Oncologia
Medica
MALIGNANT PLEURAL
MESOTHELIOMA
Giovanni Luca Ceresoli
Humanitas Gavazzeni Bergamo
POST IASLC
Milano 8 NOV 2013

1. Role of surgery and radiotherapy (IMRT)
2. How to improve results of first-line treatments
3. Role of second-line treatments
4. Response radiological assessment
5. Better understanding of the biology of the disease
Oncologia
Medica
POST IASLC
Milano 8 NOV 2013

1 Abstract presented during Plenary Session
1 Oral Abstract Session
2 Mini Oral Abstract Sessions
3 Poster Sessions
2 Mini-Simposia
5 MTE Sessions
SURGERY & MULTIMODALITY TREATMENTS
SECOND-LINE TREATMENTS
RESPONSE EVALUATION
BIOLOGY
Oncologia
Medica
POST IASLC
Milano 8 NOV 2013

Non surgical group imbalanced: older than surgical pts, less epithelioid, less treated with chemotherapy
P/D not homogeneous (different centers, 30-yr span)
1227 evaluable pts, from 1982 to 2012 in 6 Institutions
Oncologia
Medica
Bille et al., WCLC 2013
POST IASLC
Milano 8 NOV 2013

(age <70 yrs, epitheliod type, chemotherapy)
313 pts with favorable prognostic factors (25%)
Oncologia
Medica
Bille et al., WCLC 2013
POST IASLC
Milano 8 NOV 2013

Oncologia
Medica
IMIG/IASLC consensus, JTO 2011; Cao et al., WCLC 2013
POST IASLC
Milano 8 NOV 2013

175 patients
Primary endpoint: 1-yr OS; secondary endpoints: QoL, control of pleural effusion
Oncologia
Medica
Rintoul et al., WCLC 2013
POST IASLC
Milano 8 NOV 2013

Oncologia
Medica
Rintoul et al., WCLC 2013
POST IASLC
Milano 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.
Oncologia
Medica
Rintoul et al., WCLC 2013
POST IASLC
Milano 8 NOV 2013

Hemithoracic pleural IMRT after P/D
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
Wu et al., WCLC 2013
POST IASLC
Milano 8 NOV 2013

PI3K/mTOR INHIBITORS IN SECOND-LINE SETTING IN MPM
GDC 0980 , 30 mg orally daily
Phase I + MPM expanded cohort at P2RD
Overall 33 pts; 4 PR, RR 12%
PI3K mutations and pTEN loss uncommon
Oncologia
Medica
Dolly et al., WCLC 2013
POST IASLC
Milano 8 NOV 2013

Oncologia
Medica
POST IASLC
Milano 8 NOV 2013

Oncologia
Medica
POST IASLC
Milano 8 NOV 2013

Oncologia
Medica
Hassan et al., WCLC 2013
POST IASLC
Milano 8 NOV 2013

Oncologia
Medica
Hassan et al., WCLC 2013
POST IASLC
Milano 8 NOV 2013

Oncologia
Medica
Hassan et al., WCLC 2013
POST IASLC
Milano 8 NOV 2013

Oncologia
Medica
Hassan et al., WCLC 2013
POST IASLC
Milano 8 NOV 2013

Oncologia
Medica
Hassan et al., WCLC 2013
POST IASLC
Milano 8 NOV 2013

9
Oncologia
Medica
VINORELBINE and BRCA1 in MPM
Sensitivity to vinorelbine correlates with BRCA1 expression in 6 mesothelioma cell lines.
38.9 %
61.1 %
Busacca et al., J Pathol 2012
POST IASLC
Milano 8 NOV 2013

9
VINORELBINE and BRCA1 in MPM
Randomised phase II trial of oral vinorelbine as second-line therapy for patients with MPM expressing BRCA1 – VIM trial
R
Weekly oral VINORELBINE + ASC
Relapsed
MPM
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)
Oncologia
Medica
Fennell et al., Poster Session 2 Mesothelioma, P2.14-013
POST IASLC
Milano 8 NOV 2013

Tremelimumab: an anti-CTLA-4 mAb
T-cell costimulatory receptors
• Tremelimumab (CP675,206)
Pfizer/MedImmune
IgG2 isotype antibody half-life time: 22 days
T-cell potentiation
T cell
TCR
MHC
APC
CTLA-4
B7
CTLA-4 mAb
Oncologia
Medica
POST IASLC
Milano 8 NOV 2013

Immunotherapy in MPM: tremelimumab
Oncologia
Medica
Calabrò et al., Lancet Oncol 2013
POST IASLC
Milano 8 NOV 2013

Phase II Multicenter, International, Randomized Trial of
Tremelimumab in Patients With Unresectable Mesothelioma
(Trial D4880C00003 Sponsored by MedImmune)
Relapsed/Refractory Malignant
Mesothelioma (2 nd /3 rd line)
Total recruitment = 180 patients (OS events)
2:1
Treme 10mg/kg
Q4Wk x 6 doses
Placebo
Q4Wk x 6 doses
Treme 10mg/kg
Q12Wk
(Non Dosing visits: V9, 11, 13)
Placebo
Q12Wk
(Non Dosing visits: V9, 11, 13)
Primary endpoint: OS
NCT01843374
 Randomized TREMELIMUMAB: PLACEBO 2:1 (120/60)
 Stratification Factors
 European Organization for Research and Treatment of Cancer (EORTC) status (lowrisk vs high-risk)
 Line of therapy (second vs third)
 Anatomical site (pleural vs peritoneal)
Oncologia
Medica
Kindler et al., Poster Session 2 Mesothelioma, P2.14-015
POST IASLC
Milano 8 NOV 2013
23

Focal adhesion kinases (FAK) inhibitors in MPM
 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.
Poulikakos et al., Oncogene 2006
Oncologia
Medica
POST IASLC
Milano 8 NOV 2013

Focal adhesion kinases (FAK) inhibitors in MPM: VS-6063
1:1
(or Carbo/Cis)
Primary Endpoint: PFS
Approx. 370 pts included
Oncologia
Medica
Keegan et al., Poster Session 2 Mesothelioma, P2.14-014
POST IASLC
Milano 8 NOV 2013

Oncologia
Medica
Armato et al., WCLC 2013
POST IASLC
Milano 8 NOV 2013

Semi-automated method to determine MPM volume from CT scans retrospectively collected from 70 patients undergoing standard of care chemotherapy.
Oncologia
Medica
Armato et al., WCLC 2013
POST IASLC
Milano 8 NOV 2013

Oncologia
Medica
41 consecutive radical P/D
CONCLUSIONS
1. 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.
Friedberg et al., WCLC 2013
POST IASLC
Milano 8 NOV 2013

CDKN2A, NF2 and BAP1 are the most frequently mutated genes in MPM
Oncologia
Medica
POST IASLC
Milano 8 NOV 2013

BAP-1 SYNDROME
MALIGNANT
MESOTHELIOMA
UVEAL MELANOMA
CUTANEOUS MELANOMA
Oncologia
Medica
MELANOCYTIC BAP-1
MUTATED ATYPICAL
INTRADERMAL
TUMOURS
Carbone et al., WCLC 2013
POST IASLC
Milano 8 NOV 2013

Tissue microarray from 170 epithelioid MPM, MSKCC
Oncologia
Medica
Ujiiee et al., WCLC 2013
POST IASLC
Milano 8 NOV 2013

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.
Oncologia
Medica
POST IASLC
Milano 8 NOV 2013