Malignant Pleural Mesothelioma: State of the art and projects. Rolf Stahel, MD University Hospital Zurich, Switzerland

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1 Malignant Pleural Mesothelioma: State of the art and projects Rolf Stahel, MD University Hospital Zurich, Switzerland

2 Chemotherapy of malignant pleural mesothelioma Chemotherapy provides symptom relief Middleton, Ann Oncol 1998; Andreopoulou, Ann Oncol 2004 Adding a folate antagonist (pemetrexed or raltitrexed) to cisplatin leads to a improvement of survival. Cisplatin (or carboplatin) and pemetrexed as preferred chemotherapy regimen Vogelzang, JCO 2003; van Meerbeck, JCO 2005; Ceresoli, JCO 2006 There is a role for multimodality therapy (adjuvant, neoadjuvant chemotherapy) with extrapleural pneumonectomy or lesser procedures Sugarbaker JTCVS 1999; Weder Ann Oncol 2004 Optimal second line chemotherapy is not defined (vinorelbine might be a good choice) Stebbing, Lung Cancer 2009

3 Questions in 1 st line chemotherapy for malignant pleural mesothelioma Biomarker selection for standard agents? Folate receptor expression not helpful for selection of pemetrexed Nutt, BJC 2010 Potential molecular selection though TS for pemetrexed or ERCC1 for platinium Righi, JCO 2010 Potential molecular selection through TS and FPGS for pemetrexed (H-score) Christoph, ASCO 2011 Abs 7024 Treatment duration TS (median H-score)

4 Second line chemotherapy Agents identified in 2 nd line: Irinotecan/cisplatin/mitomycin C: RR 10% Fennell, Cancer 2007 Pemetrexed vs BSC: RR 18%, better disease control rate (59% vs 19%), no survival benefit (imbalance in further therapy: 28% vs 51%) 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

5 Exploring new therapeutic approaches Histone deacetylase inhibitors: Vorinostat, phase I responses, phase III in second line vs BSC: negative Krug, Clin Lung Cancer 2006; Krug, ECCO-ESMO 2011 Belinostat: Inactive in phase II Valproic acid: Preclinical activity demonstrated Vandermeers, CCR 2009

6 VANTAGE 014: OAS and response Double-blind 125 centers in 23 countries participated including 661 patients

7 Exploring new therapeutic approaches Bevacizumab: Randomized phase II study in combination with cis/gem Kindler ASCO 2007 Ongoing randomized phase II/III study of IFCT- GFPC in combination with cisplatin and pemetrexed Zalcman, ASCO 2010 Thalidomide Randomized phase III study with platin/pem Baas, ASCO 2011 Probability OS No further treatment Thalidomide until progression HR = 1.2 ( ), p= Time (mths)

8 Exploring new therapeutic approaches Multitargeted TKIs including VEGFR2 as target: No consistant activity of VEGFR2 multitarged TKIs vatalanib, sorafenib, sunitinib Janan, ASCO 06; Jänne ESMO 06; Nowak ASCO 2010 Poor tolerance of cediranib and sunitinib combined with chemotherapy Campell, ASCO 2011; Mutri, ASCO 2011 Restricted target TKIs EGFR TKIs: gefitinib, erlotinib inactive Govindan CR 2005; Garland, JCO 2007 C-kit, PDGF TKI: imatinib inactive Mathy, Lung Cancer 2005; Porta, Cancer Chemother Pharmacol 2007

9 Exploring new therapeutic approaches Antibodies to mesothelin: MORAb-009: phase II combined with chemotherapy ongoing Hassan, CCR 2010 Mesothelin-Immunotoxin SS1P Hassan, CCR 2007; Kreitman, CCR 2009 Mouse Anti-C-ERC/mesothelin: NK mediated ADCC in xenograft Inami, Cancer Sci 2010 Bortezomib Preclinical data, clinical studies ongoing Gordon, Cancer Chemother Pharmacol 2008

10 Surgery and multimodality therapy The role of surgery continues to be a matter of debate Radical resectability? Extrapleural pneumonectomy or pleurectomy and decortication? Impact on survival? Lack of prospective randomized data However: Longest median survival and long term survivors reported in series with multimodality therapy including EPP Surgical mortality in experienced centers dropped to around 3%

11 Important questions on current treatment modalities EPP or no surgery? Impossible to answer in context of a randomized study. MARS trial: 42% of 112 pts randomized, 16/24 assigned to EPP had surgery, 3/16 (18%) perioperative deaths Treasure, Lancet Oncol 2011 PORT to hemithorax after neoadjuvant chemo and EPP: SAKK 17/04 Part 1 Part 2 Registration after staging Chemotherapy Restaging Surgery Follow-up if not operable Reassessment R0 or R1 R2 Follow-up Randomisation Arm A: No Radiotherapy Arm B: Hemithoracic Radiotherapy March 2011: pts entered - 39 pts randomized

12 Feasability phase of MARS trial Question: Is it feasible to perform a randomized study on EPP in mesothelioma (in the UK) Right answer: It was not feasible to ask this question (in the context of MARS) Wrong answer: Results of the MARS trial, if accepted, would make trimodality therapy, including EPP no longer justified Senan and Treasure, Oncologist 2011 (before publication) The data suggests that [ ] radical surgery in th form of EPP within trimodal therapy offers no benefit an possibly harms patients Treasure, Lancet Oncol 2011

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

14 What might be on the horizon HSP90 inhibitors Ou, Neoplasia 2011 Increase in sonic hedgehog signaling by the inactivation of the hippo pathway (inactivation of NF2 or LATS) Activation of AKT- PI3K - mtor pathway Inactivated nuclear deubiquitinase BAP1

15 NF2 and LATS are gatekeepers during tissue repair normal tissue repair Sonic hedgehog signaling stimulation of repair in NF2-deficient cancer cells Sonic hedgehog signaling NF2 NF2 Mst WW45 Mob Lats P P Hippo pathway Mst WW45 Mob Lats P P YAP YAP Ser127P YAP X YAP NF2 survivin amphiregulin X YAP survivin amphiregulin Felley-Bosco, 2011

16 Alterations of NF2 and LATS in mesothelioma Mutations in NF2 have been described in 40% of mesothelioma Bianchi, PNAS 1995; Sekido, CR 1995; Deguen, IJC 1998 In tumors without NF2 truncation, NF2 activity is inhibited by phosphorylation, for example by increased expression of CPI-17 Thurneysen, Lung Cancer 2009 CDKN2A and NF2 are dysregulated by mirna in mesothelioma Guled, Genes Chrom Cancer 2009 LATS2 is a tumor suppressor gene in mesothelioma Murakami, CR 2011

17 Regulation of NF2 signaling pathway PTEN Activity partner NF2 active PKB/Akt PAK, PKA P Thr230 P Ser315 ubiquitination degradation Myosin-Phosphatase MYPT1-PP1δ inactive P Ser518 (Protein kinase C- potentiated phosphatase inhibitor of 17 kda) CPI 17 Thurneysen et al, Lung Cancer 2009 Felley-Bosco, 2011

18 PI3K-AKT- mtor signaling in mesothelioma AKT/mTOR pathway is frequently activated in both human and murine MM specimens cell lines. Elevated levels of phospho-akt and P-TOR in nearly two-thirds of human MM tumors Altomare et al, Oncogene 2005 Loss of NF2 correlates with activation of PI3K/mTORC1 signalling and sensitivity to rapamycin Lopez-Lago, MCB 2009 Loss of PTEN is a negative predictor of survival Opitz, EJCTS 2008

19 PI3K-AKT- mtor signaling in mesothelioma Combined cisplatin and sirolimus enhances mesothelioma cell death Hartman, JTCVS 2009 mtorc inhibitor temsirolimus inhibits MM growth in vivo and synergizes with chemotherapy Hoda, JTO 2011 Phase I study with GDC-0980, a inhibitor of class I PI3K and mtor kinase: Well tolerated. Antitumor activity in 3 patients with mesothelioma Wagner, ASCO 2011 abs 3020

20 BAP1 losses and mutations (3p21.1) in mesothelioma 3p21 9p21 22q12 BAP1: encoding BRCA1-associated protein 1 Bott, Nature Genetics, 2011

21 BAP1 and HDAC inhibotors? BAP1 function is under investigation: One role suggested is maintaining regulatory ubiquination histones:?differential sensitivity to HDAC inhibitors Bott, Nat Genetics 2011 Germline BAP1 mutations predispose to malignant mesothelioma Testa, Nat Genetics 2011

22 22 ETOP Mesoscape 19 participating centers Italy (4) Great Britain (4) Germany (3) Spain (2) France, Greece, Ireland, Netherlands, Poland, Switzerland (1) patients per year are referred to these centers (18/19) patients per center, Surgery in 5-50 pt/y

23 Malignant Pleural Mesothelioma The incidence of mesothelioma in Europe will increase and peak between 2015 and 2020 Molecular characteristics: Inactivation of tumor suppressor genes include p16 INK4A /p14 ARF and neurofibromatosis type 2 (NF2). Activation of PI3K-AKT signalling. Mutation in BAP1which encodes merlin are the major molecular characteristics Pemetrexed combined with cisplatin has become the preferred first line chemotherapy for mesothelioma Selected patients appear to benefit from a multimodality approach including neoadjuvant chemotherapy, extrapleural pneumonectomy, and potentially hemithoracic radiotherapy So far limited success with novel and targeting agents