13 th ILCC Huntington Beach July 20 th, 2012 Paul Baas NKI-AVL

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1 13 th ILCC Huntington Beach July 20 th, 2012 Paul Baas NKI-AVL

2 Advisor: Merck Sharp Dohme Pfizer Research funding: Pfizer Roche

3 The effect of the Greece situation

4 Multistep carcinogenesis in MPM Mutsaers, 2004 Durable, fire and heat resistant fibrous mineral To strengthen materials or serve as insulation Accumulation of asbestos fibers and chronic tissue injury Persistent stimulation of tissue repair Loss of contact-dependent growth inhibition and tumor progression

5 Epidemiology and tumorigenesis Incidence: Europe will peak between 2015 and 2020 US is at its peak Developing worlds are at very high risk Latency period from first exposure: years Genetic susceptibility: frequent inactivation of tumor suppressor genes include p16 INK4A /p14 ARF and neurofibromatosis type 2 (NF2) BAP1 (3p21.1) mutation involves ubiquitination of histones; germline mutations predispose to MPM J Testa 2011, Nature Genetics; Bott Nature Genetics 2011

6 Cumulative incidence of MPM and asbestos use Park, 2011

7 Mesothelioom wereldwijd Mesothelioma Incidence Worldwide ( ) ( )

8 Cell Type Epitheliod Mixed (Biphasic) Sarcomatous Pleiomorphic Tubulopapillary Epitheliod Glandular Large Cell (giant cell) Small Cell Adenoid cystic Signet ring MSKCC, Semin Thorac Cardiovasc Surg 2009; Courtesy, W. Travis

9 Diagnosis Cytology vs Histology Thoracentesis confirmatory in 35-40% Abrams Needle biopsy confirmatory in 40-50% Thoracoscopy 94-98% 1-2 x 5mm ports-no FROZEN SECTION DIAGNOSIS Cancer :389-93, Chest :1549, Chest :1362

10 Differentiation from Lung Cancer Histology Meso Adeno PAS stain Neg Pos Mucicarmine Neg Pos Immunostaining CEA Neg Pos TTF-1 Neg Pos LeuM-1 (CD 15) Neg Pos Vimentin Pos Neg Cytokeratin 5/6 Pos Neg Calretinin Pos Neg EMA Pos Neg WT1 Pos Neg HBMB1 Pos Neg Mesothelin Pos Neg D2-40 Pos Neg B72.3 Neg Pos MOC-31 Neg Pos Ber-Ep4 Neg Pos BG8 Neg Pos Epithelioid MPM Calretinin Arch Pathol Lab Med :1317, Eur Respir J :479

11 Biomarkers Blood, Serum, Effusion Mesothelin (SMRP) Osteopontin CYFRA 21-1 CA 125 PDGF MPF Tissue CDKN2A MMP2 VEGF Bax EGFR COX-2 P53 PTEN ERCC 1 TS CEA in serum must be normal!!!! NEJM :1564, Ann Thorac Surg :265, Mol Diagn Ther : 375, Eur J CT Surg :502, JCO :1534

12 Staging Systems IMIG 2003 (update 2013?) AJJC (update 2010)

13 Stage IA T1a N0M0 Stage IB T1b N0 M0 Stage II T2 N0 M0 Stage III T1, T2 N1 M0 T1, T2, N2, M0 T3, N0, N1, N2, M0 Stage IV T4 Any N M0 Any T N3 M0 Any T Any N, M1 J Thorac Cardiovas Surg : 620

14 PET Utility in the Evaluation MPM Disease extent-pleura of involved, total volume of disease and metastatic involvement, node assessment Combined with CT and Mediastinoscopy, PET-CT identifies 29% of patients who are potential inoperable T4 and M1, NPV 75%, PPV 50% Caution: not reliable after (talc) pleurodesis NEJM :1591, Eur J Cardiothor Thorac S :1090

15 FDG-PET: Prognostication Patient A-SUV max 9.6 & TGV 240 Patient B-SUV max 9.4 & TGV 2,523 Total Glycolytic Volume correlation with survival?? Semin Thorac Cardiovasc Surg : 111 Clin Cancer Res 2010;16:2409

16 Systemic Therapy Chemotherapy provides symptom relief and increased OS Based on a landmark study of Vogelzang and Meerbeeck: the combination of cisplatin and anti-folte is standard Multimodality studies use neoadjuvant chemotherapy followed by extrapleural pneumonectomy or pleurectomy/decotication with or without RT Optimal second line chemotherapy is not defined Novel and targeting agents: so far no or very limited success

17 Phase III first line MS01 study (UK) based study MST p Randomized Phase 3, 3-arm study (incomplete) MVP (mitomycin-vinblastine-cisplatin) 8.5 ns Vinorelbine ASC = active symptom control 7.6 Vogelzang study (US) Cisplatin 9.3 <0.001 Cisplatin/pemetrexed 12.3 Van Meerbeeck (EORTC) Cisplatin Cisplatin/raltitrexed 11.2 Muers MF Lancet. 2008;371(9625):

18 How to improve on platinum- pemetrexed? Do we need platinum-based combo s? Variations in scheduling Dose escalation Maintenance pemetrexed Better cytostatic drugs Other antifolates Vinca alkaloids Anthracyclins: amrubicin New platins Epothilones Better patient selection In vitro drug resistance Critical mutation (MTAPdeletion) Predictive biomarkers: TS, ERCC1 Targeted agents Anti-mesothelin immunotoxin Bevacizumab HDAC-inhibitor Thalidomide PI3Kinase inhibitor

19 Do we need platinum-based combos? IPD N=1056 OS Logrank (p value) PLATINUM 9.4 <0.001 NON-PLATINUM 8.2 IPD N=1056 OS Logrank (p value) Combination 9.5 <0.001 Single agent 8.1 Fennell, in press

20 Second line chemotherapy Irinotecan/cisplatin/mitomycin C: RR 10% Fennell, Cancer 2007 Pemetrexed vs BSC: RR 18%, better disease control rate (59% vs 19%), no survival benefit Jassem, JCO 2008 Vinorelbine and gemcitabine: 30 pts, RR10%, median OS 10.6 months Zucali, Cancer, 2008 Vinorelbine: 63 pts, RR 16%, median OS 9.6 months Stebbing, Lung Cancer 2009

21 (Switch) Maintenance Therapy

22 CT thorax Toxicity randomization Observation >4 cycles 2-9 weeks weeks chemotherapy recovery 100mg 200mg Thalidomide start Stop PD Thalidomide vs observation in non progressing patients after CT Primary Objective: 50% increase in TTP 222 patients randomized

23 Probability TTP and OS TTP OS No further treatment No Thalidomide further treatment until progression Thalidomide until progression HR = 1.0 ( ), p=0.71 HR 1.2 ( ), p= Time (weeks) Time (mths)

24 Maintenance studies Thalidomide vs. obs Phase III negative Bevacizumab vs. obs Phase III ongoing Cetuximab vs. obs Phase II ongoing Pemetrexed vs. obs Phase III planned

25 Biologicals

26 Summary of Biological Agents Gefitinib (Govindan, CCR 2005) Erlotinib (Garland, JCO 2007) Imatinib (Mathi, LC 2005) Sunitinib (Nowak pers comm) Sunitinib (Laurie, JTO 2011) Bortezomib (O Brien 2012) Thalidomide (Baas ASCO 2011) Vorinostat (Krug, ESMO 2011) Bevacizumab (Kindler JCO 2012) Axitinib (Buikhuisen) negative negative negative positive? negative negative negative negative negative in preparation

27 Operative Procedures Diagnostic pleural Bx, VATS Palliative for effusion control talc pleurodesis VATS/open parietal pleurectomy VATS/open Curative Intent Pleurectomy / Decortication (P/D) Extrapleural Pneumonectomy (EPP)

28 Comparison of EPP vs P/D 3 Institutions MSKCC, Karmanos, NYU , 663 Consecutive Patients, Retrospective Mortality EPP 7% P/D 3% Poor Prognosis for Adv Stage, NonEpitheliod Histology, EPP, Surgery alone, Male Gender EPP HR 1.4 (p<.001) controlling for stage, histology, gender and multimodal Rx J Thor Cardiovas Surg : 620

29 Multimodality therapy Goal: Intervention: 1. curative therapy 2. prolonged survival balanced with quality of life - radical resection/maximal cyto-reduction - systemic treatment - +/- radiotherapy

30 Message from MARS Courtecy Tom Treasure January 2011

31 Neoadjuvant chemotherapy, EPP and radiotherapy in MPM MARS: 16/24 randomized to EPP had intended treatment: med survival 14.4 months 3/26 randomized to no EPP eventually had EPP: med survival 19.5 months Operative mortality 18%

32 Dilemmas The role and type of surgery in MPM continues to be a matter of debate no large randomized studies avalable non-controlled case series - different staging systems - different patients selection/histology - different combinations of other treatments - different experience of a specialized surgical team

33 Conclusions (1) Role of EPP dubious, if any Small number of patients benefit Focus now on pleurectomy/decortication Never R0 resection: odds against better outcome Beware of surgical triumphalism Randomised trials needed

34 Conclusions (2) First line chemotherapy Requires a platinum-antifolate backbone Likely equipoise between different combo s Tumors recur within 2 years Second Line Chemotherapy No standard yet Future lies in better patient selection By a predictive baseline biomarker By use of molecular targeted drugs (combinations?) Both adequately studied, preferably via randomized phase 2 studies in 1st line with PFS-(R) as primary endpoint

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