Scientists have welcomed what they describe as a “truly wonderful” new drug for a hard-to-treat and aggressive form of cancer, which works by cutting a tumour’s food supply and is the first drug of its type for mesothelioma in 20 years.
The researchers, led by a team at Queen Mary University of London, said their treatment “quadrupled” three-year survival rates and increased average survival by 1.6 months.
Mesothelioma is a type of cancer that develops in the lining covering the surface of some of the body’s organs – mainly the lining of the lungs, reports The Independent. It is usually linked to asbestos exposure.
Figures from Cancer Research UK suggest there are about 2 700 new cases of mesothelioma each year in Britain, and around 2 400 deaths annually. Just 2% of people are expected to survive for 10 years beyond their diagnosis.
The new study, led by Professor Peter Szlosarek at Queen Mary, saw all patients receive chemotherapy every three weeks for up to six cycles.
Half were also given injections of new drug, ADI-PEG20 (pegargiminase) while the other half received a placebo for two years.
A total of 249 patients with pleural mesothelioma – when the disease affects the lining of the lungs – were included in the final analysis. They had an average age of 70.
The ATOMIC-meso trial, sponsored by Polaris Pharmaceuticals, was conducted at 43 centres across five countries between 2017 and 2021.
Patients involved in the study were followed up for at least a year. Those who received pegargiminase and chemotherapy survived for an average of 9.3 months, compared with 7.7 months for those who had the placebo and chemotherapy, according to the study published in JAMA Oncology.
The researchers said the average “progression-free survival” was 6.2 months with pegargiminase-chemotherapy, compared with 5.6 months among patients who had the placebo and chemotherapy.
“Median overall survival increased by 1.6 months and quadrupled the survival at 36 months compared to placebo-chemotherapy,” they wrote.
The treatment was well tolerated, with no new safety signals.
This is the first successful combination of chemotherapy with a drug that targets cancer’s metabolism developed for the disease in 20 years.
It follows two decades of work by Szlosarek after his original discovery that mesothelioma cells lack a protein called ASS1, which enables cells to manufacture the amino acid arginine.
This knowledge was used to develop the new drug.
ADI-PEG20 works by depleting arginine levels in the bloodstream: for tumour cells that cannot manufacture their arginine due to a missing enzyme, this means their growth is thwarted.
Study details
Pegargiminase Plus First-Line Chemotherapy in Patients With Nonepithelioid Pleural Mesothelioma: The ATOMIC-Meso Randomised Clinical Trial
Peter Szlosarek, Benjamin Creelan, Thomas Sarkodie, et al.
Published in JAMA Oncology on 15 February 2024
Abstract
Importance
Arginine deprivation using ADI-PEG20 (pegargiminase) combined with chemotherapy is untested in a randomised study among patients with cancer. ATOMIC-Meso (ADI-PEG20 Targeting of Malignancies Induces Cytotoxicity-Mesothelioma) is a pivotal trial comparing standard first-line chemotherapy plus pegargiminase or placebo in patients with nonepithelioid pleural mesothelioma.
Objective
To determine the effect of pegargiminase-based chemotherapy on survival in nonepithelioid pleural mesothelioma, an arginine-auxotrophic tumour.
Design, Setting, and Participants
This was a phase 2-3, double-blind randomised clinical trial conducted at 43 centres in five countries that included patients with chemotherapy-naive nonepithelioid pleural mesothelioma from August 1, 2017, to August 15, 2021, with at least 12 months’ follow-up. Final follow-up was on August 15, 2022. Data analysis was performed from March 2018 to June 2023.
Intervention
Patients were randomly assigned (1:1) to receive weekly intramuscular pegargiminase (36.8 mg/m2) or placebo. All patients received intravenous pemetrexed (500 mg/m2) and platinum (75-mg/m2 cisplatin or carboplatin area under the curve 5) chemotherapy every three weeks up to six cycles. Pegargiminase or placebo was continued until progression, toxicity, or 24 months.
Main Outcomes and Measures
The primary end point was overall survival, and secondary end points were progression-free survival and safety. Response rate by blinded independent central review was assessed in the phase 2 portion only.
Results
Among 249 randomised patients (mean [SD] age, 69.5 [7.9] years; 43 female individuals [17.3%] and 206 male individuals [82.7%]), all were included in the analysis. The median overall survival was 9.3 months (95% CI, 7.9-11.8 months) with pegargiminase-chemotherapy as compared with 7.7 months (95% CI, 6.1-9.5 months) with placebo-chemotherapy (hazard ratio [HR] for death, 0.71; 95% CI, 0.55-0.93; P = .02). The median progression-free survival was 6.2 months (95% CI, 5.8-7.4 months) with pegargiminase-chemotherapy as compared with 5.6 months (95% CI, 4.1-5.9 months) with placebo-chemotherapy (HR, 0.65; 95% CI, 0.46-0.90; P = .02). Grade 3 to 4 adverse events with pegargiminase occurred in 36 patients (28.8%) and with placebo in 21 patients (16.9%); drug hypersensitivity and skin reactions occurred in the experimental arm in 3 patients (2.4%) and 2 patients (1.6%), respectively, and none in the placebo arm. Rates of poststudy treatments were comparable in both arms (57 patients [45.6%] with pegargiminase vs 58 patients [46.8%] with placebo).
Conclusions and Relevance
In this randomised clinical trial of arginine depletion with pegargiminase plus chemotherapy, survival was extended beyond standard chemotherapy with a favourable safety profile in patients with nonepithelioid pleural mesothelioma. Pegargiminase-based chemotherapy as a novel antimetabolite strategy for mesothelioma validates wider clinical testing in oncology.
The Independent article – Cancer breakthrough as doctors celebrate new ‘wonder drug’ (Open access)
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