Mesothelioma – The Future – HESW Respiratory

What is the pathogenesis of mesothelioma? Nature vs nurture?

Nature
Genetics – in 2001 researchers found familial clustering of MM. In 2011 they identified BAP1 as a causative gene. This gene is related to a cancer syndrome – melanocytic intradermal lessons, clear cell renal carcinoma, cholangiocarcinoma. BAP1 is a tumour suppressor and a potential target for therapy. NF2 encodes merlin protein on Chromose 22. It is a tumour suppressor and inhibits of oncogenes in the mTOR pathway.

Clinical trials are ongoing with everolimus. This is a combined mTOR and AKT inhibitors. Mainly phase 1 trials. Other targets may include FAK inhibitors and CDKN2A (cyclin dependant kinase inhibitor on Ch9). It is deleted in 50-100% mesothelioma tumours. There is also epigenetic silencing. These factors have a role in regulating apoptosis and cell cycle arrest.

Nurture
The cancer cell exists within a permissive microenvironment. Arginine forms part of the urea cycle. Arginosuccinate synthetase ASS1 is an enzyme silenced in 63% mesothelioma. At Barts researchers have developed pegylated arginine deaminase ADI-PEG20. The ADAM study is a phase 1 and 2 trial, an RCT with 2:1 randomisation. There was improved progression free survivial (PFS) and overall survival. The effect was greater in tumours with greater loss of ASS1. The treatment was well tolerated. There was a greater effect seen in sarcomatoid patients. They are now conducting the ATOMIC trial – enrolling for non-epitheloid mesothelioma. cis/pem vs cis/pem+ADI-PEG. NCT02029690. Get your patients into clinical trials!

The cancer microenvironment is increasingly being recognised as a relevant treatment target. There are many immunotherapy targets – yay! Key targets: PD1/PD-L1, VEGF, PDGF, FGF.
VEGF is critical in tumour growth and is highly expressed in mesothelioma.

Strizzi, Luigi, et al. “Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma.” The Journal of pathology 193.4 (2001): 468-475.

Bevacizumab is a monoclonal antibody. The MAPS trial (480 patients) was triple therapy 1st line, in combination with cis/pem. There was improved PFS at 2 months and Overall Survival (OS) 2.7 months. Approved in USA and Europe. Not approved by NICE on cost effectiveness grounds.
Nintedanib is being investigated in the LUME-meso trial – actively recruiting in UK for patients with histologically confirmed epithelioid mesothelioma which is unresectable. 1st line therapy cis/pem + nintadenib. 4/12 longer PFS in initial phase. Now gone onto larger phase 3 trial for those with PS 0-1.

Pembroluzimab is a further target. 20-70% mesos are PD-L1 positive. Trials include:\

Checkmate-743 trial. Combined ipilimumab & nivolumab vs pemetrexed & platinum based drug.
CONFIRM trial – nivolumab vs placebo for pts who have progressed on chemo
PROMISE-meso – 2nd line treatment of mesothelioma for those who have progressed on chemo. 2nd line chemo (set by local guidelines) vs pembroluzimab. Cross-over trial.

What about surgery in mesothelioma?

MARS1 – showed that unselected surgery is bad
MARS2 – pleurectomy decortication vs no surgical intervention. Phase 3 trial
MesoVATS – did not address trapped lung
MesoTRAP – address issue of trapped lung. What is best way to manage? IPC vs VATS pleurectomy decortication.

Exciting times in mesothelioma research? Molecular stratification allows umbrella designs and personalised therapies.