Mesothelioom,

Een sluipmoordenaar

Robert Peric

Longarts-oncoloog

Erasmus MC,

Rotterdam

sterk

duurzaam

isolerend

goedkoop

Asbest

Holiday Inn 1942

Kennis

Oude Grieken

“Koop geen slaven die in asbestmijnen hebben gewerkt”

1767

Kanker van het borstvlies (Joseph Lieutaud)

1920’

Eerste publicatie vermoeden van relatie asbest– fibrose

(asbestose)

Term mesothelioom

1930’

Verdenking relatie asbest - mesothelioom

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J Lancet. 1960 Nov;80:511­4.

Primary malignant mesothelioma of the pleura.

EISENSTADT HB, WILSON FW.

PMID: 13726186 [PubMed ­ indexed for MEDLINE]

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Abstract

MeSH Terms, Supplementary Concepts

Medical

Mesothelioma, malignant ­ Genetic Alliance

Cancer ­ MedlinePlus Health Information

Lung Cancer ­ MedlinePlus Health Information

Mesothelioma ­ MedlinePlus Health Information

LinkOut ­ more resources

Wat is wat?

Asbestkanker

Longvlieskanker

Borstvlieskanker

Mesothelioom

Maligne pleuraal mesothelioom

Nederland

1969

Asbest in een bedrijfsbevolking, een onderzoek naar het voorkomen

van asbestlichaampjes en mesotheliomen op een scheepswerf en

machinefabriek

Jan Stumphius

Centraal Bureau voor de Statistiek

Bron:instituut asbestslachtoffers

Bron:instituut asbestslachtoffers

Relatie blootstelling en kans op asbestkanker

Behandeling

JAMA 1919

1943

Alfred Gilman & Louis Goodman

Gustaf Lindskog

NY Times

1946

Chemotherapie (cisplatin / pemetrexed)

Gemiddeld bescheiden verlenging leven

Vermindering / uitstel klachten

Slide 25

Presented By Gerard Zalcman at 2015 ASCO Annual Meeting

KAN DAT NIET BETER?

IMMUNOTHERAPIE

Verkrijgen van dendritische cellen

Kweken van dendritische cellen en

“trainen” tegen tumorcellen

Toedienen van dendritische cellen

Dendritische celtherapie

Weinig bijwerkingen

Nu bijna 30 patiënten behandeld

Dendritische celtherapie en

cyclofosfamide laat een hoopvolle

overleving zien

Cornelissen, submitted

Maanden na start behandeling

Pe

rce

nta

ge

le

ve

nd

e p

atië

nte

n

25

MPM cells express receptor TKs that are targetable by nintedanib

OA22.02: Nintedanib plus Pemetrexed/Cisplatin in

Patients with MPM: Phase II Findings from the Placebo-

Controlled LUME-Meso Trial – Grosso F, et al

Study objective

To evaluate the efficacy and safety of nintedanib plus pemetrexed/cisplatin

in patients with advanced malignant pleural mesothelioma

Grosso et al. J Thorac Oncol 2016; 11(suppl): abstr OA22.02

Primary endpoint

• PFS (investigator assessment)

Secondary endpoints

• OS, ORR (investigator assessment)

R

1:1

PD

PD

Stratification

• Histology (epithelioid vs. biphasic)

Key patient inclusion criteria

• Unresectable malignant

pleural mesothelioma

• Epithelioid and biphasic

histology

• Chemotherapy naïve

• ECOG PS 0–1

(n=87)

Placebo 200 mg bid +

pemetrexed/cisplatin*

(n=43)

Nintedanib 200 mg bid

+ pemetrexed/cisplatin*

(n=44)

*500 mg/m2/75 mg/m2 IV q3w.

Maximum treatment duration: 6 cycles

Nintedanib

maintenance

Placebo

maintenance

Non-PD

Non-PD

OA22.02: Nintedanib plus Pemetrexed/Cisplatin in

Patients with MPM: Phase II Findings from the Placebo-

Controlled LUME-Meso Trial – Grosso F, et al

Key results

ORR was 59% vs. 44% with nintedanib vs. placebo

Conclusion

Addition of nintedanib to pemetrexed/cisplatin in malignant pleural mesothelioma led

to an improvement in PFS with a safety profile consistent with other studies

Grosso et al. J Thorac Oncol 2016; 11(suppl): abstr OA22.02

Nintedanib Placebo

Median PFS (95%CI), months 9.4 (6.7, 11.2) 5.7 (5.5, 7.0)

HR (95%CI); p-value 0.56 (0.34, 0.91); p=0.017

PF

S,

%

100

80

60

40

20

0

PFS

Time from randomisation, months

0

44

43

Patients at risk

2

38

38

4

35

32

6

27

16

8

22

9

10

15

4

12

12

3

14

4

2

16

2

2

18

2

1

20

1

1

22

0

1

24

0

26 28

A Phase II Trial of TTFields in combination with Pemetrexed and cisplatin or carboplatin

as First-line Treatment in Malignant Pleural Mesothelioma

EF-23 STELLAR Clinical Trial

Confidential

STELLAR - Study procedures

Confidential

Baseline Every

3 weeks:

Every

6 weeksRadiological

progression

Within 3 days

of radiological

progression

Every 2

months

Baseline within 28 days

prior to enrolment

Pemetrexed + Cisplatin/Carboplatin + TTFields

150kHz start on d1/C1

Chemotherapy (maximum of 6 cycles):

• Pemetrexed IV, 500 mg/m2 day 1 together with

• Cisplatin 75 mg/m2 day 1 OR

• carboplatin AUC 5 day 1

• Cycles will be repeated every 21 days for up to 6 cycles in the absence of progression or unacceptable toxicity

TTFields (until radiological progression):

• NovoTTF-100L System for at least 18 hours per day at 150 kHz

TTFields – Applying to patients

System

Overview1. Battery

2. Battery Rack

3. Battery Charger

4. Transducer Arrays

5. Connection Cable

6. Battery

7. NovoTTF-100L Device

8. Device Bag

9. Plug-in Power Supply

54

9

1

2

36

8

7

Confidential

TTFields – Applying to patients

Confidential

TTFields – Applying to patients

Confidential

Treatment Duration:

• Treatment with the device will be continuous

• breaks allowed for personal needs (e.g. showering, array exchange)

• Use the device for at least 18 hours a day on average

• An additional treatment break of 2 days will be allowed for every 21-day course of

TTFields

Anetumab Ravtansine

Randomized Phase II

Open label

2:1 Anetumab ravtansine vs vinorelbine

Toxicity; mainly eyes (cornea)

OA13.02: Phase II Trial of Pembrolizumab in Patients

with Malignant Mesothelioma (MM): Interim Analysis –

Kindler HL, et al

Study objective

To characterize pembrolizumab activity in a large, non-selected population of patients

with previously treated malignant mesothelioma

Kindler et al. J Thorac Oncol 2016; 11(suppl): abstr OA13.02

Secondary endpoints

• Toxicity, DCR, OS

Primary endpoints

• Determine the ORR in:

– an unselected population

– a PD-L1 positive population

• Determine the optimal threshold for PD-L1 expression

using the 22C3 antibody-based IHC assay

Pembrolizumab

200 mg IV q3wPD

Key patient inclusion criteria

• Histologically confirmed pleural or

peritoneal malignant mesothelioma

• Measurable disease

• ECOG PS 0−1

• Disease progression on/after

pemetrexed/platinum

• ≤2 prior regimens

(n=35)

OA13.02: Phase II Trial of Pembrolizumab in Patients

with Malignant Mesothelioma (MM): Interim Analysis –

Kindler HL, et al

Key results

Response rate with pembrolizumab was 21% and DCR was 80%

Median PFS was 6.2 months and median OS 11.9 months (95%CI 6.4,

NR)

Conclusion

In previously treated PD-L1 unselected patients with malignant

mesothelioma, pembrolizumab has robust activityKindler et al. J Thorac Oncol 2016; 11(suppl): abstr OA13.02

Responses n (%)

Partial response 7 (21)

Stable disease 20 (59)

Disease control rate 27 (80)

Median duration of

response* NR

*6 of the 7 responders remain alive and free from progression

Time, months

0.00

0.25

0.50

0.75

1.00

0 3 6 9 12 15 18

PFS

PF

S

Median PFS 6.2 months

(95%CI 3.1, 8.2)

DENIM studie

Internationale gerandomiseerde multicenter klinische studie naar

dendritische cel immunotherapie voor de behandeling van mesothelioom

Doel van de studie:

Aantonen dat de therapie levensverlengend werkt voor patiënten met

mesothelioom na het ondergaan van chemotherapie

Voldoen aan eisen van EMA & FDA om de therapie te registreren en op

de markt te brengen

DENIM studie

Fase II/III klinische studie

Protocol opgesteld na overleg EMA & FDA mbt registratie eisen

Randomisatie van niet-progressieve patiënten na 4 – 6 cycli

chemotherapie

Consortium met 8 partners: Erasmus MC – prof. Joachim Aerts (coordinator)

CHRU Lille – prof. Arnaud Scherpereel

University Hospital Ancona – prof. Rossana Berardi

UZ Antwerpen – prof. Jan van Meerbeeck

NKI-AVL – prof. Paul Baas

University of Leicester – prof. Dean Fennell

European Cancer Patient Coalition – Kalliopi Kristoforidi

Amphera – Ilona Enninga

Opzet van de studie

Inclusie eerste patient: voorjaar 2017 (einde studie: december 2019)

Nu: productie PheraLys in clean rooms Erasmus MC

Groep 1: MesoPher + BSC (112 patiënten)

Groep 2: BSC (112 patiënten)

Inclusiecriteria:

Niet progressief na 4 – 6 cycli antifolate/cisplatin chemotherapie

Diagnose bevestigd mbv histologie & CT scan

Measurable disease volgens RECIST criteria op CT scan

> 18 jaar

WHO-ECOG status 0 of 1

Uitkomstmaten

Primaire uitkomstmaat: overall survival

Secundaire uitkomstmaten:

- % overleving 6, 12, 18 maanden na randomisatie

- progression free survival

- QoL

- veiligheid & tolerantie, immunogeniciteit

- effect op immuun-gerelateerde cytokines in bloed, tumor antigenen

- overall response rate

Team

Kliniek

Prof JGJV Aerts

Dr Cornelissen

J van Dijke

H Hakkenberk

Dr M de Jonge

Dr van der Leest

Drs APWM Maat

Dr A Odink

B Koning

Drs Peric

Dr M van der Pol

Drs J Praag

Drs M Rossius

E Stuyts

Dr J von der Thusen

Dr R Valkema

Drs van der Wall

Preklinische research

K Bezemer

F Dammeijer

P de Goeie

Dr JPJJ Hegmans

Prof RW Hendriks

M Kaijen

Drs S Lievense

L. Noordam

M Poncin

S Sittig

Klinische research

A van Efferen

LM Cavazza

A Geel

M Gerrits

E. Van Helden

L van der Hove

T Winter