1. 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

2. Current drug therapy in MPM
Vogelzang NJ et al. J Clin Oncol 2003; 21(14):

3. 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

4. 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

5. Starving MPM of L-Arg with ADI-PEG20
mTOR
ASS1
Delage et al, Int J Cancer 2010
Szlosarek et al, CCR 2006

6. ADAM: PFS (primary end point)
Szlosarek et al, ASCO 2014; under review

7. PFS and OS and the degree of ASS1 loss
Szlosarek et al, ASCO 2014; in press

8. 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
ADI-PEG20 - + - + - +
C N
RRM1
RRM2
p53R2
Tubulin
Actin

9. 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
Q (US); Q (UK and Europe)

10. ImmunoRx: Blockers of CTLA4 & PD1/PDL1
Ribas, NEJM 2012

11. 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

12. ImmunoRx works in lung cancer
PD1 antibody; Topalian, NEJM 2012
PDL1 antibody Brahmer, NEJM 2012

13. Pembrolizumab (Keytruda) in lung cancer
Garon et al, NEJM 2015

14. 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]

15. 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)
PEMCIS± Amatuximab (Morphotek, Artemis study)
Anetumab ravtansine vs vinorelbine (Bayer, P2)
PEMCIS ± CRS207
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
ADI
ADI
Black=chemo
Red = mesothelin drugs
Blue = checkpoint inh
Green = Misc
Purple = Palliative
ADI-PEG20 - + - + - +
C N
RRM1
RRM2
p53R2
Tubulin
Actin