MALIGNANT PLEURAL MESOTHELIOMA
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Oncologia Medica POST IASLC Milano 8 NOV 2013 MALIGNANT PLEURAL MESOTHELIOMA Giovanni Luca Ceresoli Humanitas Gavazzeni Bergamo
description
MALIGNANT PLEURAL MESOTHELIOMA. Giovanni Luca Ceresoli Humanitas Gavazzeni Bergamo. Unmet needs in MPM. Role of surgery and radiotherapy (IMRT) How to improve results of first-line treatments Role of second-line treatments Response radiological assessment - PowerPoint PPT Presentation
Transcript of MALIGNANT PLEURAL MESOTHELIOMA
Oncologia Medica
POST IASLCMilano 8 NOV 2013
MALIGNANT PLEURAL MESOTHELIOMA
Giovanni Luca CeresoliHumanitas Gavazzeni
Bergamo
Oncologia Medica
Unmet needs in MPM
1. Role of surgery and radiotherapy (IMRT)2. How to improve results of first-line treatments3. Role of second-line treatments4. Response radiological assessment5. Better understanding of the biology of the
disease
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MPM in WCLC 2013
1 Abstract presented during Plenary Session1 Oral Abstract Session2 Mini Oral Abstract Sessions3 Poster Sessions2 Mini-Simposia5 MTE Sessions
SURGERY & MULTIMODALITY TREATMENTSSECOND-LINE TREATMENTS
RESPONSE EVALUATIONBIOLOGY
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Role of surgery (P/D vs EPP)
Bille et al., WCLC 2013POST IASLC
Milano 8 NOV 2013
1227 evaluable pts, from 1982 to 2012 in 6 Institutions
Non surgical group imbalanced: older than surgical pts, less epithelioid, less treated with chemotherapy
P/D not homogeneous (different centers, 30-yr span)
Oncologia Medica
POST IASLCMilano 8 NOV 2013
Bille et al., WCLC 2013
Role of surgery (P/D vs EPP)
(age <70 yrs, epitheliod type, chemotherapy)
313 pts with favorable prognostic factors (25%)
Oncologia Medica
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P/D in MPM: different techniques
IMIG/IASLC consensus, JTO 2011; Cao et al., WCLC 2013
Oncologia Medica
Primary endpoint: 1-yr OS; secondary endpoints: QoL, control of pleural effusion
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Rintoul et al., WCLC 2013
175 patients
Oncologia Medica
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The mesoVATs trial: survival
Rintoul et al., WCLC 2013
Oncologia Medica
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The mesoVATs trial: QoL & pleural effusion control
1. No difference in overall survival;2. P/D has a modest advantage in QoL and effusion control;3. P/D: more toxicities & lenght of stay in hospital, more expensive.
Rintoul et al., WCLC 2013
Oncologia Medica
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Hemithoracic pleural IMRT after P/D
Wu et al., WCLC 2013
20 pts have completed RT, 1 is on treatment. 5 pts with grade 2 RP, 1 grade 3; early intervention with steroids effective in controlling RP.
Oncologia Medica
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PI3K/mTOR INHIBITORS IN SECOND-LINE SETTING IN MPM
GDC 0980, 30 mg orally dailyPhase I + MPM expanded cohort at P2RDOverall 33 pts; 4 PR, RR 12%
PI3K mutations and pTEN loss uncommon Dolly et al., WCLC 2013
Oncologia Medica
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Oncologia Medica
POST IASLCMilano 8 NOV 2013
Oncologia Medica
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Hassan et al., WCLC 2013
Oncologia Medica
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Hassan et al., WCLC 2013
Oncologia Medica
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Hassan et al., WCLC 2013
Oncologia Medica
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Hassan et al., WCLC 2013
SS1P plus PC in MPM
Oncologia Medica
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Hassan et al., WCLC 2013
SS1P plus PC in MPM
Oncologia Medica
VINORELBINE and BRCA1 in MPM
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Busacca et al., J Pathol 2012
61.1 %
38.9 %
Sensitivity to vinorelbine correlates with BRCA1 expression
in 6 mesothelioma cell lines.
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Oncologia Medica
VINORELBINE and BRCA1 in MPM
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Randomised phase II trial of oral vinorelbine as second-line therapy for patients with MPM expressing BRCA1 – VIM trial
Relapsed MPM R
Weekly oral VINORELBINE + ASC
ASC (active symptom control)2:1
BRCA1 expression IHC will be evaluated as a stratification factor.Primary endpoint: overall survival.
114 participants required (76 VNR, 38 ASC)
Fennell et al., Poster Session 2 Mesothelioma, P2.14-013
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Oncologia Medica
• Tremelimumab (CP675,206)Pfizer/MedImmuneIgG2 isotype antibodyhalf-life time: 22 days
T cell
TCRCTLA-4
APC
MHC B7
T-cell potentiation
CTLA-4 mAb
Tremelimumab: an anti-CTLA-4 mAb
T-cell costimulatory receptors
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Immunotherapy in MPM: tremelimumab
Calabrò et al., Lancet Oncol 2013POST IASLC
Milano 8 NOV 2013
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Randomized TREMELIMUMAB: PLACEBO 2:1 (120/60) Stratification Factors
European Organization for Research and Treatment of Cancer (EORTC) status (low-risk vs high-risk)
Line of therapy (second vs third) Anatomical site (pleural vs peritoneal)
Treme 10mg/kg Q12Wk
(Non Dosing visits: V9, 11, 13)Relapsed/Refractory Malignant Mesothelioma (2nd/3rd line)
Total recruitment = 180 patients (OS events)
PlaceboQ4Wk
x 6 doses
Placebo Q12Wk
(Non Dosing visits: V9, 11, 13)
Treme 10mg/kgQ4Wk
x 6 doses
Phase II Multicenter, International, Randomized Trial of Tremelimumab in Patients With Unresectable
Mesothelioma (Trial D4880C00003 Sponsored by MedImmune)
2:1
Primary endpoint: OS
Kindler et al., Poster Session 2 Mesothelioma, P2.14-015
NCT01843374
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Oncologia Medica
Pemetrexed and cisplatin increase cancer stem cells (CSCs). FAK inhibitors decrease CSCs in mesothelioma models. NF2 tumor suppressor gene is inactivated in 40-50% of MPM
pts, resulting in lack of expression of functional Merlin protein. Mesothelioma cells that lack NF2/Merlin are especially
sensitive to FAK inhibitors.
Focal adhesion kinases (FAK) inhibitors in MPM
Poulikakos et al., Oncogene 2006POST IASLC
Milano 8 NOV 2013
Oncologia Medica
Focal adhesion kinases (FAK) inhibitors in MPM: VS-6063
Keegan et al., Poster Session 2 Mesothelioma, P2.14-014
1:1
Primary Endpoint: PFSApprox. 370 pts included
(or Carbo/Cis)
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Volumetric CT tumor response in MPM
Armato et al., WCLC 2013
Oncologia Medica
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Armato et al., WCLC 2013
Volumetric CT tumor response in MPMSemi-automated method to determine MPM volume from CT scans retrospectively collected from 70 patients undergoing standard of care chemotherapy.
Oncologia Medica
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Volumetric CT tumor response in MPM
Friedberg et al., WCLC 2013
41 consecutive radical P/D
CONCLUSIONS1.OS and PFS were correlated with tumor volume (TV). 2.All radiographic techniques underestimated actual TV.3.Estimates closer to actual TV as they became less automated and more manual.
Oncologia Medica
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Gene sequencing
CDKN2A, NF2 and BAP1 are the most frequently mutated genes in MPM
Oncologia Medica
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CUTANEOUS MELANOMA
UVEAL MELANOMA
MALIGNANT MESOTHELIOMA
MELANOCYTIC BAP-1 MUTATED ATYPICAL
INTRADERMAL TUMOURS
BAP-1 SYNDROME
Carbone et al., WCLC 2013
Oncologia Medica
Ujiiee et al., WCLC 2013POST IASLC
Milano 8 NOV 2013
Tissue microarray from 170 epithelioid MPM, MSKCC
Oncologia Medica
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Conclusions
1. The debate on surgery in MPM continues: expanding role of P/D, mesoVATs.
2. IMRT after P/D or no surgery.
3. Medical treatment: SS1P plus PC promising; new options/studies: BRCA1/vinorelbine, tremelimumab, FAK-inhibitors.
4. Volumetric CT response evaluation: pitfalls and challanges.
5. Biology: gene sequencing, BAP1 syndrome. Role of the immune system.
