Relazione Carmine Pinto

GRANDE LUNG SLAM
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
1,45
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
4
I numeri del MMP in Italia
Incidenza per età (1993-2008; Casi N. 14.736)
4000
Maschi
Femmine
3000
2000
1000
0-44
ReNaM, IV Rapporto, 2012
45-54
55-64
65-74
75-84
85+
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
ReNaM, IV Rapporto, 2012
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
8
MPM da esposizione occupazionale e nonoccupazionale ad amianto
Studio caso/controllo condotto in Francia dal 1998 al 2002
437casi di MPM incidenti e 874 controlli
Maschi
Femmine
83,1%
41,7%
(99%CI 74,5-91,7%)
(99%CI 25,3-58,0%)
20,0%
38,7%
(99%CI 33,5-73,5%)
(99%CI 8,4-69,0%)
87,3%
64,8%
(99%CI 78,9-95,7%)
(99%CI 454-84,3%)
Rischio attribuibile di
esposizione ad amianto
Occupazionale
(437 Casi, M 362,F 75)
Non occupazionale
(45 Casi, M 9, F36)
Tutte le esposizioni
(437 Casi, M 362,F 75)
Lacourt et al, Thorax 2014
9
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
+14
Prostata
62
91
+29
Rene
58
69
+11
Mesotelioma
8
10
+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
+6
Mammella
78
87
+9
Rene
64
73
+9
Mesotelioma
8
10
+2
AIOM – AIRTUM, I numeri del cancro, 2015
Pinto et al, Am J Clin Oncol 2011
12
Pinto et al, Cancer Treatment Reviews 2013
13
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
CDDP
(No. 222)
CDDP/PEM
(No. 226)
RR
(%)
16.7
41.3
P < 0.001
PFS
(months)
3.9
5.7
HR 0.68
P < 0.001
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
CDDP
(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
14
CDDP/Raltitrexed
+2.6 months
12
Months
10
9 months
Phase II studies
8
CDDP
CDDP/MTA
6
CDDP
CDDP/Ral trexed
4
2
0
Trials before 2003
Vogelzang 2003
van Meerbecck
2005
Cisplatin/carboplatin + pemetrexed in first-line therapy
Author
Phase
Pts.
No.
RR
(%)
TTP
(months)
OS
(months)
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
EAP
843
26.3
7.0
NE
63.1
Carboplatin + Pemetrexed
Ceresoli, 2006
II
102
18.6
6.5
12.7
51.6
Santoro, 2008
EAP
861
21.7
6.9
NE
64.0
Phase III study with active symptom control (ASC) with or without
chemotherapy (MRC/BTS MS01 STUDY)
Treatment
ASC + CHT
vs
ASC
OS
(months)
HR
95% CI
8.5
0.89
p
• Primary outcome: OS
0.72-1.10
0.29
• First trial design: 840 pts
• Modified trial design: 420 pts
• Accrual: 2001-2006
0.99
0.78-1.27
0.95
Overall survival
0.80
0.63-1.02
0.08
7.6
Esploratory analyses
ASC + MVP
vs
ASC
7.8
ASC + N
vs
ASC
9.5
7.6
7.6
Treatment
No.
PR
SD
ASC + MVP
84
8 (10%)
52 (62%)
ASC + N
56
9 (16%)
33 (59%)
Muers et al, Lancet 2008
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%
Muers et al, 2008
ASC + MVP 57%
ASC + N
65%
•
•
•
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
Phase II
MVP
vs BSC → CHT
43
Symptoms progression time 25
vs 11 weeks
O’ Brien et al,
2006
Phase II
CDDP/GEM
21
↑Symptoms
90% in PR , 33% in SD
Byrne et al,
1999
Phase II
MMM
22
↑ Dyspnea 64%, pain33%
Pinto et al,
2001
Phase II
CDDP/GEM → MMM
54
↑ Dyspnea 53%, pain 48%
Pinto et al,
2006
Phase II
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
Phase III
CDDP vs CDDP/Raltitrexed
250
↑ Dyspnea in both arms
especially in CDDP/Raltitrexed
Bottomley et al,
2006
Phase III
ASC + MVP vs
ASC + N vs ASC
409
= Dyspnea, QoL
↑ Pain
Muers et al,
2008
Phase II
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
PSC
Non-PSC
Survival (Months)
CDDP/Pem
CDDP
PSC vs
Non-PSC
Manegold et al, Ann Oncol 2005
15.3
12.2
9.8
6.8
HR 0.56
95% CI, 0.44-0.72
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
Pem +
BSC
BSC
p
PR (%)
18.7
1.7
<0.0001
DCR (%)
59.3
19.2
<0.0001
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
Patient
s No.
I line
II line
RR (%)
DCR (%)
PFS
(months)
OS
(months)
Serke
2007
17
CDDP/PEM
CBDCA/PEM
CDDP/PEM
CBDCA/PEM
NR
65
NR
NR
Razak
2008
4
CDDP/PEM
CDDP/PEM
CBDCA/PEM
25
100
NR
NR
Hayashi
2010
4
CDDP/PEM
CDDP/PEM
50
50
3.2
NR
Steer
2010
18
CDDP/PEM
CBDCA/PEM
CDDP/PEM
CBDCA/PEM
NR
43
6.5
NR
Ceresoli
2011
31
CDDP/PEM
CBDCA/PEM
CDDP
CDDP/PEM
CBDCA/PEM
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 “rechallenge” con pemetrexed può essere
considerato
Multimodality treatment
EPP followed by CT and RT
Authors
Sugarbaker,
et al, 1999
Maggi, et al,
2001
Rusch, 2001
Aziz et al,
2002
Lee et al,
2002
Ahamad, et
al, 2003
Stewart et
al, 2004
Pts
No.
183
Age
(years)
57
F
(%)
23
Epithelioid
(%)
56
Treatment Mortality Survival
(%)
(months)
EPP + CT +
3.8
19
RT
EPP + CT +
6.2
NR
RT
EPP + RT
7.9
17
32
53
33
100
62
62
17
68
51
< 60
-
54
EPP + CT
9.1
35
26
69
19
73
6.9
18
28
59
7
78
EPP + CT +
RT
EPP + RT
NA
24
53
57
-
87
EPP + RT
7.5
17
Multimodality treatment induction CT - EPP followed by CT and RT
Centers
SAKK
Weder 2007
6
Italy
Rea 2007
1
USA
Krug 2009
9
EORTC
Van Schill 2010
11
Patients No.
61
21
77
59
Stage
T1-3N0-2M0
T1-3N0-2M0
T1-3N0-2M0
T1-3N0-2M0
Induction
CT/Compliance
CDDP/GEM
3 cycles
95%
45 (74%)
CBDCA/GEM
3-4 cycles
95%
17 (81%)
CDDP/PEM
4 cycles
83%
54 (70%)
CDDP/PEM
3 cycles
93%
42 (74%)
Operative
mortality
2.2%
0
7%
6.5%
pCR rate
2.2%
0
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
EPP vs no-EPP
Mesothelioma and Radical Surgery (MARS) Study
• 670 pts are needed in study with
OS as the primary endpoint
• 112 pts registered
• 83 (74%) pts 3 cycles CT
• Feasibility study with the
objective of randomising 50 pts
within 1 years
R
50 pts
• Five surgical centers (2 initially
and 3 added later)
• October 2005 - november 2008
112 pts registered and 50
randomized
EPP
No. 24
EPP completed
No. 16
Treasure et al, Lancet Oncol 2011
• 5 not started, 3 abandoned
• 2 (12.5%) perioperative deaths
No-EPP
No. 26
EPP vs no-EPP
Mesothelioma and Radical Surgery (MARS) Study
OS
(months)
EPP
no-EPP
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
Brigham and Women’s Hospital, Boston, USA
2003
2006
1987-2008
Glenfield Hospital, Leicester, UK
1999-2006
54
62
E 450
NE 252
105
21,9
17
M 15, F 26
M 9, F 9
14.5
MD Anderson, Houston, USA
1999-2006
100
10.2
Toronto General Hospital, Toronto, Canada
2001-2007
45
14
University Hospital, Zurich, Switzerland
2000-2003
45
23
Swedish Cancer Institute, Seattle, USA
1997-2008
46
25
Warren Magnusen clinical Center, Bethesda, USA
1993-1996
25
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
14.5
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)
Survival
13,9
14
10,8
12
Months
10
8
6
5,5
4
1,4
2
0
EORTC
CALGB
Poor group
Curran et al, JCO 1998; Herndon et al, Chest 1998
Good group
38
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
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
Retrospective studies by targeted NGS of
cancer genes in advanced MPM (123 cases)
Pathways
Genetic
variations
Mutations
p53
DNA repair
TP53
SMACB-1
BAP-1
PIK3CA c1173A>G
STK11 rs2075606 T>C
TP53 rs104522 Pro/Pro
TTP
(p<0,01)
PIK3CA
AKT
PDGFRA
Kit
KDR
HRAS
PIK3CA
STK11
NF2
Accumulation of genetic
variations
TTP
(p=0,02)
Lo Iacono et al, J Thor Oncol 2015
Outcomes
OS
(p=0,04)
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
Krug et al, ECCO-ESMO 2011, Abstract 3BA
Primary end-point: OS
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
Slide 4
Presented By Gerard Zalcman at 2015 ASCO Annual Meeting
Phase II study CDDP/GEM +/- bevacizumab
CDDP/GEM CDDP/GEM
+ BEVA
(No. 53)
(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
Slide 7
Presented By Gerard Zalcman at 2015 ASCO Annual Meeting
Slide 12
Presented By Gerard Zalcman at 2015 ASCO Annual Meeting
Slide 24
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
Phase III study with maintenance thalidomide vs observation
(NVALT5/MATES)
CDDP/CBDCA +
Pemetrexed
4 cycles
No-PD
R
Thalidomide
Obervation
No.
111
111
PFS
(weeks)
16
15
p 0.83
HR 1.0
(95%CI 0.81.4)
Thalidomide
200 mg/day os
Observation
OS
(months)
11
13
p 0.09
HR 0.78
(95%CI 0.571.1)
Baas et al, ASCO 2011, Abstract 7006
NGR-hTNF
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
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/pemetr
exed
25 (86%)
Epithelioid
histology
25 (86%)
Stage IV
18 (62%)
EORTC PS good
23 (79%)
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
Overall Survival
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