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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
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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
POST IASLCMilano 8 NOV 2013
Oncologia Medica
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
POST IASLCMilano 8 NOV 2013
Oncologia Medica
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
POST IASLCMilano 8 NOV 2013
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
POST IASLCMilano 8 NOV 2013
Rintoul et al., WCLC 2013
175 patients
Oncologia Medica
POST IASLCMilano 8 NOV 2013
The mesoVATs trial: survival
Rintoul et al., WCLC 2013
Oncologia Medica
POST IASLCMilano 8 NOV 2013
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
POST IASLCMilano 8 NOV 2013
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
POST IASLCMilano 8 NOV 2013
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
POST IASLCMilano 8 NOV 2013
Oncologia Medica
POST IASLCMilano 8 NOV 2013
Oncologia Medica
POST IASLCMilano 8 NOV 2013
Hassan et al., WCLC 2013
Oncologia Medica
POST IASLCMilano 8 NOV 2013
Hassan et al., WCLC 2013
Oncologia Medica
POST IASLCMilano 8 NOV 2013
Hassan et al., WCLC 2013
Oncologia Medica
POST IASLCMilano 8 NOV 2013
Hassan et al., WCLC 2013
SS1P plus PC in MPM
Oncologia Medica
POST IASLCMilano 8 NOV 2013
Hassan et al., WCLC 2013
SS1P plus PC in MPM
Oncologia Medica
VINORELBINE and BRCA1 in MPM
9
Busacca et al., J Pathol 2012
61.1 %
38.9 %
Sensitivity to vinorelbine correlates with BRCA1 expression
in 6 mesothelioma cell lines.
POST IASLCMilano 8 NOV 2013
Oncologia Medica
VINORELBINE and BRCA1 in MPM
9
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
POST IASLCMilano 8 NOV 2013
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
POST IASLCMilano 8 NOV 2013
Oncologia Medica
Immunotherapy in MPM: tremelimumab
Calabrò et al., Lancet Oncol 2013POST IASLC
Milano 8 NOV 2013
Oncologia Medica
23
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
POST IASLCMilano 8 NOV 2013
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)
POST IASLCMilano 8 NOV 2013
Oncologia Medica
POST IASLCMilano 8 NOV 2013
Volumetric CT tumor response in MPM
Armato et al., WCLC 2013
Oncologia Medica
POST IASLCMilano 8 NOV 2013
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
POST IASLCMilano 8 NOV 2013
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
POST IASLCMilano 8 NOV 2013
Gene sequencing
CDKN2A, NF2 and BAP1 are the most frequently mutated genes in MPM
Oncologia Medica
POST IASLCMilano 8 NOV 2013
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
POST IASLCMilano 8 NOV 2013
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.
