MESOTELIOMA Carmine Pinto GRANDE LUNG SLAM Presidente Nazionale AIOM

Presentazione sul tema: "MESOTELIOMA Carmine Pinto GRANDE LUNG SLAM Presidente Nazionale AIOM"— Transcript della presentazione:

1 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

2 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

3 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

4 I numeri del MMP in Italia
Tassi di incidenza del MMP (per ) negli anni 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 (93% MMP) 2005 2006 2007 2008 1.426 1.386 1.463 1.422 ReNaM, IV Rapporto, 2012

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

6 Andamento dell’incidenza del mesotelioma negli uomini
Lieve incremento dell’incidenza (tra il 1999 ed il ,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

7 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

8 I numeri del MMP in Italia
Distribuzione per regione ( ; Casi N ) 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

9 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 ,3%) Lacourt et al, Thorax 2014

10 Andamento della sopravvivenza a 5 anni dalla diagnosi negli uomini
(%) 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

11 Andamento della sopravvivenza a 5 anni dalla diagnosi nelle donne
(%) 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

12 Pinto et al, Am J Clin Oncol 2011

13 Pinto et al, Cancer Treatment Reviews 2013

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15 Therapies and biomarkers in MPM
Robinson and Lake, NEJM 2005

16 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

17 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

18 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

19 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 1 years S 39.6 46.2 p 0.048 Van Meerbeeck et al, J Clin Oncol 2005

20 OS in phase III Stud CDDP vs CDDP/Pemetrexed and CDDP/Raltitrexed
CDDP/Pemetrexed months CDDP/Raltitrexed months 9 months

21 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

22 Treatment OS (months) HR 95% CI p ASC + CHT vs ASC 8.5 7.6 0.89 0.29 Esploratory analyses ASC + MVP 7.8 0.99 0.95 ASC + N 9.5 0.80 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: 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

23 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 = Increase dose of analgesic drugs during the trial ASC 97% ASC + MVP 57% ASC + N 65% Muers et al, 2008

24 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

25 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

26 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, Manegold et al, Ann Oncol 2005

27 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

28 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

29 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

30 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, 32 53 33 100 6.2 NR Rusch, 2001 62 17 68 EPP + RT 7.9 Aziz et al, 51 < 60 - 54 EPP + CT 9.1 35 Lee et al, 26 69 73 6.9 18 Ahamad, et al, 2003 28 59 7 78 NA 24 Stewart et al, 2004 87 7.5

31 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

32 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 november 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

33 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 ; p 0.082) HR for OS adjusted EPP vs no-EPP 2.75 (95%CI ; p 0.016) Treasure et al, Lancet Oncol 2011

34 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 E 450 NE 252 M 15, F 26 M 9, F 9 Glenfield Hospital, Leicester, UK 105 14.5 MD Anderson, Houston, USA 100 10.2 Toronto General Hospital, Toronto, Canada 45 14 University Hospital, Zurich, Switzerland 23 Swedish Cancer Institute, Seattle, USA 46 25 Warren Magnusen clinical Center, Bethesda, USA 11 Policlinico Tor Vergata University, Rome, Italy 41 13 Royal Prince Alfred Hospital, Sydney, Australia 70 20 Hairmyres Hospital, Rast Kilbride, Scotland 13/51 13/35 Sainte Marguerite’s Hospital, Marseille, France 83 Medical University of Viena, Vienna, Austria 49 12.4 Nonepithelial histotype and nodal involvement negative prognostic factors after EPP Cao et al, Ann Surg Oncol 2011

35 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

36 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

37 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

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

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

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

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

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

43 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 rs T>C TP53 rs 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

44 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

45 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

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

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48 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

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

50 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 ) independent of treatment Kindler et al, J Clin Oncol 2012

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

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

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

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

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

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

57 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

58 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 ) OS (months) 11 13 p 0.09 HR 0.78 (95%CI ) No-PD R Thalidomide 200 mg/day os Observation Baas et al, ASCO 2011, Abstract 7006

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

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

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

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

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

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

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

66 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

67 Immunotherapy possibilities in MPM
Stahel et al, Ann Oncol 2015

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

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

70 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

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

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

81 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