Actualités en Neuro-Oncologie - cen-neurologie.fr · TMZ 229 66 35 18 9 2 0 6 12 18 24 30 0.9 1.0 TTFields / TMZ TMZ Alone 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 of S months PFS TTFields

Actualités enNeuro-Oncologie

François DucrayService de Neuro-Oncologie, Hôpital Neurologique Lyon

Conflits d’intérêt

NOVOCURE

ABBVIE

BRISTOL-MYERS SQUIBB

ROCHE

Actualités en Neuro-Oncologie

1. Diagnostic des gliomes

2. Traitement des glioblastomes

3. Traitement des métastases cérébrales

Question 1

24 ans, diplopie

Histologie: Oligo. Anaplasique

70 ans, crise

Histologie: Glioblastome

A. OuiB. Non

Une analyse moléculaire est-elle nécessaire au diagnostic ?

Trois grandes voies de gliomagenèse

Pas de mutation d’IDHMutation d’IDH

Codélétion1p/19q

Mutations p53, ATRX

GBMAstroOligo

Mauvais pronosticPronostic intermédiaireBon pronostic

Amplification EGFRGain 7, Perte 10Mutations TERT

Trois grandes voies de gliomagenèse

Pas de mutation d’IDHMutation d’IDH

Codélétion1p/19q

Mutations p53, ATRX

GBMAstroOligo

Mauvais pronosticPronostic intermédiaireBon pronostic

Amplification EGFRGain 7, Perte 10Mutations TERT

Trois grands groupes de gliomes

Sanson et al. JCO 2009; Cairncross et al. JCO 2014; Tabouret et al. Acta Neuropathol 2016

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

0 50 100 150 200 250

IDHmt

IDHwt

14 ans

5 ans

2 ans

Codélétion 1p/19q

Mutation d’IDH

Codeletion1p/19q

Mutationsp53, ATRX

Oligo grade IIgrade III

Astro grade IIgrade III

GBM IDHmt

Bonpronostic

Pronostic intermédiaire

Gliome infiltrant

Chr7+, 10-Mutation de TERT

MutationHistone


GBM IDHwt Gliome lignemédiane H3K27M

Mauvaispronostic

Gliomes diffus de l’adulte: classification OMS 2016

Louis et al. Acta Neuropathol 2016

Pas de mutation d’IDH

Question 1

24 ans, diplopie

Histologie: Oligo. Anaplasique

70 ans, crise


A. OuiB. Non

Une analyse moléculaire est-elle nécessaire au diagnostic ?

Question 1


Biologie moléculaire: Mutation d’IDH et codélétion 1p/19q

70 ans, crise

Mutation d’IDH

Codeletion1p/19q

Mutationsp53, ATRX



GBM IDHmt

Gliome infiltrant

Chr7+, Chr10-Mutation TERT

MutationHistone


GBM IDHwt Gliome H3K27M


Diagnostic intégré selon l’OMS 2016:Oligodendrogliome anaplasique avec codélétion 1p/19q

Grade IIICodélétion 1p/19q

Bras standard: RT + PCV

Bras expérimental: PCV seul

N=140

N=140

Objectif principal: survie sans détérioration cognitive

Durée de l’étude: 9 ans

Essai POLCA PCV OnLy in Codeleted Anaplastic Gliomas

30 centres

Question 1

24 ans, diplopie

Histologie: Oligo. anaplasique

Biologie moléculaire: Pas de mutation d’IDH et mutation K27M de l’histone H3.3

Mutation d’IDH

Codeletion1p/19q

Mutationsp53, ATRX



GBM IDHmt

Gliome infiltrant

Chr7+, Chr10-Mutation TERT

MutationHistone


GBM IDHwt Gliome H3K27M


Diagnostic intégré selon l’OMS 2016:Gliome de la ligne médiane avec mutation H3K27M (grade IV)

2013

Décès

2009

24 ans une crise

2012RT+chimio 3 lignes de chimio

Evolution

Progression





Glioblastomes

p<0.0001

RTRT+TMZ

Comment faire mieux que le « Stupp » ?

Stupp et al. NEJM 2005

Question 2

Une patiente de 60 ans présente des troubles phasiques.

La biopsie est en faveur d’un glioblastome.

Chez cette patiente quelle stratégie pourrait être plus efficaceque le « Stupp » ?

A. « Stupp » + vaccin anti-EGFRB. « Stupp » + Ac anti-EGFR couplé à un cytotoxiqueC. « Stupp » + électrothérapie

EGFR

• Prolifération cellulaire• Échappement à l’apoptose• Invasion

EGF

EGFR

EGFRvIIIPerte de 267 acides aminés30% des GBM

Phosphorylation

AMPLIFICATION du gène

40% des GBM

Stupp + vaccin anti-EGFRvIII

Weller et al. Lancet Oncol 2017

Articles

www.thelancet.com/oncology Published online August 22, 2017 http://dx.doi.org/10.1016/S1470-2045(17)30517-X 7

Role of the funding sourceThe funder designed the study in collaboration with the investigators, managed the clinical trial database including oversight of data collection, performed statistical analyses, and provided medical writing assistance. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

ResultsBetween Jan 26, 2012, and Dec 1, 2014, 4652 patients were screened for study eligibility (figure 1). In the cohort of 4519 patients for whom submitted tumour tissue was adequate for EGFRvIII expression analysis, 1345 (30%) had EGFRvIII-expressing tumours. Between April 12, 2012, and Dec 15, 2014, 745 eligible patients with EGFRvIII-expressing tumours were randomly assigned to receive rindopepimut (n=371) or control (n=374). Of these, 405 (195 allocated to rindopepimut and 210 allocated to control) were assigned to the MRD population by central review and included in the primary modified intention-to-treat analysis, and 741 (369 allo-cated to rindopepimut and 372 allocated to control) received at least one dose of study treatment and were included in the safety analyses. 338 patients (175 allocated to rindopepimut and 163 allocated to control) had SRD and two were unevaluable (one allocated to each group). Pretreatment patient and disease characteristics for randomly assigned patients were well balanced between treatment groups within each analysis population (table 1).

At the second preplanned interim analysis done after 212 deaths had occurred in the MRD population (data cutoff Oct 24, 2015), the futility boundary was crossed. The overall survival HR for rindopepimut versus control in the MRD population was 0·99 (95% CI 0·74–1·31), suggesting that rindopepimut was unlikely to be better than the control in terms of overall survival. Therefore, the study was closed prematurely, and preliminary primary analysis results were released. Additional survival information was obtained as patients were discontinued from the study, and final analyses were done with a data cutoff of April 29, 2016. At study closure and final analysis, 523 deaths (254 in the rindopepimut group [129 in the MRD population] and 269 in the control group [135 in the MRD population]) and 546 progression events (267 in the rindopepimut group [141 in the MRD population] and 279 in the control group [149 in the MRD population]) had occurred.

Overall survival did not differ between the treatment groups for the MRD or intention-to-treat populations (figure 2A, 2B). Median overall survival in the rindopepimut group was 20·1 months (95% CI 18·5–22·1) versus 20·0 months (18·1–21·9) in the control group in the MRD population (HR 1·01, 95% CI 0·79–1·30; p=0·93), and 17·4 months (16·1–19·4) versus 17·4 months (16·2–18·8), respectively, in the intention-to-treat population (HR 0·89, 95% CI 0·75–1·07; p=0·22). In an

exploratory analysis of the SRD population (HR 0·79, 95% CI 0·61–1·02; p=0·066), median overall survival was similar between the treatment groups (14·8 months

Figure 2: Overall survivalOverall survival in (A) the minimal residual disease (primary analysis) population, (B) the intention-to-treat population, and (C) the significant residual disease population. HR=hazard ratio.

Time since randomisation (months)

Number at risk(number censored)

Rindopepimut +temozolomide

Control +temozolomide

195 (0)

210 (0)

190 (0)

210 (3)

150 (3)

169 (6)

102 (12)

101 (24)

42 (39)

53 (41)

21 (50)

21 (62)

7 (61)

7 (69)

4 (62)

4 (71)

0 (66)

0 (75)

371 (0)

374 (0)

345 (1)

347 (3)

261 (5)

268 (7)

159 (25)

149 (35)

72 (68)

73 (61)

32 (92)

25 (90)

12 (108)

8 (98)

7 (111)

4 (101)

0 (117)

0 (105)

175 (0)

163 (0)

155 (1)

145 (0)

111 (2)

98 (1)

57 (13)

47 (11)

30 (29)

19 (20)

11 (42)

4 (27)

5 (47)

1 (28)

3 (49)

0 (29)

0 (51)

0 (29)

0 6 12 18 24 30 36 42 48

100Ov

eral

l sur

viva

l (%

)

80

60

40

20

0

90

70

50

30

10

B




0 6 12 18 24 30 36 42 48

100

Over

all s

urvi

val (

%)

80

60

40

20

0

90

70

50

30

10

C




0 6 12 18 24 30 36 42 48

100

Over

all s

urvi

val (

%)

80

60

40

20

0

90

70

50

30

10

Rindopepimut + temozolomideControl + temozolomideHR 1·01 (95% CI 0·79–1·30), p=0·93

HR 0·89 (95% CI 0·75–1·07), p=0·22

HR 0·79 (95% CI 0·61–1·02), p=0·066

A

Stupp + vaccinStupp

Ac anti-EGFR « armé »

Anticorps monoclonal anti-

EGFR (depatuxizumab) couplé à un agent

cytotoxique (mafodotin)

=depatux-m

Effet cytotoxique =

Mort cellulaire

EGFR

Cellule tumorale

Ac anti-EGFR « armé »Signal d’efficacité dans les GBM en rechute

Médiane = 8.2 mois

Médiane = 9.6 mois

Survie globale depatux-m + TMZ vs TMZ/lomustine

Question 2

Une patiente de 60 ans présente des troubles phasiques.

La biopsie est en faveur d’un glioblastome.

Chez cette patiente quelle stratégie pourrait être plus efficaceque le « Stupp » ?

A. « Stupp » + vaccin anti-EGFRB. « Stupp » + Ac anti-EGFR conjugué à un cytotoxiqueC. « Stupp » + électrothérapie

« Stupp » + électrothérapie

Stupp et al. JAMA 2017

R

RT+ TMZ + TTFields

RT+ TMZ

Progression Free Survival - ITT

TTFields 466 22

9100 62 30 18

TMZ 229 66 35 18 9 2

0 6 12 18 24 30

0.9

1.0

TTFields / TMZ TMZ Alone

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Prob

abili

ty o

fPF

S

months

PFS TTFields/TMZ

TMZ

Median 6.7mo6.1– 8.1

4.0mo3.8– 4.3

Hazardratio

0.63(CI0.52– 0.76)

P-value 0.00005

PFSfromdiagnosis:

Median 11.2mo10.0– 11.8

7.8mo7.3– 8.2

StupponbehalfofEF-14investigators.SocietyofNeuro-Oncology,18.Nov.2016

Overall Survival - ITT

TTFields

466 421 329 252 155 89 56 37 28

TMZ 229 180 127 76 44 25 17 11 7

0 6 12 36 42 4818 24 30

0.9

1.0

TTFields / TMZ TMZ Alone

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Prob

abili

ty o

f Su

rviv

al

months

Survival(fromrandom)

TTFields/TMZ

TMZ

Median95%CI

20.8mo19.0– 22.6

16.0mo13.9– 18.2

2-year95%CI

42.5%(38.0– 47.4)

30.0%(24.4– 37.0)

Hazardratio

0.65(CI0.54– 0.79)

P-value 0.0006

Survivalfromdiagnosis(!):

Median95%CI

24.5mo22.8– 26.3

19.8mo17.622.1

StupponbehalfofEF-14investigators.SocietyofNeuro-Oncology,18.Nov.2016





Question 3

55 ans, crise

> 3 métastases cérébrales

ADK pulmonaire EGFR muté

A. RadiochirurgieB. ImmunothérapieC. Thérapie ciblée anti-EGFR

Peut-on proposer un autre traitement qu’une RT de l’encéphale in toto et si oui lequel ?

Pourquoi retarder la RT panencéphalique ?

Articles

1054 www.thelancet.com/oncology Vol 18 August 2017

HR 0·47 [95% CI 0·35–0·63], p<0·0001; figure 2). Of the 93 cognitive-deterioration-free survival events in the SRS group, 49 patients (53%) had confirmed cognitive deterioration, 25 (27%) died before 6 months without confirmed cognitive deterioration, and 19 (20%) were presumed cognitive deterioration. Of the 93 cognitive-deterioration-free survival events in the WBRT group, 63 patients (68%) had confirmed cognitive deterioration, 22 (24%) died before 6 months without confirmed cognitive deterioration, and eight (9%) were presumed cognitive deterioration. Stratified analysis (with the stratification factors of age, extracranial disease control status, number of brain metastases, histology, and size resection cavity) showed a similar difference in cognitive-deterioration-free survival between the treatment groups (adjusted median 3·7 months for the SRS group and 3·1 months for the WBRT group; adjusted HR 0·47 [95% CI 0·35–0·64], p<0·0001). 20 patients in the SRS group received salvage WBRT, of whom 13 had cognitive deterioration before WBRT and seven had cognitive deterioration after WBRT. A post-hoc sensitivity analysis removing the seven patients who had cognitive deterioration after WBRT showed a similar difference in median cognitive-deterioration-free survival compared with the primary analysis: 3·7 months (95% CI 3·45–5·16) in the SRS group (86 events) compared with 3·0 months (2·86–3·25) in the WBRT group (93 events; HR 0·46 [95% CI 0·34–0·63], p<0·0001). At 6 months, for patients with a cognitive evaluation, cognitive deterioration was less frequent in the SRS group than in the WBRT group (28 [52%] of 54 patients vs 41 [85%] of 48 patients, difference –33·6% [95% CI –45·3 to –21·8], p=0·00031) and was documented for all cognitive domains evaluated (table 2). A post-hoc analysis with different definitions of cognitive deterioration (ie, a 1·5 SD drop in at least two tests, 2 SD drop in one test, or 3 SD drop in one test), and evaluation of cognitive function at 3 months, consistently revealed similar findings as the primary analysis (appendix pp 2–5).14,17

After 69 deaths in the SRS group and 67 deaths in the WBRT group, median overall survival was 12·2 months (95% CI 9·7–16·0) versus 11·6 months (9·9–18·0; HR 1·07 [95% CI 0·76–1·50]; p=0·70; figure 3). There was no evidence at the 0·05 one-sided significance level that the HR was greater than 1·3 (in favour of WBRT) or 0·8 (in favour of SRS). SRS was not found to be inferior to WBRT but neither was SRS marginally superior to WBRT.

SRS was associated with a shorter time to intracranial tumour progression than was WBRT (median 6·4 months [95% CI 5·16–8·90], 66 events vs 27·5 months [14·85–not reached], 34 events; HR 2·45 [95% CI 1·62–3·72]; p<0·0001; appendix p 6). 6-month surgical bed control was 80·4% (95% CI 72·8–88·7) in the SRS group compared with 87·1% (80·5–94·2) in the WBRT group (p=0·00068); 3-month and 12-month estimates are shown in the appendix (p 6). Local control and distant brain

SRS (n=98) WBRT (n=96)

(Continued from previous page)

Motor

Normal 89 (91%) 81 (84%)

Abnormal 8 (8%) 14 (15%)

Data missing 1 (1%) 1 (1%)

Cerebellar

Normal 90 (92%) 84 (88%)

Abnormal 5 (5%) 10 (10%)

Data missing 3 (3%) 2 (2%)

Baseline Barthel ADL index 95·8 (9·1) 98·2 (6·4)

Baseline total score FACT-Br (range 0–100)

72·2 (14·5) 71·8 (13·2)

Baseline cognitive tests

HVLT-R Immediate Recall –1·5 (1·3) –1·4 (1·2)

HVLT-R Delayed Recall –1·5 (1·5) –1·6 (1·5)

HVLT-R Recognition –0·7 (1·4) –0·6 (1·5)

TMT-A time to complete –2·2 (3·0) –1·7 (3·1)

TMT-B time to complete –3·0 (3·4) –2·8 (3·3)

COWAT Total –1·1 (1·2) –1·2 (1·0)

Data are n (%) or mean (SD) unless otherwise stated. Cognitive tests reported as standardized scores (Z scores). SRS=stereotactic radiosurgery. WBRT=whole brain radiotherapy. ECOG=Eastern Cooperative Oncology Group. ADL=Activities of Daily Living. FACT-Br=Functional Assessment of Cancer Therapy—Brain Cognitive. HVLT-R=Hopkins Verbal Learning Test—Revised. TMT-A=Trail Making Test part A. TMT-B=Trail Making Test part B. COWAT=Controlled Oral Word Association Test.

Table 1: Baseline characteristics

Figure 2: Cognitive-deterioration-free survivalWBRT=whole brain radiotherapy. SRS=stereotactic radiosurgery.

Time from randomisation (months)

Cogn

itive

-det

erio

ratio

n-fre

e sur

viva

l (%

)

0 6 12 18 240

10

20

30

40

50

60

70

80

90

100


WBRTSRS

96 (3)98 (0)

7 (3)28 (1)

1 (3)10 (1) 3 (2) 2 (3)

WBRTSRSHR 0·47 (95% CI 0·35−0·63); p<0·0001

Survie globale Survie sans détérioration cognitive

< 3 métastases traitées par chirurgie et/ou radiochirurgie

RT panencéphalique immédiateSurveillance

RT panencéphalique immédiateSurveillance

Pas de perte de chanceen termes de survie

Meilleure qualité de vieMeilleure cognition

Kocher et al. JCO 2011; Brown et al. JAMA 2016; Brown et al. Lancet Oncol 2017

Question 3

A. RadiochirurgieB. ImmunothérapieC. Thérapie ciblée anti-EGFR

Peut-on proposer un autre traitement qu’une RT de l’encéphale in toto et si oui lequel ?

55 ans, crise

> 3 métastases cérébrales

ADK pulmonaire EGFR muté

Thérapie ciblée > RT pancéphalique

Articles

6 www.thelancet.com/respiratory Published online July 19, 2017 http://dx.doi.org/10.1016/S2213-2600(17)30262-X

(IQR 3·1–12·9) in the icotinib group and 2·1 months (0·7–3·5) in the WBI group.

52 (71%) of 73 patients received chemotherapy in the WBI group, which included 18 (25%) with gemcitabine plus carboplatin or cisplatin, 17 (23%) with pemetrexed plus cisplatin or carboplatin, seven (10%) with pemetrexed plus nedaplatin, and one (1%) with pemetrexed (appendix). In the icotinib group, 60 (71%) of 85 patients switched to icotinib and WBI or chemotherapy after intra cranial disease progression

(for patients with extracranial disease progression only, WBI was not recommended). In the WBI group, 59 (81%) of 73 switched to icotinib only, and seven of these patients in the WBI group were still receiving icotinib treatment at the time of data cutoff.

Figure 2: Intracranial progression-free survival in the modified intention-to-treat population(A) Kaplan-Meier survival curve. (B) Forest plot of key subgroups. WBI=whole brain irradiation. HR=hazard ratio. PFS=progression-free survival. ECOG=Eastern Cooperative Oncology Group. EGFR=epidermal growth factor receptor.

Sex Male Female

34/64 46/94

Age (years) ≤60 >60

44/97 36/61

ECOG performance status 0 1

6/20 74/137

Smoking status No Yes

55/112 25/46

EGFR mutation status Exon 19 Del Exon 21(L858R) Del Uncommon mutation

44/93 33/57 3/8

Symptoms of brain metastases No Yes

64/132 16/26

Treatment line First Second

75/145 5/13

0·80 (0·40–1·61) 0·43 (0·22–0·80)

0·47 (0·25–0·87) 0·69 (0·34–1·40)

2·17 (0·24–19·38) 0·50 (0·31–0·80)

0·46 (0·27–0·81) 0·84 (0·35–2·03)

0·39 (0·20–0·75) 0·79 (0·37–1·67) 1·80 (0·16–20·70)

0·59 (0·35–0·99) 0·57 (0·21–1·53)

0·60 (0·37–0·97) 0·16 (0·01–1·93)

0·256

0·289

0·201

0·171

0·392

0·641

0·227

Number at riskIcotinib

WBI

IcotinibWBI

0·5320·007

0·0140·305

0·4790·004

0·0050·696

0·0040·5260·633

0·0430·254

0·0340·106

Favours icotinib Favours WBI

Events (n)/patients (n)

Intracranial PFS HR (95% CI) pinteractionp value

100

80

60

40

20

00 6 12 18 24 30

8573

4815

235

45

10

00

Follow-up (months)

n Events Median (months, 95% CI)8573

4634

10·0 (5·6–14·4) 4·8 (2·4–7·2)

HR (95% CI) 0·56 (0·36–0·90); p=0·014

0·1 0·2 0·5 1 2 5 10

A

B

Intra

cran

ial P

FS (%

)


WBI


WBI


WBI

IcotinibWBI

100

80

60

40

20

0

100

80

60

40

20

0

100

80

60

40

20

0

0 6 12 18 24 30

0 12 4824 36

0 12 24 36Follow-up (months)

n EventsMedian (months, 95% CI)

8573

7966

6·8 (5·7–7·9) 3·4 (2·1–4·8)

HR (95% CI) 0·44 (0·31–0·63); p<0·0001

IcotinibWBI


8573

4237

18·0 (15·1–20·9)20·5 (17·0–24·1)

HR (95% CI) 0·93 (0·60–1·44); p=0·734

IcotinibWBI


8573

2629

18·0 (15·1–20·9) 19·0 (12·1–25·9)

HR (95% CI) 0·75 (0·44–1·27); p=0·284

Prog

ress

ion-

free s

urvi

val (

%)

Over

all s

urvi

val (

%)

Incr

ease

d br

ain

met

asta

ses s

ympt

oms (

%)

A

C

B

8573

4512

165

40

10

00

8573

6349

128

21

00

8573

3028

43

11

Figure 3: Progression-free survival, overall survival, and time to increased symptoms of brain metastases in the modified intention-to-treat population(A) Progression-free survival. Tick marks represent data censored at the last time the patient was known to be alive and without disease progression. (B) Overall survival. Tick marks represent data censored at the last time the patient was known to be alive. (C) Time to increased symptoms of brain metastases. WBI=whole-brain irradiation. HR=hazard ratio.

Survie sans progression neurologique

Taux de réponse:Thérapie ciblée: 65%RT panencephalique: 37%

Yang et al. Lancet Resp Med 2017

Evolution

Thérapie ciblée efficace pendant 24 mois

A pu continuer à travailler

Survie: 3 ans

Messages

L’analyse moléculaire fait désormais partie intégrante du diagnostic des tumeurs cérébrales

Il y a des progrès dans le traitement des glioblastomes

Les traitements systémiques jouent un rôle croissantdans les métastases cérébrales

Documents

Actualités en Neuro-Oncologie - cen-neurologie.fr · TMZ 229 66 35 18 9 2 0 6 12 18 24 30 0.9 1.0 TTFields / TMZ TMZ Alone 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 of S months PFS TTFields