Transcript Rintoul et al., WCLC 2013
Oncologia Medica
MALIGNANT PLEURAL MESOTHELIOMA
Giovanni Luca Ceresoli Humanitas Gavazzeni Bergamo
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
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
The mesoVATs trial: survival
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
SS1P plus PC in MPM
Oncologia Medica
Hassan et al., WCLC 2013
POST IASLC Milano 8 NOV 2013
SS1P plus PC in MPM
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 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)
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 (low risk 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
Volumetric CT tumor response in MPM
Oncologia Medica
Armato et al., WCLC 2013
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.
Oncologia Medica
Armato et al., WCLC 2013
POST IASLC Milano 8 NOV 2013
Volumetric CT tumor response in MPM
Oncologia Medica
41 consecutive radical P/D CONCLUSIONS 1. OS and PFS were correlated with tumor volume (TV).
2. All radiographic more manual.
techniques underestimated actual TV.
3. Estimates closer to actual TV as they became less automated and
Friedberg et al., WCLC 2013
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 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
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