Scientists have achieved a major breakthrough in treating mesothelioma, an aggressive asbestos-linked cancer with one of the world's worst survival rates, through a novel drug that starves tumors of essential nutrients. The phase 3 ATOMIC-meso trial demonstrated that ADI-PEG20 (pegargiminase) combined with chemotherapy quadrupled three-year survival rates compared to chemotherapy alone.
The international trial, led by Professor Peter Szlosarek at Queen Mary University of London and spanning five countries, enrolled 249 patients with pleural mesothelioma who had an average age of 70. Participants received chemotherapy every three weeks for up to six cycles, with half also receiving ADI-PEG20 injections while the other half received placebo for two years.
Significant Survival Improvements
The results, published in JAMA Oncology, showed patients who received pegargiminase-chemotherapy survived for an average of 9.3 months compared with 7.7 months for those receiving placebo-chemotherapy. The median progression-free survival was 6.2 months with the combination therapy versus 5.6 months with placebo-chemotherapy.
"In this pivotal, randomised, placebo-controlled, phase 3 trial in 249 patients with pleural mesothelioma, pegargiminase-chemotherapy increased significantly the median overall survival by 1.6 months and quadrupled the survival at 36 months compared to placebo-chemotherapy," the authors wrote. The treatment was well tolerated with no new safety signals.
Novel Mechanism of Action
The breakthrough stems from two decades of research following Szlosarek's discovery that mesothelioma cells lack a protein called ASS1, which enables cells to manufacture the amino acid arginine. ADI-PEG20 works by depleting arginine levels in the bloodstream, effectively starving tumor cells that cannot produce their own arginine due to the missing enzyme.
"It's truly wonderful to see the research into the arginine starvation of cancer cells come to fruition," said Szlosarek. "This discovery is something I have been driving from its earliest stages in the lab, with a new treatment, ADI-PEG20, now improving patient lives affected by mesothelioma."
Patient Impact
The trial's impact is exemplified by an 80-year-old patient who was given four months to live but remains alive five years later after participating in the study. "This trial has changed the lives of people with mesothelioma, allowing us to live longer," the patient said. "I have five grandchildren and two great-grandchildren now – I wouldn't want to miss all that."
The ATOMIC-meso trial was conducted at 43 centers across the UK, US, Australia, Italy, and Taiwan between 2017 and 2021. The research was funded by Cancer Research UK and biotechnology company Polaris Group.
Clinical Significance
This represents the first successful combination of a new drug with chemotherapy for mesothelioma in 20 years. Mesothelioma primarily affects the lining of the lungs and is mainly caused by workplace asbestos exposure. The disease is notoriously aggressive and deadly, with thousands of people diagnosed globally each year.
Dr. Tayyaba Jiwani of Cancer Research UK emphasized the importance of the discovery research approach: "This study shows the power of discovery research which allows us to dig deep into the biology of mesothelioma to uncover vulnerabilities that we can now target with ADI-PEG20."
Liz Darlison, chief executive of Mesothelioma UK, noted the significance for the patient community: "The UK mesothelioma community, including doctors, nurses, patients and families living with mesothelioma, are extremely proud of ATOMIC. It offers another much-needed treatment option and, above all, hope to those living with mesothelioma."
