Therapy of Mesothelioma in 2019 - Paul Baas Dept of Thoracic Oncology The Netherlands Cancer Institute Preceptorship course, March 9, 2019 ...
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Therapy of Mesothelioma
in 2019
Paul Baas
Dept of Thoracic Oncology
The Netherlands Cancer Institute
Preceptorship course, March 9, 2019
Manchester, UK
Disclosures • Grants from BMS, Pfizer and Roche • Advisor for MSD, BMS, Aduro and Verastem Some slides with courtecy of Dr A Tsao
British Humour
The treatment options 2018 • Chemotherapy provides symptom relief and increased OS • The combination of cisplatin and anti-folate is standard • 80% of tumors recur after 2 years • Median OS is 16 – 18.8 months • Multimodality studies use: • neoadjuvant chemotherapy • extrapleural pneumonectomy or pleurectomy/decortication • with or without RT
Comparative evolution of targeted therapy for
mesothelioma vs lung cancer
PDL1
SqNSCLC EML4-ALK
NSCL
C NSq-NSCLC
chemosensitive
ROS1
EGFR
EGFR-T790M
MPM BAP1?
time
Mesothelin?
New targets • Mesothelin • Arginine deprivation • Bevacizumab +… • BAP1 – Somatic mutations in 20-60 % – Germline mutations in 1-2 % • Immunotherapy
Stratifying by cell surface target expression
Genetic and Epigenetic stratification
Discovering new drug-gene interactions
IO therapy
Presentation Number: SCO6.02– Stratified Therapy for Pleural Mesothelioma
Mesothelin is a selective marker for targeting
mesothelioma
SS1P
Hassan et al, 2013 Sci Trans Med
Presentation Number: SCO6.02– Stratified Therapy for Pleural Mesothelioma Clinical Cancer Research 2014, vol 8
Anetumab Ravtansine in patients in the relapsed setting
Initial phase
Presentation Number: Presentation Title – Presenting Author
Phase II Anetumab Ravtansine as 2nd Line Treatment for Malignant
Pleural Mesothelioma (MPM) - NCT02610140
Anetumab ravtansine (BAY
N=210 94-9343)
6.5mg/kg d1 q3w
MPM Primary : PFS
ECOG PS 0-1
Unresectable R Secondary: OS, RR, PRO
Epithelioid
Vinorelbine
30mg/m2 iv weekly
PI: Dr R Hassan, NCIStratifying by cell surface target expression
Genetic and Epigenetic stratification
Discovering new drug-gene interactions
IO therapy
Presentation Number: CO6.02– Stratified Therapy for Pleural MesotheliomaPresentation Number: SCO6.02– Stratified Therapy for Pleural Mesothelioma Szlosarek et al,
JAMA oncology 2016ATOMIC-Meso Phase II/III Trial Schema Background: Tumor cells require Arginine for cell division. Sarcomatoid tumors lack ASS1 With ADI-PEG20 the blood is depleted from Arginine and tumor cells will die. PI: Dr P Szlozarek, NCI Clinical Trials.gov NCT 02709512
ADAM randomised trial design
Sarcomatoid and biphasic MPM
ADI-PEG20 46
+
97 70 BSC
• MPM ASS1 ASS1
PFS
• PS 0-1
• chemonaive
screen Negative
R OS
BSC
2:1
ASS1 24
Positive
Co-Primary objective: PFS and ORR
Secondary objectives: disease-control rate (DCR), OS, duration of response, and safety
Plan: two stages Phase II for 140 pts; Phase III for 232 ptsStratifying by cell surface target expression
Genetic and Epigenetic stratification
Discovering new drug-gene interactions
IO therapy
Presentation Number: CO6.02– Stratified Therapy for Pleural MesotheliomaBAP1 Tumor suppressor regulating target genes in: • Transcription • DNA damage repair • Cell cycle control • Cellular differentiation
BAP1 mutation exposes a vulnerability to EZH2 inhibition in mesothelioma
Compacted
BAP1 Chromatin
inactivation
Transcriptional
suppression
La Fave et al, Nat Med 2015
Presentation Number: SCO6.02– Stratified Therapy for Pleural MesotheliomaEZH2 inhibitors
Modern
Medicine
BAP1 mutant Traditional Chinese
Medicine
BAP1 wildtype
LaFave, Nature Medicine, 2015 Kageyama et al. Biomedicine & Pharmacotherapy
105, 2018; 690-696Study of the EZH2 Inhibitor Tazemetostat in Malignant
Mesothelioma
MPM/peritoneal/any Histology
Stage 1
All/PK
Phase II A open label/single arm
US, France, UK
Oral Tazemetostat 800mg BID
Stage 2
BAP1
negative
Endpoint. Response rate
ASCO 2018:
DCR 50% at 12 weeks
DCR 26% at 24 weeks
(NCT02860286)A platform for accelerating stratified therapy
Mesothelioma Stratified Therapy (MiST)
Open label /single arm/2 stage
Presentation Number: SCO6.02– Stratified Therapy for Pleural MesotheliomaStratifying by cell surface target expression
Genetic and Epigenetic stratification
Discovering new drug-gene interactions
IO therapy
Presentation Number: CO6.02– Stratified Therapy for Pleural MesotheliomaWhy would IO work in MPM • PD-L1 expression • Mutational Load • Chromotripsis
NCCN update 2017 • For Subsequent Systemic Therapy, the following are added as treatment options: – Nivolumab-ipilimumab – Pembrolizumab
BEAT meso (ETOP 13-18) 320 pts
Summary of PD-1/PD-L1 + CTLA4 in MPM
Median PFS Median OS PD-L1 IHC
Agents NCT Population N ORR DCR TMB
(months) (months) status
NIBIT-Meso-1
14.1 median
Tremelimumab + 02588131 1st or 2nd line 40 27.5% 65% NR NR NR
duration DC
Durvalumab1
INITIATE
At least 1 prior
Ipilimumab + 03048474 33 28% 50% 4.7 NR NR NR
therapy
Nivolumab4
IFCT MAPS 2
Nivo-Ipi not Correlates
Ipilimumab + Nivo-Ipi 24.2% Nivo-Ipi 50% Nivo-Ipi 5.6 vs
02716272 2nd or 3rd line 125 reached vs with NR
Nivolumab vs Nivo 17.5% Nivo 44.4% Nivo 4
Nivo 10.4 response
Nivolumab2,3
NR – not reported
Safety > Grade 3 toxicity Grade 5
NIBIT-Meso-1 17.5% -
INITIATE 15% -
MAPS2 16% 3*
*treatment-related deaths 1 fulminant hepatitis, 1 encephalitis, 1 acute RF
1Calabro et al. IASLC Abstract 9202, 2017; 2Zalcman et al. ESMO abstract 2017; 3Scherpereel et al. Abstract LBA 8507, 2017;
4Baas et al. IASLC Abstract 9389Selected Ongoing I/O Frontline
Unresectable Studies
Planned Primary
Agents Phase NCT Target Population
N endpoint
CheckMate 743
PD-1+CTLA4
Ipilimumab-nivolumab vs III 02899299 Frontline 600 OS
inhibitors vs chemo
platinum-pemetrexed
Durvalumab +
PD-L1 inhibitor +
cisplatin-pemetrexed II 02899195 Frontline 55 OS
chemo
(PrE0505)
Durvalumab +
PD-L1 inhibitor + 6 month
cisplatin-pemetrexed II - Frontline 54
chemo PFS
(DREAM – Australia ALTG)
Pembrolizumab + cisplatin-
pemetrexed vs cisplatin-
PD-1 inhibitor +
pemetrexed vs pemetrexed II 02784171 Frontline 126 PFS
chemo
alone
(Canadian Cancer Trials Group)
ONCOS-102 + Immune-priming GM-
Safety
cisplatin-pemetrexed Ib/II 02879669 CSF coding oncolytic Frontline 30
Toxicity
(Spain) adenovirus + chemo
NCI Clinical Trials.gov March 2017Conclusions new therapeutic options in MPM • Mesothelin directed studies so far not successful • Treatment option for sarcomatoid type emerging • BAP1 as possible new target • Combination of IO or IO + chemotherapy will probably become standard
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