Mesothelioma Paul Baas Department of Thoracic Oncology The Netherlands Cancer Institute Amsterdam

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1 Mesothelioma 2014 Paul Baas Department of Thoracic Oncology The Netherlands Cancer Institute Amsterdam

2 Disclosures Grants from Pfizer and Roche Advisor for MSD and Verastem

3 Once upon a time.

4

5

6

7 But all comes at a price

8 Hodgson et al, 2005, British Journal of Cancer (2005) 92, Photo courtesy of the Rideau Institute.

9 Death atributable to MPM A registration issue?? Worldwide incidence Reporting by income Africa Low income Americas Middle Asia income High income Europe Oceania WHO Volume 89, 10, October 2011, C

10 Asbestos production 2012 Top Five Producers (tonnes): Russia 1,000,000 China 420,000 Brazil 306,500 Kazakhstan 241,200 India 20,000 Top Five Users (tonnes): China 530,834 India 493,086 Brazil 167,602 Indonesia 161,824 Russia 155,476

11 ADVERTISEMENT

12 A Never Ending Story Previously considered as a rare tumor Asbestos related BAP1 mutation Public health issue in developing world Many potential diagnostic pitfalls Treatment: no validated curative treatment so far 12

13 Diagnosis Difficult to make Need for invasive procedure Pathology is sometimes difficult New options??

14 Volatile Organic Compounds Electronic nose captures the spectrum of exhaled volatile organic compounds (VOCs) providing a profile of different biomarkers or a breathprint Breathprints of MPM patients (n=13) distinguished sens =92.3%, spec =85.7% Dragonieri et al, Lung Cancer 2011 (Cyranose 320 nose ) 20 MPM, 18 with benign asbestos related disease and 42 healthy subjects: correct distinction in 95% of cases for MPM 88% for control groups in 10 new MM patients after the training set Chapman et al, Eur Respir J 2011 Courtecy Prof A Scherpereel

15 Study and Treatment Issues

16 Key problems of studies Studies take very long: 2-8 years! Population: heterogeneous Pretreated + untreated Differences in stage and pathology Measurable + non-measurable disease Incomplete studies set-up Unknown impact of post-study chemotherapy Limited number of translational studies: No tumor assessments pre-post-tx

17 Studies before 2000 Agent # Trials # Pts Response Doxorubicin % Epirubicin % Mitoxantrone % Liposomal doxorubicin Liposomal daunorubicin % % Caelyx %

18 First line treatment Chemotherapy provides symptom relief and increased OS The combination of cisplatin and anti-folate is standard (2003) Multimodality studies use: neoadjuvant chemotherapy extrapleural pneumonectomy or pleurectomy/decotication with or without RT Novel and targeting agents: so far no or very limited success

19 Second-line CT in MM # RR Survival Gemcitabine/vinorelbine % 10.9 mo Imatinib % 14.3 mo Pemetrexed % 8.4 mo Raltitrexed/oxaliplatin % 10.1 mo Sorafenib % 14.3 mo Sunitinib 6, % 8.2 mo Thalidomide % 11 mo Vinorelbine % 9.6 mo ZD % 6.7 mo Ranpirnase % 7.3 mo 1. Zucali, Cancer Villano Proc ASCO Jassem, JCO Fizazi, JCO 2003; 5. Janne, Proc IMIG Nowak, Proc IMIG Laurie JTO 2011, 8 Pavlakis, Proc IASLC 2003,9. Stebbing, Lung Ca Giaccone BJC Mikulski, JCO 2002

20 Palliative treatment in MPM Too little attention in journals Remarks like: This regimen provides a satisfactory palliative treatment for some patients with advanced pleural mesothelioma. Vinorelbine shows promise in the palliation of patients the combination may constitute an advance over best supportive care radiation therapy is to offer a palliative course of treatment The patients were managed with systemic chemotherapy and palliative surgery Law: Thorax (1984);39: ; Steele: JCO (2000); ; Nowak: BJC (2002) 87, ; Davis: Australasian Radiology, (1994); 38, ; YAN: Ann Oncol (2007); 18 (5):

21 Novel Agents Recent studies Amituxamab (MORAb-9)/CDDP/Pem ORR of 39% and median OS of 14.8 months Vinorelbine No responses in 2 nd /3 rd line Maintenance Studies Thalidomide No differences in survival in Phase III trial maintenance setting vs observation (224 pts) Vorinostat failed Phase III Trial in 2 nd line (660 pts, submitted)

22 New approaches

23 Primary culture testing

24 Cell morphology Epithelial phenotype: 90% Mixed phenotype: 10% 50% succes of PTC Differentiation from reactive mesothelial cells

25 Chemosensitivity assay of PTC Blue: cisplatin & pemetrexed Orange: oxaliplatin & gemcitabine Purple: vinorelbine Red: gemcitabine Green: pemetrexed Pink: cisplatin Blue: oxaliplatin Testing in 2nd line treatment in patients

26 Other targeted therapies

27 Immunotherapy Tumor Microenvironment Activation (cytokines, lysis, proliferation, migration to tumor) Dendritic cell MHC B7 B7 TCR CD28 CTLA-4 anti-ctla T cell CTLA-4 Blockade (ipilimumab) T cell TCR MHC PD-1 PD-L1 anti-pd-1 PD-1 PD-L2 anti-pd-1 Tumor cell PD-1 Blockade (nivolumab)

28 Ongoing Studies COX2, over-expressed in % of MPM tumor samples Anti-CTLA-4 Ab, stimulating the T cell immune response Anti-PD-1/PD-L1 Ab: Measles Virus Vaccine Mesothelin: immunotoxin SS1P: promising results from R Hassan et al

29 Conclusions (1) Awareness of asbestos danger in developing world for users, producers and doctors

30 Prevent undesired behaviour Famous 1977 cartoon of Herblock in the NY Times

31 Conclusions (2) Optimal selection of patients for MMT First line therapy is still platin-pemetrexed Personalized therapies based on: Genetic screening for targets Primary cultures Immuno-modulation Palliative protocols

32 Thans for your attention Hubble telescope

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