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MALIGNANT PLEURAL MESOTHELIOMA

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

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MALIGNANT PLEURAL MESOTHELIOMA

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  1. MALIGNANT PLEURAL MESOTHELIOMA Giovanni Luca Ceresoli HumanitasGavazzeni Bergamo POST IASLC Milano 8 NOV 2013

  2. 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 • Better understanding of the biology of the disease POST IASLC Milano 8 NOV 2013

  3. 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 POST IASLC Milano 8 NOV 2013

  4. Role of surgery (P/D vs EPP) Non surgical group imbalanced: older than surgical pts, less epithelioid, less treated with chemotherapy P/D nothomogeneous (different centers, 30-yr span) 1227 evaluablepts, from 1982 to 2012 in 6 Institutions Bille et al., WCLC 2013 POST IASLC Milano 8 NOV 2013

  5. Role of surgery (P/D vs EPP) (age <70 yrs, epitheliodtype, chemotherapy) 313 pts with favorableprognosticfactors (25%) Bille et al., WCLC 2013 POST IASLC Milano 8 NOV 2013

  6. P/D in MPM: different techniques IMIG/IASLC consensus, JTO 2011; Cao et al., WCLC 2013 POST IASLC Milano 8 NOV 2013

  7. 175 patients Primaryendpoint: 1-yr OS; secondaryendpoints: QoL, control of pleuraleffusion Rintoul et al., WCLC 2013 POST IASLC Milano 8 NOV 2013

  8. The mesoVATs trial: survival Rintoul et al., WCLC 2013 POST IASLC Milano 8 NOV 2013

  9. The mesoVATs trial: QoL & pleural effusion control • No difference in overall survival; • P/D has a modest advantage in QoL and effusion control; • P/D: more toxicities & lenght of stay in hospital, more expensive. Rintoul et al., WCLC 2013 POST IASLC Milano 8 NOV 2013

  10. 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 POST IASLC Milano 8 NOV 2013

  11. PI3K/mTOR INHIBITORS IN SECOND-LINE SETTING IN MPM GDC 0980, 30 mg orallydaily Phase I + MPM expandedcohortat P2RD Overall 33 pts; 4 PR, RR 12% PI3K mutations and pTENlossuncommon Dolly et al., WCLC 2013 POST IASLC Milano 8 NOV 2013

  12. POST IASLC Milano 8 NOV 2013

  13. POST IASLC Milano 8 NOV 2013

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

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

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

  17. SS1P plus PC in MPM Hassan et al., WCLC 2013 POST IASLC Milano 8 NOV 2013

  18. SS1P plus PC in MPM Hassan et al., WCLC 2013 POST IASLC Milano 8 NOV 2013

  19. 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 POST IASLC Milano 8 NOV 2013

  20. VINORELBINE and BRCA1 in MPM Randomised phase II trial of oral vinorelbine as second-line therapy for patients with MPM expressing BRCA1 – VIM trial Weeklyoral VINORELBINE + ASC Relapsed MPM R ASC (activesymptom control) 2:1 BRCA1 expression IHC will be evaluatedas a stratificationfactor. Primaryendpoint: overallsurvival. 114 participantsrequired (76 VNR, 38 ASC) Fennell et al., Poster Session 2 Mesothelioma, P2.14-013 9 POST IASLC Milano 8 NOV 2013

  21. Tremelimumab: an anti-CTLA-4 mAb • Tremelimumab (CP675,206)Pfizer/MedImmuneIgG2 isotypeantibodyhalf-life time: 22 days T-cellcostimulatoryreceptors T-cell potentiation T cell CTLA-4 TCR CTLA-4 mAb B7 MHC APC POST IASLC Milano 8 NOV 2013

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

  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) Treme 10mg/kg Q4Wk x 6 doses Relapsed/Refractory Malignant Mesothelioma (2nd/3rd line) Total recruitment = 180 patients (OS events) Placebo Q12Wk (Non Dosing visits: V9, 11, 13) Placebo Q4Wk x 6 doses Phase II Multicenter, International, Randomized Trial of Tremelimumab in Patients With Unresectable Mesothelioma (Trial D4880C00003 Sponsored by MedImmune) 2:1 Primaryendpoint: OS NCT01843374 Kindler et al., Poster Session 2 Mesothelioma, P2.14-015 23 POST IASLC Milano 8 NOV 2013

  24. 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 POST IASLC Milano 8 NOV 2013

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

  26. Volumetric CT tumor response in MPM Armato et al., WCLC 2013 POST IASLC Milano 8 NOV 2013

  27. 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 POST IASLC Milano 8 NOV 2013

  28. Volumetric CT tumor response in MPM 41 consecutive radical P/D • CONCLUSIONS • OS and PFS were correlated with tumor volume (TV). • All radiographic techniques underestimated actual TV. • Estimates closer to actual TV as they became less automated and more manual. Friedberg et al., WCLC 2013 POST IASLC Milano 8 NOV 2013

  29. Gene sequencing CDKN2A, NF2 and BAP1 are the mostfrequentlymutatedgenes in MPM POST IASLC Milano 8 NOV 2013

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

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

  32. Conclusions • The debate on surgery in MPM continues: expanding role of P/D, mesoVATs. • IMRT after P/D or no surgery. • Medical treatment: SS1P plus PC promising; new options/studies: BRCA1/vinorelbine, tremelimumab, FAK-inhibitors. • Volumetric CT response evaluation: pitfalls and challanges. • Biology: gene sequencing, BAP1 syndrome. Role of the immune system. POST IASLC Milano 8 NOV 2013

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