therapies in
mesothelioma
Dr Allan Zimet
Financial Disclosure
•
Travel support-Astra Zeneca
•
Advisory Board -Novartis
Diseases caused by asbestos
•
Mesothelioma
•
Asbestosis
•
Lung Cancer
•
Laryngeal Cancer
•
Ovarian Cancer
•
Testes Cancer
•
Pleural plaques
•
Pleural thickening
•
Pleural effusion
Diseases caused by asbestos
•
Mesothelioma
•
Asbestosis
•
Lung Cancer
•
Laryngeal Cancer
•
Ovarian Cancer
•
Testes Cancer
•
Pleural plaques
•
Pleural thickening
•
Pleural effusion
Introduction
•
Current treatments
•
Newer treatments
•
Chemotherapy and Avastin
•
Pembrolizumab
•
Clinical Trials
•
Added cost of therapy
•
Quality of life improvement with therapy
Optimal Treatment of Patients With Malignant Mesothelioma
Mesothelioma: Epidemiology
•
•
•
•
•
Male:female 3:1
Latency period: 20-50 yrs
from time of environmental
exposure
Age: 6th-8th decade
Main causative agent:
asbestos
3 main histologic subtypes
• epithelioid 50-70%,
• sarcomatoid 10-20%
• biphasic or mixed 20-35%
Tsao AS, et al. J Clin Oncol. 2009;27:2081-2090.
Timeline
Courtesy Dr Tom John
Mesothelioma Current Therapy
Multimodality therapy
Surgeon
Medical oncologist
Radiotherapy Oncologist
Symptom control
Experienced team
Mesothelioma Current Therapy
Surgery
• Pleurectomy/Decortication
• EPP Extra pleural pneumonectomy, Radical Surgery
Radiotherapy
• Radical, Adjuvant
• Palliative
Chemotherapy
• median OS of ~13 months with first-line therapy 1
• response rates <10% with second-line treatment
options
1. Goudar RK et al. Ther Clin Risk Manag. 2008;4:205–11
Surgery for Mesothelioma
Surgery for mesothelioma
•Multidisciplinary
team management
•Surgery
generally not curative
•Surgical
options:
•Radical
•
Surgery
Extrapleural pneumectomy (EPP) - en block resection
of pleura, lung, diaphragm and often pericardium
•Pleurectomy/Decortication
(PD) - lung sparing pleurectomy
EPP-no survival benefit
Treasure T, Lancet Oncology Volume 12, Issue 8, 2011, 763–
772
EPP - no quality of life benefit
Treasure T, Lancet Oncology Volume 12, Issue 8, 2011, 763–772
Radiotherapy for MPM
Radiotherapy
• Radical, Adjuvant
• Palliative
• main role
Post operative adjuvant radiotherapy
does not improve survival
151 patients
Neoadjuvant Cis/prem
113 EPP
96 R0 resection
25/27
RT 55.9 Gy
27
No RT
Stahel R etc Lancet Oncology Nov 2 2015
Post operative adjuvant radiotherapy does
not improve survival
•
•
•
•
•
RT severe toxic effects
• nausea or vomiting 11%
• oesophagitis 7%
• pneumonitis 7%
One patient died of pneumonitis.
no toxic effects in the control group.
Median locoregional relapse-free
survival from surgery
• 7·6 months (95% CI 4·5–10·7)
in the no radiotherapy group
• 9·4 months (6·5–11·9) in the
radiotherapy group.
Survival
• 19 months radiotherapy
• 20.8 months no radiotherapy
Stahel R etc Lancet Oncology Nov 2 2015
1st line chemotherapy
•
Cisplatin and Pemetrexed - Phase III/category 1 (Vogelzang,
JCO 2003)
•
Other options - Phase II evidence:
•
•
Carboplatin and Pemetrexed (Ceresoli, JCO 2006);
•
Cisplatin and Gemcitabine (Nowak, BJC 2002; Van Haarst,
BJC 2002)
Monotherapy:
•
Pemetrexed (Taylor, JTO 2008);
•
Vinorelbine (Muers, Lancet 2008)
Pemetrexed + Cisplatin Superior to Cis
PFS
OS
Vogelzang et al., J Clin Oncol 21:2636-2644, 2003
Optimal Treatment of Patients With Malignant Mesothelioma
Cis-Pem vs Cis better Q of L
Event
Cisplatin
Cisplatin
+
Pemetrexe
d
HR
P Value
Response rate, %
41.3
16.7
< .001
Median TTP, mos
5.7
3.9
0.68
.001
Median OS, mos
12.1
9.3
0.77
.028
Global QoL score
45
38
.012
Improved symptom distress
51
44
.009
Vogelzang NJ, et al. J Clin Oncol. 2003;21:2636-2644.
2nd Line chemotherapy
•
no standard of care after pemetrexed failure
•
<10 % Response rate
•
5-14 M survival
•
Options
•
Pemetrexed - Phase III/category 1 (Jassem, JCO 2008)
•
Vinorelbine (Stebbing, Lung Cancer 2009)
•
Gemcitabine (Manegold, Ann Oncol 2005; van Meerbeek, Cancer 1999)
•
Immunotherapy
•
Clinical trials
Bevacizumab (Avastin) Therapy with
Cis/Gem
N = 108
OS
Survival Probability
1.00
Bevacizumab 15.6 mos
Placebo 14.7 mos
0.80
Log-rank P = .91
0.60
0.40
0.20
N = 108
0
0
12
24
36
48
Mos
Kindler HL, et al. J Clin Oncol. 2012;30:2509-2515.
Improved Survival with
Avastin+ Chemotherapy
1.0
Pemetrexed + cisplatin (n=225)
Pemetrexed + cisplatin + bevacizumab (n=223)
OS estimate
0.8
HR 0.76 (0.61–0.94)
p=0.0127
0.6
0.4
0.2
16.07
18.82
0
0
10
20
30
Time (months)
40
50
60
166
171
77
91
36
45
16
20
10
8
7
8
No. at risk
225
223
Scherpereel, et al. WCLC 2015
Improved Survival with
Avastin+ Chemotherapy
1.0
Pemetrexed + cisplatin (n=225)
Pemetrexed + cisplatin + bevacizumab (n=223)
OS estimate
0.8
HR 0.76 (0.61–0.94)
p=0.0127
0.6
0.4
0.2
16.07
18.82
0
0
10
20
30
Time (months)
40
50
60
166
171
77
91
36
45
16
20
10
8
7
8
No. at risk
225
223
Scherpereel, et al. WCLC 2015
Immunotherapy for
Mesothelioma
Pembrolizumab
Background For Pembrolizumab
PN028
•
•
T-cell inflamed phenotype and PD-L1
expression have been observed in
MPM3-6
PD-L1 expression associated with
poor prognosis in mesothelioma4
Median OS: 5.0 months for PD-L1+
vs 14.5 mo for PD-L1–
• PD-L1 positivity an independent risk
factor for OS: RR 1.71
Anti–PD-1 antibody pembrolizumab
•
•
WCLC 2015
2. 3. Kindler HL et al. Abstr. 7589 . Presented at 2014 ASCO Annual Meeting, May 30-Jun 3, 2014; Chicago, IL; 4. Cedrés S et al. PLoS ONE. 2015; 10:
e0121071; 5. Kao SC et al. Presented at iMiG 2014, Oct 21-24; Cape Town, South Africa; 6. Mansfield AS et al. JTO. 2014; 9: S7-S52.
PN028
Mesothelioma Response to Keytruda
Best Overall
Response
Complete responsea
Partial responsea
Stable disease
Progressive disease
No assessmentb
n
0
7
12
4
2
%
0
28.0
48.0
16.0
8.0
95% CI
0.0–13.7
12.1–49.4
27.8–68.7
4.5–36.1
1.0–26.0
Disease control ratea: 76.0% (95% CI, 54.9–90.6)
aBoth
confirmed and unconfirmed responses are included.
patients who discontinued therapy before the first post-treatment scan due to progressive
disease.
Data cutoff date: June 24, 2015.
bIncludes
WCLC 2015
Antitumor Activity
Treatment Exposure and
Response Durationa
Change From Baseline in Tumor Size
100
Change FromBaseline, %
80
60
PN028
60.9% with
decrease
from baseline
40






20
0
-20
-40
-60
-80
-100
0
• Duration of response
• Median: NR
• Range: 10.4 to 40.3+ wk
8
16
.
PR
PD
24
32
40
48
56
Time, weeks
Last pembrolizumab dose
→ Treatment ongoing
• 4 of 7 responses ongoing
at time of data cutoff
aBar
length is equivalent to the time to the last imaging assessment. Includes patients with ≥1
postbaseline tumor assessment (n = 23). Data cutoff date: June 24, 2015.
WCLC 2015
Treatment-Related Adverse EventsPN028
Any Grade, Occurring in
≥2 Patients
Any
N = 25
n (%)
15 (60.0)
Fatigue
6 (24.0)
Nausea
Arthralgia
Pruritus
Dry mouth
6 (24.0)
5 (20.0)
4 (16.0)
3 (12.0)
Diarrhea
2 (8.0)
Headache
2 (8.0)
Pyrexia
2 (8.0)
Rash maculopapular
2 (8.0)
Grade 3-4, Occurring in ≥1
Patient
N = 25
n (%)
Any
4 (16.0)
ALT increased
1 (4.0)
Thrombocytopenia
1 (4.0)
Iridocyclitis (uveitis)
1 (4.0)
Pyrexia
1 (4.0)
AEs of Interest Based on
Immune Etiology Ocurring
in ≥1 Patient
N = 25
n (%)
Erythema multiformea (grade
1)
1 (4.0)
Iridocyclitis (uveitis)a (grade 3)
1 (4.0)
• Median follow-up duration: 11.5 mo (range, 1.4-13.1)
• No treatment-related deaths
aOccurred
in the same patient.
Data cutoff date: June 24, 2015.
WCLC 2015
Pembrolizumab in mesothelioma AZ
July 2015
September 2015
Progression-Free Survival with Pembrolizumab
No. at risk 25
19
Data cutoff date: June 24, 2015.
14
Median, mo
(95% CI)
5.8 (3.48.2)
6-mo rate, %
50.0
12
7
2
PN028
0
WCLC 2015
Level of PD-L1 Expression and Response
Using prototype IHC assay,
no relationship between level
of PD-L1 expression on
tumor and immune cells
within tumor nests and
frequency of response
One-sided P = 0.284 by logistic
regression
Patients were eligibile for enrollment if
they had PD-L1 expression in ≥1% of
tumor or immune cells in
tumor nests or staining in the stroma.
Data cutoff date: June 24, 2015.
Cells With PD-L1 Expression, %
PN028
100
80
60
40
20
0
Responder Nonresponder
WCLC 2015
Tremelimumab 2nd line
•
Monoclonal antibody to cytotoxic T-lymphocyte antigen 4
•
29 patients
•
tremelimumab 15mg/kg (median two doses).
•
Response rate
•
2 PR (7%) 6 months, 18 months
•
disease control in nine (31%)
•
median progression-free survival of 6·2 M (95% CI 1·3–11·1)
•
median overall survival of 10·7 M (0·0–21·9).
•
14% had at least one grade 3–4 treatment-emergent adverse event wo gastrointestinal,
one neurological, two hepatic, and one pancreatic
New Studies
Morad -009-201 Amatuximab
1st line therapy with chemotherapy
MORAb-009 (amatuximab)
•
•
•
•
chimeric IgG1kappa murine
monoclonal antibody
high affinity for human
mesothelin
antibody is rapidly
internalized
induces antibody-dependent
cellular cytotoxicity
Morab Study design
New Studies
Anetumab Ravtansine
2nd line therapy
Targeted delivery of chemotherapy to
mesothelin-positive cancer cells
n 3
Phase 1 Study of Anetumab Ravtansine
Tumor response in mesothelioma population at the RP2D of 6.5 mg/kg Q3W
•
16 patients overall; 11 in 2L
•
5/16 PR (31%) in mesothelioma (4/5 MPM)
• 5/11
PR in 2L mesothelioma (45%)
→ target pivotal Phase II population
•
3/16 durable SD in mesothelioma (>126 days)
•
only 4 related SAEs, low rate of related Grade 3/4 AEs
•
Corneal epitheliopathy (ADC class effect) in 11/38 (29%) patients
•
CTCAE grade ≥3 in 3/38 patients (8%)
•
Detectable early, fully reversible, manageable through treatment interruptions and
dose reductions
Phase II 2nd-line 15743 Study design
General 2nd L
Mesothelioma
Population
Ventana IUO Kit
Patient
mesothelin
expression data
Anetumab ravtansine (Q3W)
Vinorelbine (QW)
Phase ll Design - Two-arm, controlled, open label
Primary endpoint:
Study Design:
Significance level:
Power:
P0:
P1:
Patients:
Stratification:
Accrual period:
Follow up:
Study duration:
Total number of patients:
PFS
Two-arm, anetumab ravtansine vs vinorelbine* (2:1 radomization)
0.025 (one-sided)
90%
3.6 mo
7.2 mo
advanced MPM following platinum-based 1st line
mesothelin expression level (2+ vs 3+); geographic region
19 months
3 months
22 months (FPFV-Data available)
165 randomized
*Choice of comparator not finally decided
New Studies
•
Nintedanib and chemotherapy in first line
therapy
Rationale for Nintedanib Activity in MPM
VEGF Axis and Other Pathways Important
VEGFR-2, VEGFR-3 and PDGFR
FGFR
Src and Abl
NINTEDANIB
Kinase
BIBF
IC50 (nM)
Kinase
BIBF
IC50 (nM)
VEGFR-1
24
FGFR-1
69
VEGFR-2
21
FGFR-2
37
VEGFR-3
13
FGFR-3
137
PDGFR-α
59
Src
156
PDGFR-β
60
Abl
41
1st Line+Maintenance Malignant Pleural
Mesothelioma
ARM
Patients with
unresectable MPM
(all histologies)
ECOG 0-1
No prior chemo
(evaluable or
measurable disease)
----------------Tolerability Lead-In
3-6 pts treated with
Pem/Cis+Nintedanib
 Proceed to
randomization if no
tolerability issues
R
A
N
D
O
MI
Z
E
Nintedanib: 200 mg BID
+ Pemetrexed / Cisplatin*
Non-PD
Nintedanib
Pts
Maintenance
PD
A
N = 40
N = 80
Randomized 1:1
N =40
ARM
Placebo: 200 mg BID
+ Pemetrexed / Cisplatin*
Non-PD
Placebo
Pts
Maintenance
PD
B
* 500 mg/m2 / 75 mg/m2 iv, every 21 days
Maximum Treatment Duration 6 Cycles
Primary Endpoint: - PFS: Arm A vs. Arm B
Stratification for: - Histology (epitheloid versus non epitheloid)
- Measurable versus non-measurable disease
PI: Giorgio Scagliotti, University of Turin, IT
Christian Manegold, Heidelberg University, DE
Nick Pavlakis, Royal North Shore Hosp, AU
Mesothelioma Trials on cancer.Gov
Courtesy Dr Tom John
Clouds ahead
•
Not all trials are successful
•
Cost of treatment will be
expensive
Failed trial in mesothelioma
Targeted therapy
Multitargeted Tyrosine Kinase
•
Cediranib
•
Sunitinib
•
Sorafenib
•
Pazopanib
•
Dasatinib
Future cost of treatment
•
Avastin 15mg/kg Q 3
weeks
•
~$10,000
•
6 cycles= ~$60,000
•
Possible role of
maintenance for 12 M
•
•
17 cycles
=~$170,000
Total cost =~$230,000 in
extra costs
•
Pembrolizumab 3 mg/kg Q 3
weeks
•
~$10,000
•
•
•
9 cycles= ~$90,000
Total cost =~$90,000 in
extra costs
Extra hospital admissions/tests
•
•
$1500 /admission x 15
Total hospital =$22,500
Future cost of treatment
•
Avastin 15mg/kg Q 3
weeks
•
~$10,000
•
6 cycles= ~$60,000
•
Possible role of
maintenance for 12 M
•
•
17 cycles
=~$170,000
Total cost =~$230,000 in
extra costs
•
Pembrolizumab 3 mg/kg Q 3
weeks
•
~$10,000
•
•
•
9 cycles= ~$90,000
Total cost =~$90,000 in
extra costs
Extra hospital admissions/tests
•
•
$1500 /admission x 15
Total hospital =$22,500
Future cost of treatment
•
Avastin 15mg/kg Q 3
weeks
•
~$10,000
•
6 cycles= ~$60,000
•
Possible role of
maintenance for 12 M
•
•
17 cycles
=~$170,000
Total cost =~$230,000 in
extra costs
•
Pembrolizumab 3 mg/kg Q 3
weeks
•
~$10,000
•
•
•
9 cycles= ~$90,000
Total cost =~$90,000 in
extra costs
Extra hospital admissions/tests
•
•
$1500 /admission x 15
Total hospital =$22,500
Q of L in mesothelioma
•
73 consecutive patients with
MPM
•
first-line chemotherapy with
pemetrexed and
cisplatin\carboplatin
•
followed up for a minimum of 12
months
•
focussed on the HRQoL
•
58 received chemotherapy and
15 opted for best supportive
care (BSC).
Arnold D, BJC 2015 112,1183-1189
Q of L in mesothelioma
•
the chemotherapy group maintained
HRQoL compared with the BSC
group whose overall HRQoL fell
(P=0.006) with worsening dyspnoea
and pain.
•
impact of chemotherapy was
irrespective of histological subtype
•
non-epithelioid disease had worse
HRQoL at later time points (P=0.012).
•
a falling mesothelin or improvement
on modified-RECIST CT at early
follow-up had a better HRQoL at 16
weeks.
Arnold D, BJC 2015 112,1183-1189
Summary
•
Progress in the therapy of mesothelioma has been slow
till now
•
But now a new era of promise
•
•
Bevacizumab with cisplatinum and pemetrexed
•
immunotherapy
•
monoclonal antibodies
Quality of life is improved by effective therapies