Rintoul et al., WCLC 2013

MALIGNANT PLEURAL
MESOTHELIOMA
Giovanni Luca Ceresoli
Humanitas Gavazzeni Bergamo
Oncologia
Medica
POST IASLC
Milano 8 NOV 2013
Unmet needs in MPM
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
MPM in WCLC 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
Role of surgery (P/D vs EPP)
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
Role of surgery (P/D vs EPP)
(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
P/D in MPM: different techniques
IMIG/IASLC consensus, JTO 2011; Cao et al., WCLC 2013
Oncologia
Medica
POST IASLC
Milano 8 NOV 2013
175 patients
Primary endpoint: 1-yr OS; secondary endpoints: QoL, control of pleural effusion
Rintoul et al., WCLC 2013
Oncologia
Medica
POST IASLC
Milano 8 NOV 2013
The mesoVATs trial: survival
Rintoul et al., WCLC 2013
Oncologia
Medica
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.
Rintoul et al., WCLC 2013
Oncologia
Medica
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.
Wu et al., WCLC 2013
Oncologia
Medica
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
Hassan et al., WCLC 2013
Oncologia
Medica
POST IASLC
Milano 8 NOV 2013
Hassan et al., WCLC 2013
Oncologia
Medica
POST IASLC
Milano 8 NOV 2013
Hassan et al., WCLC 2013
Oncologia
Medica
POST IASLC
Milano 8 NOV 2013
SS1P plus PC in MPM
Hassan et al., WCLC 2013
Oncologia
Medica
POST IASLC
Milano 8 NOV 2013
SS1P plus PC in MPM
Hassan et al., WCLC 2013
Oncologia
Medica
POST IASLC
Milano 8 NOV 2013
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
9
Oncologia
Medica
POST IASLC
Milano 8 NOV 2013
VINORELBINE and BRCA1 in MPM
Randomised phase II trial of oral vinorelbine as second-line therapy
for patients with MPM expressing BRCA1 – VIM trial
Relapsed
MPM
Weekly oral VINORELBINE + ASC
R
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
9
Oncologia
Medica
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
CTLA-4
TCR
CTLA-4 mAb
MHC
B7
APC
Oncologia
Medica
POST IASLC
Milano 8 NOV 2013
Immunotherapy in MPM: tremelimumab
Calabrò et al., Lancet Oncol 2013
Oncologia
Medica
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 (2nd/3rd line)
Total recruitment = 180 patients (OS
events)
2:1
Treme 10mg/kg
Q4Wk
x 6 doses
Placebo
Q4Wk
x 6 doses
Primary endpoint: OS
Treme 10mg/kg
Q12Wk
(Non Dosing visits: V9, 11, 13)
Placebo
Q12Wk
(Non Dosing visits: V9, 11, 13)
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)
Kindler et al., Poster Session 2 Mesothelioma, P2.14-015
Oncologia
Medica
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
(or Carbo/Cis)
1:1
Primary Endpoint: PFS
Approx. 370 pts included
Keegan et al., Poster Session 2 Mesothelioma, P2.14-014
Oncologia
Medica
POST IASLC
Milano 8 NOV 2013
Volumetric CT tumor response in MPM
Armato et al., WCLC 2013
Oncologia
Medica
POST IASLC
Milano 8 NOV 2013
Volumetric CT tumor response in MPM
Semi-automated method to determine MPM volume from CT scans
retrospectively collected from 70 patients undergoing standard of care
chemotherapy.
Armato et al., WCLC 2013
Oncologia
Medica
POST IASLC
Milano 8 NOV 2013
Volumetric CT tumor response in MPM
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
Oncologia
Medica
POST IASLC
Milano 8 NOV 2013
Gene sequencing
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
MELANOCYTIC BAP-1
MUTATED ATYPICAL
INTRADERMAL
TUMOURS
CUTANEOUS MELANOMA
Carbone et al., WCLC 2013
Oncologia
Medica
POST IASLC
Milano 8 NOV 2013
Tissue microarray from 170 epithelioid MPM, MSKCC
Ujiiee et al., WCLC 2013
Oncologia
Medica
POST IASLC
Milano 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.
Oncologia
Medica
POST IASLC
Milano 8 NOV 2013