Results from a phase I clinical trial led by Professor Peter Szlosarek of Barts Cancer Institute, Queen Mary University of London, were recently published in JTO Clinical and Research Reports. The trial was investigating the safety and efficacy of a new drug combination for the treatment of mesothelioma - a cancer that can develop in the lining of the lungs due to exposure to asbestos.

We spoke to Professor Szlosarek to find out more about the trial, and how the drug combination may be able to help patients with mesothelioma.

What was the aim of the trial?

This trial is an expansion study of the phase I dose-escalation study named TRAP, published in the Journal of Clinical Oncology in 2017 (Beddowes et al), and had two main aims. The first was to obtain more safety and efficacy data on the combination of the drug ADI-PEG 20 (pegargininase) with standard chemotherapy (cisplatin and pemetrexed) for patients with aggressive mesotheliomas. The second aim was to explore potential resistance mechanisms to ADI-PEG 20 by taking biopsies of patients' tumours when their cancer progressed.

Cancer biopsies are performed infrequently in mesothelioma clinical studies for a whole number of reasons, including perception of risk and patient benefit, time and expense; but biopsies are critical to understanding how to improve treatments going forward.

How does ADI-PEG 20 work?

Previous work in my laboratory found that malignant mesothelioma cells lack a protein called ASS1. This protein is responsible for the production of a key amino acid called arginine, which is required for the growth and metabolism of many aggressive tumours, including mesothelioma. As these tumour cells can’t produce their own arginine, they rely on the arginine supply in the blood stream to survive. ADI-PEG 20 works by depleting the arginine in the blood, and as a result tumour cells lacking ASS1 are ‘starved’ of this essential amino acid.

What were the outcomes of the trial, how did the patients respond to the treatment?

We found in 31 patients with mesothelioma that the treatment has a very high disease control rate of 93.5% with good safety, thus validating our previous smaller dose-escalation study (Beddowes et al, JCO 2017). In addition, twice as many patients were alive at 12 and 18 months compared to historical controls.

Analyses of patient biopsies have uncovered that mesothelioma resistance to ADI-PEG 20 was linked to a robust influx of a type of white blood cell - called macrophages - to the tumour site. Our findings point to an escape mechanism, which we have identified separately is due to ADI-PEG 20 inducing the release of an arginine precursor from macrophages at the cancer site which triggers resistance to arginine starvation.

Why is this study important for patients with mesothelioma?

Sadly, patients with aggressive mesotheliomas have a short survival of 3-10 months, thus new treatment approaches are needed urgently to improve outcomes for patients. The data so far in the dose-expansion TRAP study is encouraging and suggests a novel way to improve upon standard chemotherapy by starving the tumour cells of arginine.

What are the next steps?

The TRAP expansion study has evolved into an ongoing phase III global study called ATOMIC-meso, where about 400 patients with aggressive mesotheliomas are being recruited to receive standard chemotherapy with either ADI-PEG 20 or a placebo.

The results are expected in 2021/22 and may provide a new treatment option for patients with mesothelioma and potentially other hard-to-treat arginine-dependent cancers. We are also looking at the role of macrophages in greater detail in the laboratory and clinic to further optimise arginine depletion for cancer therapy in the future.

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The trial was funded and sponsored by Polaris Pharma Inc and the study was conducted in collaboration with partners at the Cambridge and King’s College London Experimental Cancer Medicine Centres.