 10 0.01 2

Indigocarmine (RCT) 44 62 0.03 3

Indigocarmine (RCT) 35 53 0.02 4

Cap (Consecutive group) 59 75 0.02 48 61 0.07 5

RCT, randomized controlled trial; C, control

C, control; WE, water exchange; [ ], right colon data

Conclusion

• Hypothesis to be tested in RCT

– With optimal withdrawal techniques, water

exchange during insertion, with or without

being combined with new approaches,

enhances the detection rate of adenomas

Sponsors Water Exchange Research ProjectsAmerican College of

Gastroenterology 2010

RCT water infusion vs. air for scheduled unsedated

colonoscopy

Am Soc GI Endoscopy 2010 RCT to compare ADR of combined indigocarmine with

water infusion in lieu of air insufflation

American College of

Gastroenterology 2011

WE increases ADR by reducing colonic contractions

during withdrawal

VA Clinical Merit (USA) 2012 Comparative efficacy of water & indigo carmine vs.

water or air method on ADR - a RCT

Canadian Digestive Res

Foundation 2012

Potential of the water method of colonoscopy as a

universal screening test

Tzu Chi Hospital (Taiwan)

Research Funds 2012

A RCT comparing WE, WI and AI methods during

colonoscopy with option of on demand sedation

Norwegian GI Association

2012

Water exchange vs. carbon dioxide insufflation to

improve colonoscopy screening – a RCT

European Society of GI

Endoscopy 2013

RCT comparing AI, WI and WE for ADR during on

demand sedation screening colonoscopy

Josep TaberneroVall d’Hebron University Hospital

Vall d’Hebron Institute of OncologyBarcelona

Targeted agents

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

EGF

TGF-α

Amphiregulin

Epiregulin

Grb2

SosEGFR

Anti-EGFR MoAbs:CetuximabPanitumumab

(RAS inh.)

RAF inh.

MEK inh.

ERK inh.

Inhibitors

1Douillard JY, NEJM 2013; 2Schwartzberg L, JCO 2013 (A 3631);3Stintzing S, EJC 2013 (Proc ECCO)

Among KRAS ex 2 wt patients, an additional14-20% of tumors with other RAS mutations were found

EGFR targeted population: 100% 40-46%

KRAS EXON 2 EXON 3 EXON 4EXON 1

12 13 61 117 14640% 4% 5-7%

5912 13 61 117 14659

NRAS EXON 2 EXON 3 EXON 4EXON 1

12 13 61 117 146

BRAF EXON 15 EXON 16…EXON 1…

600

3-5% 2-6% 0%59

6-10%

12 13 61 117 14659

600

Analysis of PRIME1, PEAK2 and FIRE-33 studies

Expanded RAS analysis

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, SU5416, SU6668,

Sunitinib, Vatalanib, Sorafenib,

Cediranib, AEE788, AMG-706, KRN-

951)

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

Study mOS (m)Control arm

mOS (m)Exp. arm

Chemotherapy N9741 15 19.5

GERCOR 21.5 20.6

GONO 16.7 22.6

Chemotherapy + Bevacizumab NO16966 19.9 21.3

AV2107 15.6 20.3

Chemotherapy + Cetuximab* OPUS 18.5 22.8

COIN 17.9 17

CRYSTAL 20 23.5

Chemotherapy + Panitumumab* PRIME 19.7 23.9

*Only KRAS ex 2 wt population

Clinical Trials in 1st line: targeted agents

Chemo + Cet Chemo + Bev

N 578 559

OS (m) 29.9 29 HR 0.92; NS

PFS (m) 10.4 10.8 HR 1.04; NS

CALGB 80405 study

Venook A et al. Proc ASCO 2014

Study mOS (m)Control arm

mOS (m)Exp. arm

Chemotherapy N9741 15 19.5

GERCOR 21.5 20.6

GONO 16.7 22.6

Chemotherapy + Bevacizumab NO16966 19.9 21.3

AV2107 15.6 20.3

Chemotherapy + Cetuximab* OPUS 18.5 22.8

COIN 17.9 17

CRYSTAL 20 23.5

Chemotherapy + Panitumumab* PRIME 19.7 23.9

Chemotherapy + Bevacizumab vsChemotherapy + Cetuximab*

CALGB 80405 29 29.9

*Only KRAS ex 2 wt population

Clinical Trials in 1st line: targeted agents

1st line cytotoxic 3rd line cytotoxic2nd line cytotoxic

1st line biologic 2nd line biologic

At progressionchange chemo,

biologic or both?

Independentsequences?

FluoropyrimidinesOxaliplatinIrinotecan

BevacizumabCetuximab/panitumumabAfliberceptRegorafenib

How to start?What is best strategy?

What to do for liver metastases?

Locoregional therapy:

SIRS

Surgery

3nd line biologic

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

The continuum of care of mCRC

Meropol NJ. J Clin Oncol 2007;25:180-186

20 m 30 m

Cost-effectiveness of mCRC treatment

StrategyTotal cost

in dollars

Life

expectancy

in weeks

CE Ratio/

week

compared

to 5FU

CE Ratio/

week

compared

to FOLFOX

5FU/LV 4,000 54.7 Base Case

FOLFOX 44,000 70 2,600 Base Case

FOLFIRI then FOLFOX 55,000 84.4 1,700 800

FOLFOX /Bevacizumab then Irinotecan 114,000 95.1 2,700 2,800

FOLFOX then Irinotecan then

Irinotecan/Cetuximab118,000 104.7 2,300 2,100

FOLFIRI/Bevacizumab then FOLFOX then

Cetuximab132,000 113.8 2,200 2,000

FOLFOX/Bevacizumab then Irinotecan

then Cetuximab138,000 111.9 2,300 2,240

FOLFIRI/Bevacizumab then FOLFOX then

Cetuximab/Irinotecan165,000 118.3 2,500 2,500

FOLFOX/Bevacizumab then Irinotecan

then Cetuximab/Irinotecan173,000 116.7 2,700 2,800

Based on a 70 year old, 70 kg male with a BSA 1.7m2

Meropol NJ. J Clin Oncol 2007;25:180-186

Incremental Cost per Life Week gained

Patient with 1st-line mCRC

↓Treatment goal

↓Treatment strategy

↓ Treatment intensity

(Best combination of targeted therapy and chemotherapy to achieve treatment goal)

Algorithm in the treatment of mCRC

• Target discovery has resulted in numerous novel drugs in

clinical development

• Treatment choice should consider efficacy, safety, cost, drug

availability and some other important parameters for the

treatment aim in each patient

• 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

• Need for molecular profile and selection

• Combinations: mechanistic interactions, rationale-based

• Need to sequentially evaluate tumor cells (tumor tissue,

CTCs, cfDNA, …)

Summary and challenges

11st 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 and metastatic diseaseColon 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 will remain the standard treatment in patients up to 70-75 years

In stage III elderly patient: fluoropyrimidine alone is still an acceptable choice

Duration could decrease to 3 months if the ongoing IDEA collaboration will be positive (but data expected only in 2016-2017)

Avenues for progress

The interventions on lifestyle (diet, physical exercise, smoking habits…) will gain an increased role

New independent studies will evaluate aspirin (or COX-2 inhibitors) +/- chemotherapy

Also immunotherapy could be evaluated in this setting

The opportunities for translational research linked to adjuvant trials will increase

Adjuvant and metastatic diseaseColon Cancer

Adjuvant and metastatic diseaseRectal Cancer

In preoperative setting: fluoropyrimidine alone (capecitabine or 5FU) will remain the standard, without a role for oxaliplatin

In postoperative setting: adjuvant chemotherapy (fluoropyrimidine + oxaliplatin) will be more frequently used in clinical practice

Through better neoadjuvant treatment: more sphincter saving surgery

Biological/genomic characterization: not ready for use

Metastatic disease in the next 12 months

Oral therapy (e.g. XELOX instead of FOLFOX) will increase

The multidisciplinary approach will increase in many clinical institutions (chiefly in the “hub” centres)

A flexible, patient-based strategy (chemo-free intervals, de-potentiation of therapy, maintenance treatment vs observation, drug re-challenge…) will be the rule in clinical practice

Metastatic disease in the next 12 months

• The cost of drugs will be an increasing concern, with potential (or real!) inequality in access to therapy

Triplet chemotherapy instead of doublets +/-biologicals will be an increasing choice for selected patients

The constraints for independent clinical research will further increase

11st 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

The future of colo-rectal cancer surgical oncology

- Small: is it beautiful ?

- Combined treatment: before or after?

« Mini invasive surgery »

COLORECTAL CANCER: CLASSICC trial: long term resultsGreen BL et al, Br J Surg 2013

• 794 pts (526 laparoscopic vs 268 open)

• OS and DFS similar: confirms the interest of the laparoscopic approachfor colorectal cancers cancer

Colon Rectum

• Cancer of the RECTUM: • Corean trial: final results published soon

Next step: one port…

• 38 studies; 565 patients with SILS compared to 3526 with lap resection

• Similar outcomes• But heterogeneous studies; retrospective analysis; selection

biases for patients and surgeons …

Makino T et al, Ann Surg 2012

Fung AKY, Br J Surg 2012

Ma J et al, Ann Surg 2012

0

5

10

15

20

25

30

35

2008 2009 2010 2011 2012 2013

• 43 patients

• No obvious functionnal or cosmeticbenefit

• Trend to higher complication rate (NS)

… or robot- assisted…

• 71 patients

• Similar results

• At the moment the overcost of robot assisted surgery is not justified by data

Park JS et al, Br J Surg 2012

Robot- assisted vs conventionnal laparoscopic surgery for colo-rectaldisease( benign or malignant) focusing on rectal cancer : a metaanalysis-16 studies; 2 controlled (66 pts)…- less blood loss, -fewer conversions to open, - longer duration of surgery, - similar quality of surgery and complication rate- higher cost

Yang Y et al, Ann Surg Oncol 2012

Progress… and fashion

• New procedures must be evaluated and validated

• Many patients still do not get adequat surgery for cancer of the rectum, whatever the approach, open or laparoscopic, resulting in increased riskof relapse of cancer

Extended colonic cancer surgery

• pathologic examination of mesocolon (distance colon/lig, surface of mesocolon…)

• 73 to 88% of intact mesocolon• 21% of patients had laparoscopic surgery

West NP et al, J Clin Oncol 2012

Pre-operative vs post-operative

Before is the future !

Neoadjuvant treatment is already the standard of care in several GI cancers:

- Rectum

- Stomach

- Esophagus

- Metastases

- … and now colon?

FOXTROT trial: Randomized ph II; n=150

FOXTROT trial, Lancet Oncol 2012

Foxtrot Trial, preliminary results

• Arm with post operative chemo (51 pts): 98% ≥ T3

• Arm with pre operative chemo (99 pts): – 85% of patients received preoperative treatment (3 cycles)

– Good tolerance:100% of patients underwent surgery without increasein rate of complications

– Pathological response

• 2 pCR

• Proximal N+: 1% (vs 20% without pre-op chemo)

• R0 resection 96% (vs 80% without pre-op chemo)

• Tumor regression 22% (vs 0 without pre-op chemo )

FOXTROT trial, Lancet Oncol 2012

• Next: Phase III study

Eckinoxe: FFCD trial1003 Randomized Ph II

Karoui M et al, FRENCH 2012

Surgery

Folfox4 (12 cycles)

(according to local practices)

FOLFOX4 (4 cycles)

Surgery

Folfox4 (8 cycles)

Folfox4 – Cetuximab (4 cycles)

Surgery

Folfox4 – Cetuximab (8 cycles)

RCt High risk T3

T4 / N2

KRAS wt

Surgery

Folfox4 (12 cycles)

(according to local practices)

Surgery

Folfox4 (12 cycles)

(according to local practices)

FOLFOX4 (4 cycles)

Surgery

Folfox4 (8 cycles)

FOLFOX4 (4 cycles)

Surgery

Folfox4 (8 cycles)

Folfox4 – Cetuximab (4 cycles)

Surgery

Folfox4 – Cetuximab (8 cycles)

Folfox4 – Cetuximab (4 cycles)

Surgery

Folfox4 – Cetuximab (8 cycles)

RRCt High risk T3

T4 / N2

KRAS wt

Primary endpoint: Pathological response)

Secondary endpoints: Morbidity, tolerance, QOL, quality of surgery, radiological response

11st ESO Colorectal Cancer Observatory:Innovation and care in the next 12 months

Mario Dicato

Centre Hospitalier de Luxembourg

View of a Medical Oncologist

Survival improvement in CRC over the past 20 years. Can we project into the near future?

Survival improvement:

1. Screening and prevention: colonoscopy

2. Surgery

3. Treatment of metastatic disease

1

OPUS Trial: incidence of additional RAS mutations in patients Exon-2 KRAS-wt

Considering all RAS mutations, mCRC RASwt has now an expectedmedian OS of about 29 months

30 years of progress in cancer

research

1983

Normal cell Cancer

MYC+RAS

NOW

A quantum leap forward in understandingthe molecular basis of cancer….

First Drug of XXI Century

STI 571Chromosome 9 Chromosome 9+

Chromosome 22 Ph

ABL

BCR

BCR-ABL

Philadelphia Chromosome Translocation t(9;22)

Why is Glivec (Gleevec) so great?Bcr-abl: a de novo gene (not a mutation, deletion… ), is the

primary cause of the disease. The biomarker is the cause of the disease

one gene

one protein

one (?) disease (CML, GIST, PDGF)

Resistance is next genetic event in this same gene !! 2nd and 3rd

generation drugs available M.DICATO, 2012

M. DI 2011CATO 2010

A. Grothey3 mCRC: ?palliative

Gerlinger M et al, NEJM 2012

Preliminary Results of associated targeted treatments in BRAFmut mCRC (ASCO 2014 abstr.:3513,3514, 3515, 3516, 3517, 3518)

D: dabrafenib; T:trametinbib; P: panitumumab; V: vemurafenib;C: cetuximab; E: encorafenib; Ir: irinotecan; BYL: BYL719:

C. Tournigand, 2014

Treatment n RR% SD% Dis Control %

Genomics• 2001: first 2 human genomes decoded: >3 Bill $

• 2009: first complete sequencing of human cancer genomes

• 2010: deep sequencing of a single patient’s Ca

• Large- scale sequencing: new targets…

• Personalized genomics faisable soon 1000$ (?)

• We are there now 2014: Illumina HSeq X:1000$

-Equipment cost: 250.000$, table model 100.000$

• ?When 100$ (IBM: DNA Transistor)?M.DICATO 2013

ASCO 2014, L. Schnipper

ASCO 2014: Health Services Research Value, Quality, Cost:Oral abstracts session: D. Goldstein

Payment increases for doing more- but for delivering more expensive care instead of better care.

Bevacizumab (Bev) in addition to 5U based CT for mCRC. US based 1st and 2nd line FOLFOX +/- Bev. Incremental cost effectiveness of adding Bev:

1st line: QALY 240.195$, 2nd line 219.724$

QALY threshhold debate in US. Authors thought 50.000- 100.000$ to be acceptable in regards to CALGB 80405 CT + Bev or Cetux in 1st line OS of 29 months.

ASCO 2014: Value in Cancer MedicineThe US Situation

• Cost: 39% increase from 2010 to 2020

• 2018: medical cost for insurance and out of pocket expenditures for a family will equate 50% of the household income

• 62% of all bankruptcies result from medical expenses

• Effectiveness = cost/benefit

• Proliferation of expensive therapies for marginal improvements. « Me- too drugs » divert « safer » finances from possibly more innovative but riskier research (finances)

• Incorporating cost information into (ASCO) guidelines

Newer Concept?

• Pay for performance pricing

• The Velcade case: response after 4 cycles. UK reimbursement if therapeutic effect proven

• US: Cigna insurance Co: patient treated for hyperlipidemia gets a heart attack, company of lipid lowering drug pays for the costs?

Prevention and early detection remain very important. Improvements: coloscopy; indications (?) of coloscopy…

Long term predictability: difficult/impossible

Short term improvements:

- Surgery and local therapy: embolisation…

- Drugs: Targets are the problem: heterogeneity of cancer and cancer stem cells. Redundancy…

Progress will continue at a slow and probably financially unsustainable pace

Conclusions:

Jolien PonPatient Advocate EuropaColon and

President Darmkanker Nederland - The Netherlands

”The patient’s perspective”

View of an Advocate Representative

11th ESO Colorectal Cancer Observatory:Innovation and care in the next 12 months

1of the

13.200 new Dutch stories per year

Achieved:

Innovations from the patients point of view:

•the colorectal cancer screening

•the update of the Dutch CRC-guidelines

•participation in clinical studies

•Patients advocates in 2 dream teams

•Participating in several activities with clinicians

•Participating in ‘Els Borst talks: The patient as lecturer’

Coming up:

•CRC quality criteria from patients point of view

•Start visiting those hospitals which perform below our standard for good CRC patient care

•Start CQI and PROM’s measured by questioning the patients directly (3x in 1,5 year) within the Dutch audit system

Nothing about us, without us!

To empower the patient, professionals and patients need to work together

With patients participating there will be better cancer healthcare

My challenge:

Can we work together in order to

•Give patients better control over their own illness•Create a new health professional?

What are the next steps?

2014-2015 Predictions