mesothelioom, een sluipmoordenaar - asbestslachtoffer...2017/05/27 · robert peric...
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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