Download AMD2016 Peter Szlosarek

Treatment options in
mesothelioma
TUC 1st July 2016
Dr Peter Szlosarek MRCP PhD
Clinical Senior Lecturer & Consultant in Medical Oncology
Barts Cancer Institute and St Bartholomew’s Hospital
London, UK
Current drug therapy in MPM
Vogelzang NJ et al. J Clin Oncol 2003; 21(14): 2636-44.
Surgery in MPM: lack of randomized data
“In mesothelioma…complete tumor removal cannot be followed in the
sense of an R0 resection. Some microscopic disease is always left
behind…” (Sugarbaker and Wolf, Expert Rev Resp Med 2010)
Treasure et al Lancet Oncol 2011
Rintoul et al Lancet 2014
 MARS2: A Feasibility Study of Upfront chemotherapy followed by
(Extended) Pleurectomy Decortication Versus no Pleurectomy
Decortication in Patients With Malignant Pleural Mesothelioma
First things to consider with a diagnosis of MPM
Following VATS pleurodesis and biopsy
Type of mesothelioma? Epithelioid or non-epithelioid
• Is this a fast growing mesothelioma (assess by CT)?
• Is the patient symptomatic (weight loss, significant chest wall
pain etc)?
If NO to the above (i.e an indolent tumour):Expectant management or ‘watchful waiting’
If YES to the above:Biomarkers & trial enrolment/standard chemotherapy
Starving MPM of L-Arg with ADI-PEG20
120
Cell survival (% untreated)
110
mTOR
100
90
80
70
MSTO-Ctrl
MSTO-AS
60
50
40
30
20
10
0
-10
1
10
100
1000
10000
ADI-PEG (ng/mL)
ASS1
Delage et al, Int J Cancer 2010
Szlosarek et al, CCR 2006
100000
ADAM: PFS (primary end point)
Figure 1.
M e d ia n (m o n th s )
% a liv e a n d
p r o g r e s s io n - f r e e
100
90
BSC
2 .0
A D I-P E G 2 0 + B S C
3 .2
80
H a z a rd ra tio 0 .5 6 , 9 5 % C I 0 .3 3 -0 .9 6
70
lo g ra n k p = 0 .0 3
60
50
40
30
20
10
0
0
3
6
9
12
15
18
21
T im e s in c e r a n d o m is a tio n ( m o n t h s )
N o . a t ris k
BSC
24
A D I-P E G 2 0 4 4
9
1
0
0
0
24
9
4
2
2
0
1
Szlosarek et al, ASCO 2014; under review
PFS and OS and the degree of ASS1 loss
Figure 2.
#
Szlosarek et al, ASCO 2014; in press
ADAM Trial  TRAP Trial (NCT02029690)
TRAP – Tumors Requiring Arginine to Assess ADI-PEG20 with
Pemetrexed and cisPlatin: Mesothelioma & adeno NSCLC
ADI
ADI
Allen et al, Cancer Res 2014
You et al. Exploiting obligate
arginine auxotrophy in tumor
cells lacking argininosuccinate
synthetase 1 (ASS1) expression
to develop targeted molecular
therapy for non-small cell lung
cancer (NSCLC). Cancer Res
2014; 1435
Phillips et al, Cancer Res Treat 2013
ATOMIC-Meso study
• P2/3 ADIPEMCIS vs PlaceboPEMCIS
• Biphasic and sarcomatoid biology only
• Requirement for ASS1-deficiency
• PS0/1, no major comorbidities
• Multi-centre in the US, UK, Europe, Asia and Australia
• Phase 2 primary endpoint: ORR
• Phase 3 primary endpoint: PFS
• Q3 2016 (US); Q1 2017 (UK and Europe)
ImmunoRx: Blockers of CTLA4 & PD1/PDL1
Ribas, NEJM 2012
ImmunoRx revolution in metastatic melanoma
Ipilimumab
Nivolumab, PD1 blocker
(34% at 5 years)
17.9% at
5 years,
SEER
Schadendorf et al, JCO 2015; Hodi et al, AACR 2016
ImmunoRx works in lung cancer
PD1 antibody; Topalian, NEJM 2012
PDL1 antibody Brahmer, NEJM 2012
Pembrolizumab (Keytruda) in lung cancer
Garon et al, NEJM 2015
Trials of immunoRx in mesothelioma
• Alley et al: first PD1 blockade data of (Pembrolizumab, Merck) in patients
with PDL1-expressing mesothelioma post chemotherapy (≥ 1%
expression; 45% of patients), with a DCR of 76% (24% or 6/25 had a
PR/CR). 10% of patients had grade 3 AEs [IMIG 2016]
• Quispel-Janssen et al: Nivolumab in PDL1 agnostic patients revealed a
DCR of 39% (7/18 with 5 partial responses; 2 patients had
pseudoprogression prior to a partial response, including a patient with
pneumonitis and pericardial tamponade) [IMIG 2016]
• Hassan et al: Avelumab (10mg/kg; 2 wkly) in 53 PDL1 agnostic pts with a
DCR of 56.6% (5 patients with a PR; 9%). 1 grade 3 colitis [ASCO 2016]
• Kindler et al: Tremelimumab 2nd and 3rd line versus placebo (negative trial
in 571 patients) [ASCO 2016]
Sunmmary of UK Trials in MPM




PEMCIS + ADI-PEG20 or PEMCIS + placebo (ATOMIC)
PemCis + nintedanib or PemCis + placebo (NEMO)
VIM (2nd line vinorelbine versus placebo)
Pem/Cis rechallenge or vinorelbine (2nd line)
ADI
 PEMCIS± Amatuximab (Morphotek, Artemis study)
 Anetumab ravtansine vs vinorelbine (Bayer, P2)
 PEMCIS ± CRS207
ADI
 ETOP-PROMISE (Pembro vs Gem/Vin - 2nd line)
 CONFIRM P3 nivo vs placebo (2nd and 3rd line)
 EZH2 trial of tazemetostat (Epizyme)
 MARS2 (feasibility trial)
 RESPECT-meso
Black=chemo
Red = mesothelin drugs
Blue = checkpoint inh
Green = Misc
Purple = Palliative