Diapositiva 1 - eso...• T1-3 N1: CAPOX (FOLFOX) for 3 months can be a new standard of care based...

14th ESO Colorectal Cancer Observatory: Innovation and care in the next 12 months

Wednesday 28th June 2017, 19:00 – 20:30

Panellists:

Josep Tabernero, ES Roberto Labianca, IT Eric Van Cutsem, BE

Bernard Nordlinger, FR Wolfram Nolte, DE

D. Arnold, PT

Chair: Mario Dicato, LU Co-Chair: Jola Gore-Booth, UK

New Therapies for Colorectal Cancer

Josep Tabernero, MD PhD

Vall d’Hebron Institute of Oncology (VHIO) Barcelona, Spain

View of a Medical Oncologist

14th ESO Colorectal Cancer Observatory : Innovation and care in the next 12 months

• Consultant/Advisory role:

Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai, Imclone, Lilly, MSD, Merck Serono, Millennium, Novartis, Roche, Sanofi, Symphogen and Taiho

Disclosure / COIs

Acquired capacities of cancer: phenotype

Hanahan & Weinberg, Cell 2011

BRAF (V600E) mutated CRC

Small population:

8-10% early stage

4-5% late stage

BRAF V600E mutations as a biomarker?

very poor prognosis in late stage (mCRC)

no clear prognostic effect in early stage

predictive: negative predictive effect for

anti-EGFR MoAbs in some studies:

Cetuximab: refractory (European

cons.)1,2 & first-line setting (CRYSTAL

study)3

Panitumumab: 2nd line setting

(PICCOLO study)4

No change in the label by any

regulatory authority predicted 1 Di Nicolantonio F, J Clin Oncol 2018; 2 De Roock et al, Lancet Oncol 2010;

3Van Cutsem et al, J Clin Oncol 2011; 4Seymour MT et al, Lancet Oncol 2013

Regimen N PR/CR

(%)

SD

(%)

mPFS

(m)

Vemurafenib + Cetuximab1 27 4 69 3.7

Dabrafenib + Panitumumab2 20 10 80 3.4

Dabrafenib + Trabetinib + Panitumumab2 35 26 60 4.1

Encorafenib + Cetuximab (RP2)3 26 (42) 23 (29) 54 (53) 3.7

Encorafenib + Cetuximab + Alpelisib (RP2)3 28 (49) 32 (35) 61 (44) 4.3

Hyman D et al. NEJM 2015; Van Cutsem E et al. Proc ESMO GI 2015; Elez E et al. Proc ESMO GI 2015

BRAFi + EGFRi in BRAF mut CRC

Heracles: trastuzumab + lapatinib (HER2+)

• 46/849 (5.4%) HER2+

(KRAS ex 2 wt)

• 24 patients included

(EGFR pre-treated)

• ORR: 34%

• DCR: 78%

• mTTP: 5.5 m (3.7-

7.8+ m)

Pat

ien

t #

12

10

16

baseline Week 54 - PR +

Pat

ien

t #

12

10

23

baseline Week 24 - PR +

Siena S et al. Lancet Oncol 2016

Tumour

Lymph node

Blood vessel

Therapies that might affect the cancer-

immunity cycle

Chen & Mellman. 2013

Release of cancer cell antigens Chemotherapy

Radiation therapy

Targeted therapy

1

Cancer antigen presentation Vaccines

IFN-α

GM-CSF

Anti-CD40 (agonist)

TLR agonist

2

Priming and activation Anti-PD1

Anti-PDL1

Anti-CTLA-4

Anti-CD137 (agonist)

Anti-OX40 (agonist)

Anti-CD27 (agonist)

IL-2

IL-12

3

Infiltration of T cells into

tumours Anti-VEGF

5

Recognition of cancer

cells by T cells CARs

6

Killing of cancer cells Anti-PDL1

Anti-PD1

IDO inhibitors

7

Trafficking of T cells

to tumours 4

Pembrolizumab (anti-PD1) in mismatch

repair-deficient/-proficient CRC: phase II

Le DT et al. ASCO 2015, Le DT NEJM 2015

MSI-H Nivo

3mg/kg

MSI-H Nivo 3 +

Ipi 1

MSS Nivo 1 +

Ipi 3

MSS Nivo 3 +

Ipi 1

≥12w follow-up N=47 N=27 N=10 N=10

ORR, N (%) 12 (25.5) 9 (33.3) 1 (10) 0

CR 0 0

PR 12 (25.5) 9 (33.3)

SD 14 (29.8) 14 (51.9)

PD 17 (36.2) 3 (11.1)

UNK 4 (8.5) 0

All pts N=70 N=30 N=10 N=10

mPFS (m) 5.3 (1.5-NE)

NE (3.4-NE)

2.28 (0.6-4.4)

1.31 (0.9-1.7)

mOS (m) 17.1 (8.6-NE)

NE (NE-NE)

11.5 (0.6-NE)

3.7 (1.2-5.6)

Nivolumab +/- Ipilimumab (Checkmate 142)

Overman MJ et al. Proc ASCO 2016



Response in patients with MSI-H tumors



Survival in patients with MSI-H tumors

Immune vs Transcriptomic subtypes of CRC

dMMR – MSI Hypermutation

Immune-activated

Th1 cells

PDL1

Macrophages NK cells

Cytotoxic T cells

Th1 cells IFNγ IFNγ

CXCL9/10/13

Cancer cell

Cancer cell

Immune-ignorant

Inflammation

Cancer cell

TGFβ

Complement

Stromal cells Th17 cells

MDSC

Stromal cells

Macrophages NK cells

Cytotoxic T cells

CCL2

CCL2 TGFβ IL-23

IL-17

Immune-tolerant Inflamed

Monocytes

• Binds simultaneously with 1 arm to CD3 on T cells and with 2 arms to CEA on tumor cells

• Flexible 2-to-1 format enables high-avidity binding and selective killing of high CEA-expressing tumor cells

• Longer half-life compared with other TCB formats

• Silent Fc results in reduced risk of FcγR-related cytokine release/IRRs

2-to-1 Format1 Flexible range of motion in Fabs1,2

CEA-TCB is the first T-cell bispecific antibody with a novel

2-to-1 format, optimized for efficacy and safety

Fab, fragment antigen-binding region; IRR, infusion-related reaction. 1. Bacac M, et al. Clin Cancer Res. 2016;22:3286-3296; 2. Roche. Data on file.

17

Presented by: Dr. Josep Tabernero,

Phase I Studies of CEA-TCB in mCRC. http://tago.ca/BfO

• Binds simultaneously with 1 arm to CD3 on T cells and with 2 arms to CEA on tumor cells

• Flexible 2-to-1 format enables high-avidity binding and selective killing of high CEA-expressing tumor cells

• Longer half-life compared with other TCB formats

• Silent Fc results in reduced risk of FcγR-related cytokine release/IRRs

2-to-1 Format1 Flexible range of motion in Fabs1,2

CEA-TCB is the first T-cell bispecific antibody with a novel

2-to-1 format, optimized for efficacy and safety

Fab, fragment antigen-binding region; IRR, infusion-related reaction. 1. Bacac M, et al. Clin Cancer Res. 2016;22:3286-3296; 2. Roche. Data on file.

18



CEA-TCB at doses ≥ 60 mg + atezolizumab demonstrated promising

clinical activity in 3L+ patients with MSS mCRC

Data reported by investigators, cutoff: March 3, 2017. a Patient had the confirmatory CT scan on March 23, 2017.

Study 2: CEA-TCB + atezolizumab (n = 11, 80 and 160 mg of CEA-TCB)

19



Weeks after treatment start

Ch

an

ge

in

ta

rge

t le

sio

ns

fro

m b

as

eli

ne, %

p

*p

*

p

-50

0

50

100*p

WithdrawalProgressionOngoingFirst new lesion

a

160 mg80 mg

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Partial metabolic and RECIST-confirmed response in a patient

with MSS mCRC

MSS mCRC: CEA-TCB 160 mg qw + atezolizumab 1200 mg q3w

Patient from MSKCC (Neil H. Segal). PET, positron emission tomography.

18F-FDG PET CT scans

Baseline Week 16 Baseline Week 4

20



Molecular-driven therapeutic hypothesis

Atezolizumab (PDL1 block) + cobimetinib (MEK inh) in mCRC

Bendell et al, ASCO 2016

CRC subtypes multi-omics

CIN

MSI Highly

immuno-

genic

Poorly

immuno-

genic

Inflamed

(immune-

tolerant)

Mu

tatio

n c

oun

t Co

py n

um

ber

Me

thyla

tion

RA

S a

nd

BR

AF

mu

tatio

ns

CMS1

CMS3

CMS2

CMS4

Fib

rob

lasts

Inna

te (I

mm

une

re

spo

nse

) A

dap

tive

D

ista

l (T

um

or

Loca

tion

) P

roxim

al

Thank you

14th ESO Colorectal Cancer Observatory : Innovation and care in the next 12 months

Roberto Labianca

Ospedale Papa Giovanni XXIII

Bergamo, Italy


ADJUVANT THERAPY OF COLORECTAL CANCER

Roberto Labianca Cancer Center, Director

Ospedale Papa Giovanni XXIII Bergamo, Italy

2017: A STILL VALID CONCEPT IN THE

GENERAL POPULATION

«..the addition of adjuvant chemotherapy for patients with regional (node-positive) disease has been demonstrated to reduce longer-term mortality…»

Welch GH and Robertson DJ: Colorectal cancer on the decline-Why screening

can’t explain it all. NEJM, April 28, 2016

Colon Cancer: stage II

In clinical practice: stage II patients will continue to receive adjuvant CT only if “high-risk”, according to clinic-pathological criteria Fluoropyrimidine alone for 6 months is still the standard of care (duration data conflicting/not yet mature: TOSCA vs SCOT, ASCO 2017) Recently emerging biological criteria: 2016: CDX2 , Immunoscore, circulating DNA… 2017: MSI, sidedness… Any of them ready for prime time ? NOT YET

Colon Cancer: stage III

• T1-3 N1: CAPOX (FOLFOX) for 3 months can be a new standard of care based on IDEA analysis (Shi et al, LB abstr # 1, ASCO 2017), with less neurotoxicity

• T 4 and/or N2: FOLFOX (CAPOX) for 6 months will remain the standard treatment for patients up to 70 (75) years

• In elderly patients: fluoropyrimidine alone for 6 months is still an acceptable choice

Presented By Qian Shi at 2017 ASCO Annual Meeting

Presented By Jeffrey Meyerhardt at 2017 ASCO Annual Meeting

• Lifestyle intervention (diet, physical exercise, smoking cessation…) YES

• Aspirin PROBABLY YES (increasing evidence in 2017)

• Immunotherapy TO BE ASSESSED (ALLIANCE/AIO trial…)

• Other interventions TO BE IDENTIFIED

• Increasing need of international collaboration (IDEA, ACCENT, PETACC re-loaded…)

Colon Cancer: new avenues

In preoperative setting: fluoropyrimidine alone (capecitabine or 5FU) will remain the standard, without a clear role for oxaliplatin (STAR, ASCO 2016) In postoperative setting: adjuvant chemotherapy (fluoropyrimidine + oxaliplatin) will be more frequently used in clinical practice (see also: Expert Discussion at WCG IC 2015) Through better neoadjuvant treatment: more sphincter saving surgery Biological/genomic characterization: not ready for use Avoiding surgery: still matter of research

Rectal Cancer

Presented By Jeffrey Meyerhardt at 2017 ASCO Annual Meeting

Eric Van Cutsem University Hospitals Leuven

Leuven, Belgium



The evolving treatment landscape

in metastatic CRC:

looking into the future.

Prof Eric Van Cutsem, MD, PhD

Digestive Oncology

Leuven, Belgium [email protected]

mailto:[email protected]

Published online 5 July 2016 Version 2.2017 – March 13, 2017

Metastatic colorectal cancer

CHEMOTHERAPY: combination of cytotoxic

and biological targeted drugs

Cytotoxic agents Biological

agents

5-FU/capecitabine (S1)

irinotecan

oxaliplatin

raltitrexed

(mitomycine)

Trifluridine/tiparicil

bevacizumab

cetuximab

panitumumab

aflibercept

ramucirumab

regorafenib early: Sym004, dabrafenib, vemurafenib

encorafenib, trametinib, binimetinib,

nivolumab, pembrolizumab,

atezolizumab, cobimetinib,

napabucasin, alpelisib,

bispecific antibodies (eg:

RO6958688:

antiCD3-CEA, crossMab RG7716 …),

vantictumab, cabozantinib

(nintedanib, MABp1, tremelimumab...)

Other contributing factors to improved outcome: surgery,….

OS

30 months

A classical case of mCRC in 2017 CONTINUUM OF CARE

5 months

first-line induction

3 months

reintroduction (or

treatment beyond

progression)

3 months

“rechallenge”

3 months

break

6 months

maintenance

4 months

second line

3 months

third line

3 months

preterminal phase

1991: OS 6 months

Locoregional therapy:

toolbox: surgery, Hipec,

RFA, Radioembolisation,…

Targeting multiple

signalling pathways

involved in

tumorigenesis

Induction of

immune responses

to target tumor cells

Further molecular

definition of

individual patient

subgroups

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

MSI tumors:

Anti-PD(L) antibodies

* Pembrolizumab,

Nivolumab

Ongoing advances in personalized

treatment of mCRC

MSS tumors:

Innovative

combination

treatment

CMS 1-4 tumors

BRAF inhibitors for BRAF mt mCRC:

Triple combinations

BRAF inhibitor-

containing combination

(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

inhibitor

PI3K/AK

T

inhibitor

Chemo-

therapy + or o

r

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)

Dienstmann R et al, Nat Rev Cancer, 2017, online jan 4

Tumors Use Complex, Overlapping Mechanisms to

Evade and Suppress the Immune System1

A. Ineffective presentation

of tumor antigens

(eg, downregulation of

MHC I)

B. Recruitment of

immunosuppressive cells with

inactive T cells

(eg, Tregs, MDSCs)

C. T-cell checkpoint

dysregulation

(eg, CD27, CD137,

CTLA-4, LAG-3, OX-40,

PD-1, TIM-3)2

D. Tumor release of

immunosuppressive

factors (eg, TGF-β, IDO, IL-

10, IL-4 from CSCs2)

Inactive T cell Tumor-

associated antigens

DC

Immunosuppressive factors

Treg

Tumor

cells

Active T cell

CD, cluster of differentiation; CSC, cancer stem cells; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; IDO, indoleamine 2,3-dioxygenase; LAG-3; lymphocyte activation gene-3; IL, interleukin; MDSC, myeloid-derived suppressor cell; MHC, major histocompatibility complex; PD-1, programmed death-1; TGF-β, transforming growth factor beta; TIM-3, T cell immunoglobulin and mucin domain-3; Treg, regulatory T cell.

1. Vesely MD et al. Ann Rev Immunol. 2011;29:235-271. 2. Todaro M et al. Cell Stem Cell. 2007;1(4):389-402. 3.Clinicaltrials.gov.

Active immunotherapy

Adoptive cell transfer

immunotherapy

IL-2

IFN

IL-15

IL-21

Peptide vaccine

DC vaccine

Genetic vaccine

OX40

CD137

CD40

PD-1

CTLA-4

T-cell cloning TCR or CAR

genetic engineering

General Approaches for Cancer

Immunotherapy

Slide credit: clinicaloptions.com

Immune checkpoint

inhibitors

Immune agonists

http://www.clinicaloptions.com/oncology

Immuno-oncology Therapies for Tumor

Immune Subgroups in CRC

Becht E et al. Curr Opin Immunol. 2016;39:7-13.

Immune

Subgroup

Molecular

Subgroups

Escape

Mechanisms

Immuno-therapeutic

Goals

Potential

Approach

Immunogeni

c

CRC

hypermutated

Immune

checkpoints:

PD-1 axis,

LAG-3, CTLA-4

Boost intratumor

CTLs

Checkpoint

blockade

Inflammator

y

CRC

mesenchymal

• Hypoxia

• TGFβ

• PD-1 axis

• Dampen

inflammation and

suppression

• Establish normoxia

• Boost intratumor

suppressed CTLs

• Anti-angiogenic

• Anti-TGFβ

• Checkpoint

blockade

Immune

neglected

CRC canonical

and metabolic

Low class I

MHC

expression

• Attract CTLs in

tumors

• Bypass class I

MHC presentation

• CAR T cells

• Bi-specific

antibodies

Phase III trial of Cobimetinib and

Atezolizumab in chemotherapy-

refractory mCRC (COTEZO – IMBlaze 370)

• Primary endpoint = OS

NCT02788279

*Experienced disease progression or was

intolerant to at least two systemic

chemotherapy regimens including

fluroropyrimidines, irinotecan, or oxaliplatin

Patients with

unresectable

locally advanced

or metastatic

CRC

(received at least

2 chemotherapy

regimens)*

n=360

Atezolizumab +

cobimetinib

Atezolizumab R

P

D

P

D

Regorafenib

2:1:1

P

D

Selected Ongoing Immuno-Oncology

Trials for mCRC

Adjuvant 1st Line 2nd Line

Anti–PD-1,

Anti–PD-L1, or

Anti–CTLA-4

Clinicaltrials.gov. Accessed November 2016.

Trials with MSI-H cohort or

selection

Efficacy data recently

presented

Pembro+RT/ablation*

(Ph II)

Pembro + azaC (Ph II)

Pembro (Ph II) Pembro+mFOLFOX6

(Ph II)

Pembro vs SOC (Ph III)

Pembro+RT/ablation* (Ph II)

FP + bev vs FP + bev +

atezo (Ph II)

Durva (Ph II)

Atezo ± cobimetinib vs

regorafenib (Ph III)

Atezo + cobimetinib

(Ph Ib)

Nivo + Ipi + cobimetinib (Ph I/II)

Pembro (Ph II)

Nivo ± Ipi (Ph I/II)

MSI:

mFOLFOX

6

± Pembro

MODUL TRIAL Utilizing Maintenance Setting for Biomarker-

directed Drug Development

Induction

phase

FOLFOX/

XELOX +

bevacizumab

CR

PR

SD

Biomarker-driven maintenance

phase Cohort

1 BRAFmut

R

FP + cetuximab +

vemurafenib

FP + BEV

Cohort

2 ‘NO

BM’

R

FP + BEV + atezolizumab

FP + BEV

Cohort

α R

Maintenance X

FP + BEV

Treatment

until PD

X: Trastuzumab + pertuzumab

Cobimetinib + atezolizumab

Molecular subtyping has the potential to drive

treatment decisions in mCRC

Adapted from Mallmann MR, et al. EPMA J 2010

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

Biomarker

profiling

Subtype D Therapy D


Bernard Nordlinger

Hospital Ambroise Paré

Parsi, France

View of a Surgical Oncologist

Surgical progress in the treatment of colon and rectal cancers

Bernard Nordlinger, Paris

• Laparoscopic colon and rectal resections • One port surgery • Natural Orifice Transluminal Endoscopic Surgery

(NOTES) • Transanal TME ( Total Mesorectal Excision) • NOTES • TEM : Transanal Microscopic Microsurgery

Laparoscopic resection of colon cancer

• Has become the reference treatment: - less operative morbidity than open surgery - shorter hospital stay - faster restoration of bowel function - similar oncologic results • But technically demanding

• Whatever the approach the most important is to do adequate TME

• Randomized trials: Lancet 2002; N. Engl. J. Med. 2004; J. Clin. Oncol.2007; Lancet Oncol 2009.

Laparoscopic surgery: rectal cancer

- shorter hospital stay (8 vs 9 days)*

- faster restoration of bowel function (2vs3d)*

- similar operative morbidity*

- similar oncologic long term results: COLOR II * COREAN**

Single port laparoscopy for colon resection

• Shorter incision* ** • Similar duration of surgery, hospital stay , restoration of

bowel function, • Similar operative morbidity**

* Maggiori et al. Review colorectal disease 2012; **Watanabe Randomized study BJS 2016

Surgery without scars Natural Orifice Transluminal Endoscopic Surgery ( NOTES ) *

• Transvaginal, transrectal

• Colon resections

• Mostly benign diseases

• 3% required addition of percutaneous trocarts

• 3% operative complications

• 12% post operative morbidity

• 4% conversion rate to open or laparoscopy

German Notes registry 139 pts. Bulian et al. Int. J Colorectal Dis. 2014

TRANS ANAL TME

From L. Maggiori

Transanal TME

• Mesorectum is dissected from the transanal approach + laparoscopic approach

• Technically demanding to find the correct plan for intact mesorectum excision

• Similar intestinal aud urinary function, trend better sexual function*

• Ongoing trials: GRECCAR 11, COLOR 3

Pontallier et al

TEM : Transanal Microscopic Microsurgery

• Local resection: for adenomass or pTis or

pT1 sm1 adenocarcinoma

• TEM superior to transanal resection without microscope; fewer tumor fragmentation and better resection margins*

*Moore, Dis. Colon Rectum. 2008

Message

• Recent progress in surgery improve the tolerance to surgery and in some cases the quality of resection

• Are technically demanding

• Never compromise the quality of cancer resection, and TME in particular.

Wolfram Nolte Patient Advocate

”The patient’s perspective”

View of an Advocate Representative


The patient‘s point of view

Nobody is sick just by him- / herself

A successful therapy does not target just

a disease rather than holistically a human being

Nobody is sick just by him- / herself

• Spouse / partner

• Family

• Friends

• and so on……

All of these are contracting problems in one way or the other

Coming down with cancer has a tremendous mental impact

• Hopelessness

• Feeling of entrapment, threat

• ……………..

• Loss of self-esteem in particular - when it comes to annoyance in partnership caused by sexual disorders - in times when nearness is notably looked for

Sexual disorders and cancer

Coherency can arise from:

• Side effects of CTx

• Side effects of surgical intervention

Resulting in:

• Loss of libido

• Loss of sensitivity

• Erectile dysfunction

A successful therapy does not target just a disease but holistically a human being

Are sexual disorders generally discussed between doctors and patients? Yes No Don‘t know When addressed by the patient

Are patients likely to deal with the topic? * Yes No Don‘t know When addressed by the doctor

* (men rather not at all)


Sorry doctor – it’s your turn: • The surgeon in a pre-operative informative conversation • The oncologist in a pre-therapy informative conversation • The oncologist in the course of CTx • The oncologist when realizing coping problems Obviously the brunt is left to the oncologist – who otherwise is not suspected for running idle Who can help out?


Who can help out?

• Psycho-oncologists

• Urologists (optimally with andrology qualification)

• Nurses

• Patient organizations & groups (Europe wide survey on unmet patient needs by EuropaColon)

• Public health counselling

These disciplines together with oncologists are typically co-operating in Comprehensive Cancer Centers (CCC), (however to which extent throughout Europe????)


Only a multi-discipline combination of therapy can help patients to:

• Regaining self-esteem and confidence

• Generating resilience

• Developing coping strategies

• Activating self healing effects

• Adding to QoL

Thank you All


Dirk Arnold

CUF Hospitals Cancer Center

Lisbon, Portugal


Magnitude of clinical benefit from anticancer therapies

Dirk Arnold, Portugal & Germany

Instituto CUF de Oncologia,

Lisbon, Portugal

Endpoints used in CRC oncology

Overall survival

Progression or

disease free

survival

Lack of symptoms

Toxicity

„Quality of life“

Surrogate parameters?

Assessment of benefits: Dimensions

Benefit in trials (in Dimension x)

Toxicity ( = Safety)

Benefit in trials (in Dimension x)

Costs


Benefit in trials (in dimension x)

Toxicity ( = Safety)


Benefit in trials (in dimension y)

costs


A ‘model’ of Kaplan-Meier figure showing the four OS-related parameters

HR = hazard ratio; OS = overall survival

Sobrero A, et al. Clin Cancer Res. 2015;21:1036–43

Pro

bab

ility o

f su

rviv

al (%

)

Time

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

1. HR (Cox model)

2. Gain in median OS (a1 b)

3. Absolute increase in OS (c1 d) at 2–3 years

4. Proportional increase in OS (ce/de) at 2–3 years

c

d

e

ba

The four ways to assess OS benefit

MST = median survival time; pts = patients

Sobrero A, et al. Clin Cancer Res. 2015;21:1036–43

OS BENEFIT

Large benefit for few

Absolute and proportional gain in long term OS

(2–3 years)

HR and gain in MST

Small benefit for many

Hard to understand

Hard to communicate to pts

Easily communicated, but

rarely available

Assessing benefit in a technical dimension

Adapted from: Sobrero A et al., Clin Cancer Res. 2015;21:1036–43

The ESMO MCBS

5

4

3

2

1

A

B

C

Curative Non-curative

Data derived from comparative research:

1. Priority: Strong level of evidence from large phase III studies

2. Careful analyses “control arm” and identification of endpoints.

3. Subgroup analysis

– preplanned in ESMO-MCBS when ≤ 3 subgroups defined «a priori»: benefit in a subgroup for the primary endpoint can be «scaled», provided adjusted for multiple comparisons

The ESMO MCBS: Governance

1.0

a. More than one outcome may be applicable

b. For a required HR, not the point estimate but the lower limit of the 95% CI is used to take into account the variability of the estimate

Example: for threshold set at HR ≤ 0.70

it is the lower limit of the 95%CI which has to be ≤ 0.70

0.7 0.5

Trial X 0.71 0.78 0.86

Trial Y 0.65 0.76 0.89 Trial X does not qualify

Trials Y and Z do qualify

Trial Z

HR

0.58 0.69 0.82

The ESMO MCBS: Statistical rules

Check for:

• indicators of severe toxicity or reduced grade 3-4 toxicity that bothers patients

• global QoL advantage using validated scale

quality of life

toxicity

Report final adjusted grade taken into account toxicity

and QoL when applicable

The ESMO MCBS: Denominating factors

The ESMO MCBS: New versions, additional topics

Evaluation form 3: for single-arm studies in “orphan diseases” and for diseases with “high unmet need” when

primary outcome is PFS or ORRGrade 3

Mark with X if

relevant

PFS >6 months

ORR (PR+CR) >60%

ORR (PR+CR) >20 <60% AND Duration of response >9 months

PFS >3- <6 months

ORR (PR+CR) >40 <60%

ORR (PR+CR) >20 <40% AND Duration of response >6 months <9 months

PFS 2-<3 months

ORR (PR+CR) >20 <40% AND Duration of response <6 months

ORR (PR+CR) >10 <20% AND Duration of response >6 months

Grade 2

Grade 1

Implementation ESMO-MCBS scale June 2017

Information based on:

• Questionnaire of ESMO-members about implementation of the scale

• Interviews of people

• asking ESMO for information

• with known expertise with regards to implementation

• Publications

• Near future questionnaire for research funders, Commission, ministries, regulatory bodies

The ESMO MCBS: Implementation and adjustment Implementation ESMO-MCBS by:

1. ESMO organisation

2. Doctors to make decisions for individual patients

3. Teachers

4. Academic groups

5. Industry

6. Organisations and country(s) using the scale as a policy tool

7. Groups looking to application in other settings

EMA approved since 2016,scored with ESMO-MCBS

Tumor type Drug ESMO-MCBS score

NSCLC Nivolumab 5

NSCLC Pembrolizumab 5 in PD-1 > 50%

Renal cell carcinoma Nivolumab 5

Melanoma Nivolumab 4 nivolumab alone

Renal cell carcinoma Lenvatinib 4

NSCLC Pembrolizumab 3 in PD-L1 > 1%

Colorectal cancer Ramucirumab 3

Neuroendocrine tumor Everolimus 3

Renal cell carcinoma Cabozantinib 3

NSCLC Bevacizumab 2

Colorectal cancer Trifluridine/tipiracil 2

Melanoma Nivolumab 2 nivolumab + ipilimumab

NSCLC 2nd line Afatinib 1

NSCLC Necitumumab 1

NSCLC maintenance Erlotinib 1

NSCLC Ramucirumab 1

The ESMO MCBS: Newly registered compounds (EMA since 2016)

Benefit of the individual patient

Benefit of all treated patients


Instruments to evaluate RCT´s and meta-analyses

Meta-analyses

Randomized controlled trials (RCT)

Evidence by „real practice“ study / phase IV

Oberservations in (my) clinical routine

Mr. S. (=my patient)

How to seek evidence for my patient?


Meta-analyses



Observations in (my) clinical routine




Meta-analyses



Oberservations in (my) clinical routine



(Lost in) translation...?

Diapositiva 1 - eso...• T1-3 N1: CAPOX (FOLFOX) for 3 months can be a new standard of care based...

Documents

Transcript of Diapositiva 1 - eso...• T1-3 N1: CAPOX (FOLFOX) for 3 months can be a new standard of care based...