MESOTELIOMA Carmine Pinto GRANDE LUNG SLAM Presidente Nazionale AIOM Roma, 8 Ottobre 2015 MESOTELIOMA Carmine Pinto Presidente Nazionale AIOM Oncologia Medica, IRCCS-Arcispedale S.Maria Nuova, Reggio Emilia

Un bilancio nel 2015 L’impatto epidemiologico e clinico Il plateau raggiunto dalla chemioterapia Target molecolari e potenzialità terapeutiche I risultati degli antiangionetici Realtà e prospettive dell’immunoterapia

Nuovi casi di tumori polmonari e di mesotelioma stimati in Italia nel 2015 Maschi Femmine Totale Polmone 29.400 11.700 41.100 Mesotelioma 1.400 500 1.900 Rapporto 22 a 1

I numeri del MMP in Italia Tassi di incidenza del MMP (per 100.000) negli anni 2005-2008 Sesso 2005 2006 2007 2008 M 3,85 3,42 3,73 3,84 F 1,27 1,45 1,31 N. Casi di mesotelioma nei due sessi negli anni 2005-2008 (93% MMP) 2005 2006 2007 2008 1.426 1.386 1.463 1.422 ReNaM, IV Rapporto, 2012

I numeri del MMP in Italia Incidenza per età (1993-2008; Casi N. 14.736) 4000 Maschi Femmine 3000 2000 1000 0-44 45-54 55-64 65-74 75-84 85+ ReNaM, IV Rapporto, 2012

Andamento dell’incidenza del mesotelioma negli uomini Lieve incremento dell’incidenza (tra il 1999 ed il 2010 +1,7% per anno) I nuovi casi sono concentrati nel Nord del Paese con un’incidenza inferiore al Centro (-42%) e al Sud (-26%) Stabile la mortalità (+ 0,2% per anno) AIOM – AIRTUM, I numeri del cancro, 2015

Andamento dell’incidenza del mesotelioma nelle donne Stabile l’incidenza (nessuna variazione annuale) I nuovi casi sono concentrati nel Nord del Paese con un’incidenza inferiore al Centro (-70%) e al Sud (-50%) Stabile la mortalità (+ 0,2% per anno) AIOM – AIRTUM, I numeri del cancro, 2015

I numeri del MMP in Italia Distribuzione per regione (1993-2008; Casi N. 14.736) Regione N. Lombardia 2.626 Piemonte 2.595 Liguria 1.836 Emilia Romagna 1.294 Veneto 1.206 Toscana 912 Campania 808 Sicilia 780 Puglia 757 Friuli VG 727 Lazio 504 ReNaM, IV Rapporto, 2012

MPM da esposizione occupazionale e non-occupazionale ad amianto Studio caso/controllo condotto in Francia dal 1998 al 2002 437casi di MPM incidenti e 874 controlli Maschi Femmine Rischio attribuibile di esposizione ad amianto Occupazionale (437 Casi, M 362,F 75) 83,1% (99%CI 74,5-91,7%) 41,7% (99%CI 25,3-58,0%) Non occupazionale (45 Casi, M 9, F36) 20,0% (99%CI 33,5-73,5%) 38,7% (99%CI 8,4-69,0%) Tutte le esposizioni 87,3% (99%CI 78,9-95,7%) 64,8% (99%CI 454-84,3%) Lacourt et al, Thorax 2014

Andamento della sopravvivenza a 5 anni dalla diagnosi negli uomini 1990-92 (%) 2005-07 Variazione Stomaco 25 34 +9 Colon-retto 50 64 +14 Pancreas 4 7 +3 Polmone 10 14 +4 Melanoma 70 84 Prostata 62 91 +29 Rene 58 69 +11 Mesotelioma 8 +2 AIOM – AIRTUM, I numeri del cancro, 2015

Andamento della sopravvivenza a 5 anni dalla diagnosi nelle donne 1990-92 (%) 2005-07 Variazione Stomaco 32 36 +4 Colon-retto 51 63 +12 Pancreas 6 9 +3 Polmone 12 18 +6 Melanoma 83 89 Mammella 78 87 +9 Rene 64 73 Mesotelioma 8 10 +2 AIOM – AIRTUM, I numeri del cancro, 2015

Pinto et al, Am J Clin Oncol 2011

Pinto et al, Cancer Treatment Reviews 2013

Therapies and biomarkers in MPM Robinson and Lake, NEJM 2005

Un bilancio nel 2015 L’impatto epidemiologico e clinico Il plateau raggiunto dalla chemioterapia Target molecolari e potenzialità terapeutiche I risultati degli antiangionetici Realtà e prospettive dell’immunoterapia

La chemioterapia nel MPM La chemioterapia di I linea L’impatto sul controllo dei sintomi e qualità di vita La chemioterapia di II linea La chemioterapia neo-adiuvante nel trattamento multimodale

Phase III Study CDDP vs CDDP/Pemetrexed (No. 222) CDDP/PEM (No. 226) RR (%) 16.7 41.3 P < 0.001 PFS (months) 3.9 5.7 HR 0.68 OS (months) 9.3 12.1 HR 0.77 P 0.020 1 years S 38.0 50.3 p 0.012 Vogelzang et al, J Clin Oncol 2003

Phase III Study CDDP vs CDDP/Raltitrexed (No. 103) CDDP/RTX (No. 110) RR (%) 13.6 23.6 p 0.056 PFS (months) 4.0 5.3 P 0.058 OS (months) 8.8 11.4 p 0.0487 1 years S 39.6 46.2 p 0.048 Van Meerbeeck et al, J Clin Oncol 2005

OS in phase III Stud CDDP vs CDDP/Pemetrexed and CDDP/Raltitrexed CDDP/Pemetrexed +2.8 months CDDP/Raltitrexed +2.6 months 9 months

Cisplatin/carboplatin + pemetrexed in first-line therapy Author Phase Pts. No. RR (%) TTP (months) OS 1 years S (%) Cisplatin + Pemetrexed Vogelzang, 2004 III 226 41.3 5.7 12.1 50.3 Obasaju, 2007 EAP 709 20.8 NR 10.9 45.9 Santoro, 2008 843 26.3 7.0 NE 63.1 Carboplatin + Pemetrexed Ceresoli, 2006 II 102 18.6 6.5 12.7 51.6 861 21.7 6.9 64.0

Treatment OS (months) HR 95% CI p ASC + CHT vs ASC 8.5 7.6 0.89 0.72-1.10 0.29 Esploratory analyses ASC + MVP 7.8 0.99 0.78-1.27 0.95 ASC + N 9.5 0.80 0.63-1.02 0.08 Phase III study with active symptom control (ASC) with or without chemotherapy (MRC/BTS MS01 STUDY) Primary outcome: OS First trial design: 840 pts Modified trial design: 420 pts Accrual: 2001-2006 Overall survival Treatment No. PR SD ASC + MVP 84 8 (10%) 52 (62%) ASC + N 56 9 (16%) 33 (59%) Muers et al, Lancet 2008

Increase dose of analgesic drugs during the trial Phase III study with active symptom control with or without chemotherapy (MRC/BTS MS01 STUDY) Chest pain palliation ASC + MVP vs ASC p = 0.0017 Increase dose of analgesic drugs during the trial ASC 97% ASC + MVP 57% ASC + N 65% Muers et al, 2008

Multi-centre, prospective, observational study evaluating biomarkers and radiological tecniques 58 pts CHT group 15 pts comparator group with similar PS and fit for CHT who declined therapy

Symptom control and quality of life Study Regimen Pts No. Results Authors Phase II MVP 39 ↑ Symptoms 62%, in all pts , 100% in PR Middleton et al, 1998 vs BSC → CHT 43 Symptoms progression time 25 vs 11 weeks O’ Brien et al, 2006 CDDP/GEM 21 ↑Symptoms 90% in PR , 33% in SD Byrne et al, 1999 MMM 22 ↑ Dyspnea 64%, pain33% Pinto et al, 2001 CDDP/GEM → MMM 54 ↑ Dyspnea 53%, pain 48% Pinto et al, 2006 Oxaliplatin/ Raltitrexed 70 ↑ Dyspnea 36%, pain 30% Fizazi et al, 2003 Phase III CDDP vs CDDP/Pemetrexed 456 ↑ Respiratory tests in responder pts Paoletti et al, 2003 CDDP vs CDDP/Raltitrexed 250 ↑ Dyspnea in both arms especially in CDDP/Raltitrexed Bottomley et al, 2006 ASC + MVP vs ASC + N vs ASC 409 = Dyspnea, QoL ↑ Pain Muers et al, 2008 CT vs BSC 73 = HRQol ↑ Dyspnea , ↑ Pain Arnold et al, 2015

Second-line (post-study) chemotherapy (PSC) in phase III trial CDDP vs CDDP/Pemetrexed Non-PSC Survival (Months) CDDP/Pem CDDP 15.3 12.2 9.8 6.8 PSC vs HR 0.56 95% CI, 0.44-0.72 Manegold et al, Ann Oncol 2005

Phase III study pemetrexed plus BSC vs BSC in pretreated patients Pem + BSC BSC p Postdiscont. CHT 28.5% 51.7% 0.0002 Pemetrexed 4.3 % 15.7 % <0.0001 Phase III study pemetrexed plus BSC vs BSC in pretreated patients Pem + BSC BSC p PR (%) 18.7 1.7 <0.0001 DCR (%) 59.3 19.2 PFS (months) 3.6 1.5 0.0148 OS (months) 8.4 9.7 0.7434 Jassem et al, J Clin Oncol 2008

Re-challenge in pemetrexed-pretreated patients Author Patients No. I line II line RR (%) DCR (%) PFS (months) OS (months) Serke 2007 17 CDDP/PEM CBDCA/PEM NR 65 Razak 2008 4 25 100 Hayashi 2010 50 3.2 Steer 2010 18 43 6.5 Ceresoli 2011 31 CDDP 19 48 3.8 10.5

La chemioterapia di seconda linea può essere considerata nei pazienti con buon PS, in assenza di comorbilità e non anziani Per i pazienti con una PFS ≥ 6 mesi un “re-challenge” con pemetrexed può essere considerato

Multimodality treatment EPP followed by CT and RT Authors Pts No. Age (years) F (%) Epithelioid (%) Treatment Mortality (%) Survival (months) Sugarbaker, et al, 1999 183 57 23 56 EPP + CT + RT 3.8 19 Maggi, et al, 2001 32 53 33 100 6.2 NR Rusch, 2001 62 17 68 EPP + RT 7.9 Aziz et al, 2002 51 < 60 - 54 EPP + CT 9.1 35 Lee et al, 2002 26 69 73 6.9 18 Ahamad, et al, 2003 28 59 7 78 NA 24 Stewart et al, 2004 87 7.5

Multimodality treatment induction CT - EPP followed by CT and RT SAKK Weder 2007 Italy Rea 2007 USA Krug 2009 EORTC Van Schill 2010 Centers 6 1 9 11 Patients No. 61 21 77 59 Stage T1-3N0-2M0 Induction CT/Compliance CDDP/GEM 3 cycles 95% CBDCA/GEM 3-4 cycles CDDP/PEM 4 cycles 83% 93% EPP 45 (74%) 17 (81%) 54 (70%) 42 (74%) Operative mortality 2.2% 7% 6.5% pCR rate 5.0% 4.8% Compliance RT 36 (59%) 15 (88%) 40 (52%) 37 (65%) OS (months) ITT/PP 19.8/23.0 25.5/27.5 16.8/21.9 18.4/21.5

EPP vs no-EPP Mesothelioma and Radical Surgery (MARS) Study 112 pts registered 83 (74%) pts 3 cycles CT 670 pts are needed in study with OS as the primary endpoint Feasibility study with the objective of randomising 50 pts within 1 years Five surgical centers (2 initially and 3 added later) October 2005 - november 2008 112 pts registered and 50 randomized R 50 pts EPP No. 24 No-EPP No. 26 EPP completed No. 16 5 not started, 3 abandoned 2 (12.5%) perioperative deaths Treasure et al, Lancet Oncol 2011

EPP vs no-EPP Mesothelioma and Radical Surgery (MARS) Study OS (months) 14.4 19.5 NS HR for OS EPP vs no-EPP 1.90 (95%CI 0.93-3.93; p 0.082) HR for OS adjusted EPP vs no-EPP 2.75 (95%CI 1.21-6.26; p 0.016) Treasure et al, Lancet Oncol 2011

Prognostic factors after EPP Institution Study No. Survival (mths) MSKCC, NY, USA 2003 2006 54 62 21,9 17 Brigham and Women’s Hospital, Boston, USA 1987-2008 E 450 NE 252 M 15, F 26 M 9, F 9 Glenfield Hospital, Leicester, UK 1999-2006 105 14.5 MD Anderson, Houston, USA 100 10.2 Toronto General Hospital, Toronto, Canada 2001-2007 45 14 University Hospital, Zurich, Switzerland 2000-2003 23 Swedish Cancer Institute, Seattle, USA 1997-2008 46 25 Warren Magnusen clinical Center, Bethesda, USA 1993-1996 11 Policlinico Tor Vergata University, Rome, Italy 1985-2004 41 13 Royal Prince Alfred Hospital, Sydney, Australia 1994-2008 70 20 Hairmyres Hospital, Rast Kilbride, Scotland 1989-1999 13/51 13/35 Sainte Marguerite’s Hospital, Marseille, France 1989-2007 83 Medical University of Viena, Vienna, Austria 1994-2005 49 12.4 Nonepithelial histotype and nodal involvement negative prognostic factors after EPP Cao et al, Ann Surg Oncol 2011

Prognostic factors after EPP and EPD Records of 252 patients (112 EPP, 140 EPD who survived at least 90 postoperative days) Median OS 18.2 months; no difference in OS between EPP and EPD (p=0.92) Factors predicting survival over 24 months p Age at operation under 60 years 0.014 Epitheliod histology <0.001 Negative nodes 0.002 Administration of chemotherapy 0.022 Nakas and Waller, Eur J Cardiothorac Surg 2014

Prognostic factors after EPP and EPD Records of 252 patients (112 EPP, 140 EPD who survived at least 90 postoperative days) Median OS 18.2 months; no difference in OS between EPP and EPD (p=0.92) Factors predicting survival over 24 months p Age at operation under 60 years 0.014 Epitheliod histology <0.001 Negative nodes 0.002 Administration of chemotherapy 0.022 Nakas and Waller, Eur J Cardiothorac Surg 2014

Un bilancio nel 2015 L’impatto epidemiologico e clinico Il plateau raggiunto dalla chemioterapia Target molecolari e potenzialità terapeutiche I risultati degli antiangionetici Realtà e prospettive dell’immunoterapia

Fattori prognostici (EORTC/CALGB Score) Curran et al, JCO 1998; Herndon et al, Chest 1998

Genetic/epigenetic changes and therapy possibilities in MPM Stahel et al, Ann Oncol 2015

Classificazione molecolare del MMP De Reyniès et al, Clin Cancer Res 2014

Classificazione molecolare del MMP De Reyniès et al, Clin Cancer Res 2014

Classificazione molecolare del MMP De Reyniès et al, Clin Cancer Res 2014

Retrospective studies by targeted NGS of cancer genes in advanced MPM (123 cases) Pathways Genetic variations p53 DNA repair TP53 SMACB-1 BAP-1 PIK3CA AKT PDGFRA Kit KDR HRAS STK11 NF2 Mutations Outcomes PIK3CA c1173A>G STK11 rs2075606 T>C TP53 rs104522 Pro/Pro TTP (p<0,01) Accumulation of genetic variations (p=0,02) OS (p=0,04) Lo Iacono et al, J Thor Oncol 2015

BAP1 - BRCA Associated Protein 1 BAP1 is a nuclear amino acido ubiquitin hydrolase implicated in cell proliferation, DNA repair, chromatin level control of gene expression 40% of patients with BAP1 mutation or loss Gemline BAP1 mutations in rare family Ventii et al, Cancer Res 2008; Machida et al, J Biol Chem 2009; Ladany et al, Clin Cancer Res 2012

Phase III study vorinostat vs placebo after CDDP/CBDCA + pemetrexed failure (VANTAGE 014 ) VORINOSTAT 300 mg orally, twice per day 3 of day in a 3-week cycle No. 329 STRATIFICATION KPS (<80 vs ≤80) Histology (epitheliod vs other) Prior chemotherapy regimen (1 vs 2) R PLACEBO orally, twice per day 3 of dayin a 3-week cycle No. 332 Primary end-point: OS Krug et al, ECCO-ESMO 2011, Abstract 3BA

Phase III study vorinostat vs placebo after CDDP/CBDCA + pemetrexed failure (VANTAGE 014) Krug et al, ECCO-ESMO 2011, Abstract 3BA

Un bilancio nel 2015 L’impatto epidemiologico e clinico Il plateau raggiunto dalla chemioterapia Target molecolari e potenzialità terapeutiche I risultati degli antiangionetici Realtà e prospettive dell’immunoterapia

Presented By Gerard Zalcman at 2015 ASCO Annual Meeting Slide 4 Presented By Gerard Zalcman at 2015 ASCO Annual Meeting

Phase II study CDDP/GEM +/- bevacizumab (No. 53) CDDP/GEM + BEVA (No. 55) p PR (%) 21.8 24.5 0.74 PFS (months) 6.0 6,9 0.88 SM (months) 14.7 15.6 0.91 Higher pretreatment plasma VEGF associated with shorter PFS (p 0.02) and OS (p 0.0066) independent of treatment Kindler et al, J Clin Oncol 2012

Presented By Gerard Zalcman at 2015 ASCO Annual Meeting Slide 7 Presented By Gerard Zalcman at 2015 ASCO Annual Meeting

Presented By Gerard Zalcman at 2015 ASCO Annual Meeting Slide 12 Presented By Gerard Zalcman at 2015 ASCO Annual Meeting

Presented By Gerard Zalcman at 2015 ASCO Annual Meeting Slide 24 Presented By Gerard Zalcman at 2015 ASCO Annual Meeting

Presented By Gerard Zalcman at 2015 ASCO Annual Meeting Slide 25 Δ + 2.75 months Presented By Gerard Zalcman at 2015 ASCO Annual Meeting

Forest Plot (OS, Univariate) Presented By Gerard Zalcman at 2015 ASCO Annual Meeting

MAPS trial conclusions Presented By Gerard Zalcman at 2015 ASCO Annual Meeting

Phase I-II study with cediranib plus cisplatin/pemetrexed in first-line chemotherapy SWOG 0905 Phase I-II Study Tsao et al, ASCO 2013 Abstract 7527

CDDP/CBDCA + Pemetrexed Phase III study with maintenance thalidomide vs observation (NVALT5/MATES) CDDP/CBDCA + Pemetrexed 4 cycles Thalidomide Obervation No. 111 PFS (weeks) 16 15 p 0.83 HR 1.0 (95%CI 0.8-1.4) OS (months) 11 13 p 0.09 HR 0.78 (95%CI 0.57-1.1) No-PD R Thalidomide 200 mg/day os Observation Baas et al, ASCO 2011, Abstract 7006

Presented By Rabab Gaafar at 2015 ASCO Annual Meeting NGR-hTNF Presented By Rabab Gaafar at 2015 ASCO Annual Meeting

Presented By Rabab Gaafar at 2015 ASCO Annual Meeting Study design Presented By Rabab Gaafar at 2015 ASCO Annual Meeting

Overall survival (primary endpoint) Presented By Rabab Gaafar at 2015 ASCO Annual Meeting

OS by treatment in the short TFI subset Presented By Rabab Gaafar at 2015 ASCO Annual Meeting

OS by chemotherapy agent in the short TFI subset Presented By Rabab Gaafar at 2015 ASCO Annual Meeting

PFS in the short TFI subset Presented By Rabab Gaafar at 2015 ASCO Annual Meeting

Presented By Rabab Gaafar at 2015 ASCO Annual Meeting Conclusions Presented By Rabab Gaafar at 2015 ASCO Annual Meeting

Un bilancio nel 2015 L’impatto epidemiologico e clinico Il plateau raggiunto dalla chemioterapia Target molecolari e potenzialità terapeutiche I risultati degli antiangionetici Realtà e prospettive dell’immunoterapia

Immunotherapy possibilities in MPM Stahel et al, Ann Oncol 2015

Expression of PD-L1 in human mesothelioma cell lines Calabrò et al, Cancer Imunol Immunother 2015

Clinical trial investigating immunotherapy in MPM Stahel et al, Ann Oncol 2015

Tremelimumab in II second-line after platinum-based chemotherapy Patients No. 29 Platinum/pemetrexed 25 (86%) Epithelioid histology Stage IV 18 (62%) EORTC PS good 23 (79%) Overall Survival PR 2 (6.9%) SD 7 (24.1%) DCR 9 (31.%) PFS 6.2 months OS 10.7 months Calabrò et al, Lancet Oncol 2013

Phase II study of amatuximab, a chimeric antimesothelin antibody, with cisplatin/pemetrexed in advanced unresectable MPM Hassan et al, Clin Cancer Res 2014

Phase II study of amatuximab, a chimeric antimesothelin antibody, with cisplatin/pemetrexed in advanced unresectable MPM Hassan et al, Clin Cancer Res 2014

A che punto siamo Riconosciuto il ruolo della chemioterapia Regimi con composti del platino/antifolati Impatto su OS, controllo dei sintomi Possibilità di II linea di chemioterapia Da definire l’impatto della chemioterapia pre-chirurgia Necessità di definire gruppi di pazienti a differente prognosi per fattori clinici e bio-molecolari Necessità di definire le alterazioni genetiche “driver” per trattamenti target Nuove evidenze per i farmaci anti-angiogenetici Promettenti risultati dell’immunoterapia Necessità di implementare la Rete Nazionale