Clinical trials in the treatment of mesothelioma: an update

This trial considered whether chemotherapy alone or chemotherapy and surgery was better for patients with pleural mesothelioma. It was open to patients whose mesothelioma affected one side of the chest and were able to have surgery between 2015 and 2021. The results of the trial were published in 2024.

The trial involved 392 patients who underwent two cycles of chemotherapy followed by a CT scan. The result of the CT scan and the wishes of the patients determined whether they went onto the next phase of the trial. 335 patients were put forward, 166 of whom received chemotherapy alone and 169 of whom received chemotherapy as well as surgery comprising a pleurectomy decortication or an extended pleurectomy decortication.

A pleurectomy decortication involves the removal of any visible mesothelioma, the hardened and thickened outer layer of the lung surface and the lung covering (the pleura). An extended pleurectomy decortication involves removal of part or all of the heart lining and the diaphragm.

Not everyone on the trial completed their treatment with 81 out of the 335 having no further chemotherapy after the second cycle because of their mesothelioma worsening, their own choice not to take part in the trial any longer, their doctor deciding it was no longer beneficial for them to take part, or sadly as a result of their death.

157 out of the 169 patients in the chemotherapy and surgery group underwent surgery (most had an extended pleurectomy decortication).

It was revealed that, on average, patients in the chemotherapy group lived for 24.8 months whilst patients in the surgery and chemotherapy group lived for 19.3 months. Survival after 5 years was, however, quite similar between the two groups with 6 of those in the former group still alive compared to 7 in the latter group. Quality of life for those in the surgery group was considered worse than those in the former group.

The results of the trial demonstrated that extended pleurectomy decortication with chemotherapy did not extend life or improve the quality of life for those with pleural mesothelioma. Notwithstanding this, the results of MARS 2 were the subject of intense debate.

This trial was open for pleural mesothelioma patients to join between 2017 and 2021 with the results published in 2024. It considered the effect of adding a drug called ADI-PEG 20 to standard chemotherapy treatment. Professor Peter Szlosarek, Consultant Oncologist, led the trial.

The standard combination of drugs for chemotherapy treatment for patients with mesothelioma at the time was (and still is) pemetrexed and cisplatin. The doctors involved in this trial used ADI-PEG 20 to remove a substance called arginine from cancer cells to stop them growing. To assess the effectiveness of the drug, some of the mesothelioma patients receiving pemetrexed and cisplatin as part of the trial were given a placebo (or a dummy) drug as an alternative to ADI-PEG 20.

A total of 249 patients took part in the trial (124 receiving standard chemotherapy and the placebo drug and 125 receiving standard chemotherapy and ADI-PEG 20). Having followed the patients for around a year, it was revealed that those receiving ADI-PEG 20 survived almost an additional two months compared to those receiving the dummy drug. Those in the former category also found that the growth of their cancer was delayed by almost one month compared to those in the latter category.

The trial found that chemotherapy and ADI-PEG 20 resulted in some patients with pleural mesothelioma living longer. More research, including more trials, is planned to determine whether ADI-PEG 20 can also be used to treat patients with other forms of cancer.

This trial was open for lung cancer patients, including those with pleural mesothelioma, between 2015 and 2018, with the results published in 2024. Unlike the other clinical trials listed above, which explored new treatment options for pleural mesothelioma, this trial considered how to improve the process of diagnosing mesothelioma. More specifically, it looked at the effectiveness of using a PET-CT scan to find the best place to take a biopsy from the lung. It applied to patients who had already undergone at least one biopsy but were due to have another one because those biopsy results were inconclusive.

A biopsy is usually taken from thickened pleura around the outside of a patient’s lungs and guided by a CT scan (i.e. a CT-guided biopsy). Sometimes the biopsy result does not show cancer cells or the result is inconclusive even though the doctor might still suspect an underlying cancer. A PET-CT scan highlights areas where cells are more active (cancer cells are usually more active than normal cells) and so it was thought that it might be helpful for such a scan to indicate the best place to take a biopsy.

The 59 mesothelioma patients taking part in the trial were randomised into two trial groups; 29 had a usual CT-guided biopsy whilst the other 30 had a PET-CT scan followed by the usual CT-guided biopsy. The trial found that the number of patients correctly identified as having cancer following the above procedures was similar between the two groups. Furthermore, it found that it took an average of 35 days for those in the former group to receive the results of their biopsy compared to an average of 92 days for those in the latter group.

The trial revealed that a PET-CT scan was not a useful addition to the biopsy process and that repeating a CT-guided biopsy was reliable if previous biopsy results were not clear.

This trial is a prime illustration of the status quo being more beneficial to the patient but nevertheless helping to add to the knowledge base of how best to diagnose mesothelioma and other types of lung cancer.

This trial, led by Consultant Oncologist, Professor James Spicer, has been recruiting since March 2022 and will continue recruitment until the end of June 2025. It is available in several hospitals including ones in Bristol, Leeds, Manchester and London to patients suffering from a solid cancer, including pleural mesothelioma.

A new drug called RSO-021 is at the heart of this trial. RSO-021 targets an enzyme called PRX3 in cancer cells to kill them without affecting normal cells. Part 1 of the trial, which is now closed for recruitment, considered the best dose of RSO-021. Part 2 of the trial, which is still open for recruitment, is testing this dose in a higher number of patients. RSO-021 has not been used to treat people before and so more needs to be understood about its safety, efficacy, and optimum dosage.

The treatment involves having an indwelling pleural catheter inserted under the skin in the pleural space. RSO-021 is then administered through a tube in the catheter.

Patients wishing to take part in the trial have to meet certain criteria (as with all clinical trials) and will receive treatment in the outpatient department. They will also have an MRI scan, CT scan or PET-CT scan once every 6 weeks and be required to see the trial team every three months after treatment has ceased.

eVOLVE-Meso is a trial comparing volrustomig (MEDI5752) and chemotherapy with standard treatment (chemotherapy or IpiNivo) in pleural mesothelioma patients who have not yet received treatment and whose mesothelioma has spread elsewhere in the body but cannot be removed by surgery. It is a worldwide clinical trial and 40 patients are to be selected from the UK with hospitals in London, Leicester and Taunton amongst others taking part. Professor Dean Fennell, Consultant Oncologist, is the Chief Investigator leading the trial.

Volrustomig is a new immunotherapy drug, which blocks two different proteins in cancer cells. It is hoped that the trial will demonstrate that blocking these two proteins boosts the immune system’s ability to detect and fight cancer. Along the way, more will be learned about the safety of volrustomig alongside chemotherapy, its efficacy and its side effects.

Treatment is administered intravenously and, if receiving volrustomig alongside standard chemotherapy, will be given once every three weeks. Six cycles of chemotherapy is given (usually over the course of 18 weeks) and volrustomig is given for up to two years. If receiving the standard treatment of IpiNivo and standard chemotherapy, patients are given nivolumab (“Nivo”) once every 3 weeks and ipilimumab (“Ipi”) once every 6 weeks. Chemotherapy is administered in the same way as it is in the other trial group.

As with other clinical trials, patients taking part in the eVOLVE-Meso trial will be required to undergo regular scans and follow up appointments with the trial team after treatment has stopped.

Professor Dr Crispin Hiley, Consultant Oncologist, heads up this trial, which looks at the effectiveness of proton radiotherapy in treating pleural mesothelioma patients.

Proton radiotherapy is different to conventional photon radiotherapy routinely used on small areas of tissue only due to its side effects. It results in less radiation to healthy tissues surrounding the cancer and has been shown to be effective in helping patients with other lung cancers (covering a smaller area) to live longer.

The trial aims to use proton radiotherapy to treat patients with pleural mesothelioma and improve their overall survival whilst maintaining a better quality of life for longer.

Patients who meet the eligibility criteria will be randomly allocated to receive either proton radiation or the current standard of care for mesothelioma treatment, i.e. chemotherapy and photon radiation to small areas for symptom control.

The trial is available in London or Manchester and aims to recruit 148 patients in total.

New clinical trials are always coming up as doctors and researchers strive to continue to improve treatment options for mesothelioma patients but also to improve the diagnosis process, consider risks and causes of the condition, control symptoms and improve support for patients and their families.

Every result from a trial comes with it a deeper understanding, a lesson learned and, ultimately, more hope for mesothelioma patients both now and in the future. It is therefore hugely important that mesothelioma patients put themselves forward to take part in trials, that pharmaceutical companies and charities offer their financial support and medical professionals dedicate their time and expertise.