Recherche Clinique

en Onco Gériatrie

Dr Etienne BRAIN

Institut Curie / Hôpital René Huguenin

Saint-Cloud, France

etienne.brain@curie.fr & www.siog.org 1

Spring 2017 8842 studies found for:

Open Studies | Interventional Studies | cancer | Adult, Senior | Phase 1, 2, 3

www.clinicaltrials.gov 2

298 studies found for: older OR elderly +

Open Studies | Interventional Studies | cancer | Senior | Phase 1, 2, 3

3.4%!!!

www.clinicaltrials.gov 3

Agent Name Approval N Age ≥ 65 N Age ≥ 75

Palbociclib 2/2015 37 44% 8 10%

86 25% --

Everolimus 7/2012 290 40% 109 15%

Pertuzumab 6/2012 60 15% 5 1%

Eribulin mesylate 11/2010 121 15% 17 2%

Lapatinib 1/2010 34 17% 2 1%

282 44% 77 12%

Ixabepilone 10/2007 45 10% 3 <1%

32 13% 6 2.5%

Package Insert, “Geriatric Usage” section

Few older adults included in registration studies!

Breast cancer as an example

Courtesy to Arti Hurria (adapted) 4

In standard trials

- Younger

- Less comorbidities

- Less organ dysfunctions

- Fitter

Trial Population versus Real-Life Data

5

• SEER database

• 3,039 patients ≥ 66, stage IV breast, lung, colon cancer, 2004-2007,

bevacizumab

– Contra-indication defined as 2 claims for thrombosis, cardiac disease, stroke,

hemorrhage, hemoptysis, or GI perforation

– Toxicity defined as 1st development of 1 condition > beva

– Beva use associated w/ white race, later year of diagnosis, tumor type, and decreased

comorbid conditions

– 35.5% had contra-indication

• Black race, increased age, comorbidity, later year of diagnosis, lower socioeconomic status, lung and CRC

– If no contra-indication 30% complication (black race)

Hershman J Clin Oncol 2013 6

1. Therapeutic nihilism – Elderly patients do not receive any treatment

2. The intermediate position? – Elderly patients may benefit from treatments

3. Blind therapeutic enthusiasm – Elderly patients receive futile/non beneficial treatments

Place and role of geriatrician and oncologist Pelike from Attica 480–470 BC

Musée du Louvre

Current Dilemna & Extreme Positions

7

Need for Distinction between…

1. Non-eligibility

– Upper age limit & stringent inclusion/exclusion criteria

• Under-representation and misrepresentativeness

2. Non-invitation (physician’s reluctance)

– To avoid toxicity & drop out rate; long accrual time; difficulty to handle elderly

in trials; belief of less adhesion of elderly to trials; cost increased; institutional

support lacking; informed consent

3. Non-inclusion (patient’s decline)

– Distrust/mistrust; randomization; fear for toxicity, uncertainty; QoL; logistics

(cost, transportations); dependence; understanding; fear from patient’s circle

of family and friends

8

National Call for Coordinating Units

in GO (UCOG) - 2011

• Aims: To support national development of GO according to health care

mapping, including French overseas departments and territories to

cover the whole French territory

1. To better adjust treatments for elderly cancer patients, emphasizing on

shared decision making process between oncologists and

geriatricians

2. To promote access to all in all regions

3. To strenghten specific research (clinical & translational)

4. To support teaching and general information

9

GERICO

= To use geriatric parameters & items

in methods & design

Adding & integrating

Predicting

Screening

Interventions

Real life

Population

Specific criteria

Translational

Ethics

GERICO (UNICANCER) etienne.brain@curie.fr (chair)

s-nenan@unicancer.fr

v-plence@unicancer.fr

10

GERICO ≥ 2,500 patients 2002 Creation (F Pein & AC Braud) Age Phase Primary endpoint N Ancillary Publication

2002 G-01: X+VNR PO breast, lung, prostate 70+ II ADL 80 PK CROH 2010

G-02: CT XELOX CCR M+ 70+ II ADL 60 PK JGO 2011

2004 G-03: per op brachyXRT breast < 3 cm pN0 70+ II Feasibility, QoL 40 Cost Brachy 2013

2005 G-04: CT TxT q2w breast M+ 70+ II IADL 27/60 NA Poster

G-05: CT TxT q2w NSCLC M+ 70+ II IADL 5/60 NA Poster

2006 G-06: CT adjuvant anthra (MC) breast ER- 70+ II ADL 40 Will CROH 2010

2009 G-09: breast M+ HER2+++ X + lapatinib 70+ II Composite 4/52 NA Poster

Retrospective L1 CT M+ breast (Bergonié) 75+ Cohorte Description 500 NA CROH 2001

DOGMES L1 DXR lipos (GINECO) 70+ II RR 60 NA EJC 2012

2010 G-10/GETUG P-03: CT TxT prostate + PK 75+ II R Composite 66/60 :144 PK Poster

PRODIGE 20 (G-08): CT ± beva CCR M+ 75+ IIR/III Composite 102 CTC/RX Pending

2011 ASTER 70s/G-11/PACS 10: CT adj breast RH+ HER2- GGI 70+ III OS (competing risks) 1,080/2,000 TR, cost, acc Poster, oral

2012 ELAN (PAIR ORL, GORTEC/GERICO) 70+ II/III OS 446 NA Poster

SHS (cognition, acceptability, etc.) 70+ SHS Qualitative res NA Poster

2014 UCGI-30 (G-12) XRT/CTneo vs XRT rectum

OSAGE (Besançon) 75+

III

I/II

R0 + IADL

MTD, RR EOT

420

54 acc

2016 ASTER 2/3 + EORTC/BIG 70+ III Outcome + QoL 1,200/2,500 Acc

2017 MBC, SCSC, STS, palliative XRT 11

The importance of patient-centred priorities in science cannot be understated

w/ multifarious factors Race

Culture Socioeconomic background

Diet Life-style choices

Immunity Access to cares Transportation

Insurance systems Family unit

Health economics Stage of development Access to innovation

Spirituality Political support

Acceptability 12

Ce qui compte hors cancer

0

20

40

60

80

100

Mobilité Tenue Courses Ménage Hobbies Conduite Religion Confiance Famille Douleur Travail

31 patients 75+

Dempster & Donnelly. Qual Life Res 2000 13

Functional status

• ADL (Katz)

Activities of Daily Living

1. Bathing

2. Dressing

3. Toileting

4. Transferring

5. Continence

6. Feeding

• IADL (Lawton)

Instrumental ADL

1. Ability to use the telephone

2. Shopping

3. Food preparation

4. Housekeeping

5. Laundry

6. Mode of transportation

7. Responsability for own medication

8. Ability to handle finances

Decline in 1 task 2-yr mortality Need for cares at home

ADL 30% Full time

IADL 15% Partial

Carey J Gen Intern Med 2004; Inouye JAMA 1998 14

Fried. NEJM 2002

226 patients 60+

Limited life expectancy No treatment resulting in death

= due to cancer, congestive heart failure, or chronic obstructive pulmonary disease

Burden of treatment

= length of the hospital stay, extent of testing, and invasiveness of interventions

Scenario 1

Low-burden treatment restoring participant's current state of health

98.7% accept treatment

Scenario 2

High-burden treatment restoring participant's current state of health

11% rate of acceptance

Scenarios 3 & 4

Low- or high-burden treatment with survival

but severe functional or cognitive impairment

74-89% rate of acceptance

West Haven Veterans Affairs

1

2

3

4

15

GERICO 06 (EUDRACT N° 2005-000069-20, PHRC national 2005)

MC MC MC MC XRT

ADL

Tolerance CGA

ADL + MNA +

MMS + GDS +

CIRSG

QLQ-C30

Willingness

CGA ADL + MNA +

MMS + GDS +

CIRSG

QLQ-C30

Willingness

Tolerance

CGA ADL + MNA +

MMS + GDS +

CIRSG

QLQ-C30

Willingness

Tolerance

1 & 2 year

DFS & OS

ADL

Tolerance

ADL

Tolerance

± trastuzumab

if HER2+++

trastuzumab

if HER2+

q3w q3w q3w

4 cycles of “AC-like” chemo In MC, M stands for liposomal non pegylated doxorubicin

16

1. Febrile neutropenia 15%

2. Risk of denutrition 15% vs 38%

3. Impact on QoL (social & role functioning)

4. Cardiac tolerance of trastuzumab

5. No palmar plantar erythrodysesthesia

6. DFS3A 85%

17

Hurria J Clin Oncol 2016

1. 58% grade ≥ 3 toxicity

2. Risk increased w/

increasing risk score

3. AUC/ROC 0.65 (95%CI

0.58-0.71) ~ development

cohort 0.72 (95%CI 0.68-

0.77) (P = .09)

4. No association between

PS and chemo toxicity (P

= .25)

A true predictive model for

chemo-related grade 3-5 toxicity

18

6/2013-01/2018

592 pts screened

342/592 (58%) in trials

II 81/80 III 181/202 III 80/164

H&N program

GORTEC / GERICO

ONCOVAL / ELAN

FIT definition

• GDS 4 = 0/4

• MMSE > 23/30

• Caregiver

• No fall

• TGUG < 20’

• ADL = 6/6

• CCI ≤2 if 80+

• CCI ≤3 if 75-80

19

Co-primary & Composite endpoints

• Co-primary: combine ≥ 2

primary endpoints (i.e.

hierarchy) w/ dimensions

potentially equally/closely

weighted

– Toxicity/efficacy

– Efficacy/functional status

• But

– Correlation between events not

always known and measurable

– sample size

• Composite: combine several criteria in 1

– Cardiology: angor, MI or death

– Oncology: death, M+ or LR relapse (DFS)

– Treatment success (efficacy/toxicity & compliance) • % pts w/ response w/o major AE > n Cy chemo at dose planned

and w/o delay

• But

– Mix of events • Each event should have the same clinical importance for treatment

decision making & describe same clinical issue

– Threshold?

– N events and sample size

– Difficult conclusion if divergent criteria

Time to treatment failure

Treatment failure-free survival

Time w/o symptoms or toxicity

Overall treatment utility

20

GA

Frail

Vulnerable Docatexel q3w

Docetaxel qw

Docatexel q3w

Docetaxel qw

randomization

Feasibility defined as 1. 6 cycles of docetaxel (qw or q3w) 2. w/o • Treatment stop > 2 w • Need for dose reduction > 25% • Febrile neuropenia or grade 3-4 non haematological toxicity • Loss of ADL 2 points

Simon Optimum 2-step design

α=5%, 1-β=90%

p0=0.70 & p1=0.90

1. 15 pts/arm (>11)

2. 36 pts/arm ( 30)

Total 60-144 pts

GERICO 10 (treatment x frailty level design)

CRPC

21

GERICO 10 results

• 12/2010-08/2012

– 66 patients (45+21) --> per protocol = 49 patients (30+19)

– Group vulnerable (N = 30) • No deaths

• But not feasible (7/15 & 10/15)

– Group frail (N = 19) • 5 toxic deaths

Standard docetaxel

qw or q3w

is not feasible

in most frequent

CRPC elderly patients 22

GA: 1 for all or all for 1?

• For whom?

– Curative vs palliative

– Adjuvant vs metastatic

– Agressive vs chronic

– 65+, 70+, 75+? Etc.

• Screening tool?

23

G8 & Oncodage

• G8 vs VES 13

– Sensitivity 76.6 vs 68.7%

– Specificity 64.4 vs 74.3%

– Both 2 ~ 4’

• ~ 2/3 of patients 70+ have a G8 score 14/17

• Strong 1-yr prognosis impact (w/ stage, PS, but not age)

– HR 2.72 (95%CI 1.66-4.47)

2011/2012 INCa recommandations

(UPCOG/UCOG)

Patients 75+ with G8 score 14

Soubeyran PLOS 2014 24

Geriatric intervention • Pennsylvania, follow up 44 mths

• Surgery for cancer 2/1993-12/1995

McCorkle JAGS 2000

60+ yo

Standard

Intervention: 3 visits at home

+ 5 phone calls by trained

nurses

375 pts 60-92

1/ OS 2/ Depression, anxiety,

functional status

Standard Intervention p

N 185 190

Advanced stage (%) 26 38 0.01

Death (%) 28 22 0.02

2-yr OS

early stage (%)

late stage (%)

88

40

90

67

NS

< 0.05

COX HR 2.04 (IC95% 1.33-3.12, p = 0.001) 25

26

Nutritional vs standard: 1-yr mortality

70+ w/ MNA 17–23.5

341 patients enrolled/820 planned power!

CRC (22.4%), NHL (14.9%), lung (10.4%), pancreas (17.0%)

27

28

29

Treatment failure-free survival

- Standard 3.2 mths

- GA 3.1 mths (HR 0.91; 95%CI 0.76-1.1)

Corre J Clin Oncol 2016

Treatment STD

(%)

CGA

(%) P

All grade toxicity 93.4 85.6 .015

Treatment failure

related to toxicity 11.8 4.8 .007

There is more to life

than survival!

Demonstrate the impact of GA on cancer prognosis in elderly patients

• PREPARE program (Pierre Soubeyran, French PHRC 2013-2014)

Initial cares with first or second line chemotherapy

L1: breast, colorectal gastric, lung, prostate, bladder, ovarian, myeloma, NHL

L2: breast, colorectal, prostate, myeloma, NHL

Co-primary endpoints: 1-yr OS (+10%) & HrQoL (+10 points)

P Soubeyran

> 14 Standard treatment

≤14

Standard treatment

Case management ("G8-guided", nurse, geriatrician, etc.)

> 70 yo

L1 or L2 R

1:1

G8

31

ASTER 70s (EUDRACT N° 2011-004744-22, PHRC national 2011, NCT01564056)

Adjuvant chemotherapy for ER+ HER2- BC in 70+ patients

CGA Microarray

qRT-PCR

screened

randomized

Chemo = 4 TC or 4 AC or4 MC

4-yr OS 32

• Specifically for 70+ EBC women

• Common question

• Non-exclusive inclusion criteria (40% G8 ≤14 & 20% previous

cancer w/ 50% local or controlateral relapse)

• Question of treatment escalation & de-escalation

• Observational arm for ineligible patients selection bias

• Education of both patients & physicians

• Taking/spending time to explain the relevance of a trial

• Collaboration w/ geriatrician

• QoL and acceptability

• Translational research (biobank)

ASTER 70s 10 key points

33

Research challenges in GO

1. Address frailty (vulnerable/frail patients are more frequent than fit ones!)

2. Older elderly patients (octogenarians, nonagenarians, centenarians, etc.)

3. Specific co-primary or composite endpoints (weighing QoL + cancer-related targets)

4. Dose-escalation strategies (from doses lower than those approved in younger and fit

adults, based on PK and assessment of functional reserves)

5. De-escalation strategies (targeted therapies vs conventional treatment)

6. GA & case management: impact on cancer prognosis

7. Consensual minimal set of geriatric data to share across groups and countries

8. Translational research (ageing biology and cancer)

9. Pharmaco-economic issues

10. International collaboration

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80 pts HER2+ MBC

≥ 70 Years

(≥65/≥60y with co-morbidity)

Pertuzumab

+

Trastuzumab

Pertuzumab + Trastuzumab +

metronomic CT

® 1:1 T-DM1

Primary endpoint

PFS at 6 months of PH or PHM

Pertuzumab 840 mg loading dose, further 420 mg q3w iv

Trastuzumab 8 mg/kg loading dose, further 6 mg/kg q3w iv

Chemotherapy Metronomic chemotherapy: cyclophosphamide 50 mg/d po continuously

On progression Option to have T-DM1 (3.6 mg/kg iv q3w) till progression

PD

Stratification: ER/PgR, previous HER2 treatment, G8 Secondary endpoints

OS, BCSS, toxicity, RR (RECIST v1.1),

HRQoL, evolution of GA during treatment

EORTC 75111-10114 (Co-PI Hans Wildiers & Etienne Brain)

35

Elderly/frail HER2+ MBC population

TP + metronomic CT 7-mth longer median PFS vs TP

Acceptable safety profile

T-DM1 at progression active

36

RESPECT (N-SAS BC07)

Accrual of 275 patients from 2009 to 2014

Non-inferiority

HR 1.22-1.69 β 20%

Median FU ~ 4 years

ASCO 2018??

(175 patients as parrallel cohort)

37

EORTC-1625 QoL-ROG-ETF-BCG

R

1:1

70+

pT1 ≤ pN0(i+)

Luminal A ER+ ± PgR+ ≥20%

HER2- Ki67 < 20%

Exclusive APBI

Endocrine therapy

600 patients, 3-yr recruitment

Stratification for nuclear grade, G8 and institution

Primary endpoint: PRO HRQoL (QLQ-C30)

(at baseline, 6, 12, and 24 months)

2-sided α 5% β 20% superiority

Total duration 5 years

Phase III trial

38

1. Social environment: Q1 “do you live alone?” + Q2 “do you have a person or caregiver able to provide care and support?”

2. Autonomy: Activities of Daily Living (ADL) (abnormal if <6/6) and 4-Instrumental ADL (IADL) (abnormal if <4/4)

3. Mobility: Time Get Up and Go test (TGUG) (abnormal if >20 sec) 4. Nutrition: unintentional weight loss (>10% in 6 months) and BMI (< 21) 5. Cognitive status: Mini-Cog (abnormal if <4/5) 6. Mood: Mini-Geriatric Depression Scale (Mini-GDS) (abnormal if ≥ 1/4) 7. Comorbidities: updated Charlson index score

National & International validation

Geriatric COre DatasEt (G-CODE) (Delphi/RAND + Consensus Methods)

DIALOG = GERICO + UCOG = intergroup of clinical research in GO labeled by INCa in 2014 & 2017 39

• « Action 2.16 : Améliorer la prise en charge des personnes âgées atteintes

de cancer et la prise en compte de leurs besoins spécifiques, notamment en

s’appuyant sur une recherche clinique renforcée pour cette population. La

prise en charge des personnes âgées, caractérisées par plusieurs éléments

de fragilité dans la prise en charge du cancer (polypathologies fréquentes,

difficultés de mobilité), est une priorité »

Research

• Review 2005-2012 (National Call PHRC)

– Number of projects

• 27/479 (6%)

– 400 patients 2,400 patients

– 1% of eligible population (vs 7.5% for the rest of the population)

– Funding

• 7,5/139 M€ (6%)

• All calls include GO since 2005!!!

42

• Young patient

– Social and family obligations (children)

– Quantity of life +++

• Elderly patient

– QoL+++

– Independence

– Staying at home

• Oncology

– Therapies and innovation

– Toxicity, response, survival

• RECIST

• NCI CTC v4.0

• Survival (DFS, PFS, DDFS, OS)

– Fast-moving world

– "Molecular portrait" of tumour & GEP

• Geriatrics

– Symptoms, diagnosis

– Quality of survival, i.e. amount of life

with good QoL

• Cognition

• Functional status

• QoL

• Nutrition, etc.

– Requiring time

– "Global portrait" of patient & GA

GA versus

or + ?

Genomic defects

targeted therapy

GA defects

targeted geriatric

intervention

Two Worlds Confronting One Another?

43

Competing Causes for Mortality

Kendal Cancer 2008 44

Jaffee Lancet Oncol 2017

Clinical trials must include large populations that have not been traditionally served.

For example, age is an important risk factor for most cancers, yet elderly patients are often excluded from clinical trials because

of eligibility criteria, which might be too restrictive, or insurance coverage that makes their trial participation too expensive. 45

Conclusions

• New promising therapies exacerbate prognostic uncertainty, unknown

treatment AE, and uncertainty about ideal treatment duration, especially for

elderly patients w/ functional impairments or multiple comorbidities

• Clinical trials that establish the safety and efficacy of new therapies often

exclude or have limited representation of elderly patients and do not collect

PROs

• Need for better guidance for patients, their caregivers, and health-care

providers

• Elderly cancer patients prioritise outcomes like function and treatment burden

in different ways, requiring PROs, HrQoL assessment and data sharing

• HrQoL and international data sharing + data ecosystem

46

From a "prejudice-based" to…

….an "evidence-based" medicine…

• 10 institutions CALGB

– 77 « paires » cancer du sein (< 65A vs > 65A)

– Etude des cas de propositions d’essai

– Analyse multifactorielle : stade, âge (comorbidités contrôlées)

– Aucune différence de participation si proposition +++ : 56% vs 50%

Kemeny JCO 2003

< 65A

N (%)

> 65A

N (%) p

I 11/35 (31) 13/40 (33)

II 22/34 (68) 11/29 (38) 0.0004

IV 2/2 (100) 1/2 (50)

Total 36/71 (51) 25/71 (35)

47

Franck Bonnetain 1974-2017

48

FEC, AACR, FAC, ASCO, anti-PDL1, anti-PD1, CMF, SABCS, PD-1, PDL1, DXR, PK/PD, CEX, 5FU CDDP, Calvert AUC, ESMO, Chatelut AUC, CTC, TILs,

population PK, EORTC, FOLFIRI, ctDNA, FOLFOX 7, CPA, DFS, CALGB, DDFS, OS, TTP, NCI, CYP P450, JCO, JNCI, HER2, PI3K, mTOR, Phase 0,

ECCO, ib and ab, Unicancer, EORTC, SWOG, CALGB, etc.

Charlson, CIRSG, CGA, AD, MCI, MNA, GDS, MMS, ADL,

IADL, GFI, CMR2, JAGS, EUGMS, G8, CARG,

Oncodage, VES-13, TRFs, JGO, NIA, SoFOG, Walter’s score, Lee’s score, CRASH,

etc.

49

FEC, FAC, SoFOG, ADL, IADL, CMF, SABCS, DXR, PK/PD, CEX, G8, EORTC, 5FU CDDP, MCI, Calvert and Chatelut AUC, CARG, GDS, population PK, AD, FOLFIRI, MMS, FOLFOX, CPA, CRASH,

SWOG, DFS, OS, TTP, NCI, GERICO, TILs, CARG, anti-PDL1, anti-PD1, EORTC TFE, JCO, JNCI, Charlson, JGO, CIRSG, PD-1, PDL-1, ctDNA, EGS, EGA, MNA, GFI,

Unicancer, Lee’s score, JAGS, etc.

To be practice changing, let us be practice sharing!

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January 8, 2018

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