Last week, the Polaris Group announced positive results of its Phase 2/3 clinical trial evaluating the effectiveness of an arginine degrading enzyme agent called ADI-PEG 20. The study was conducted in patients with pleural mesothelioma who had not been previously treated, who were not candidates for surgery, and who had the sarcomatoid or biphasic type of disease. This group of patients traditionally does not respond well to standard chemotherapy treatment of pemetrexed (Alimta)/cisplatin alone.
In this study, patients were randomized into two groups. One group received the experimental drug ADI-PEG 20 in combination with pemetrexed/cisplatin. The other group received only chemotherapy. When results between the two groups were compared, the experimental group demonstrated a significant improvement in “Overall Survival” (OS) as well as “Progression Free Survival” (PFS).
“The top-line results from the ATOMIC-Meso study are nothing short of tremendous leveraging a novel area of cancer metabolism for patients by targeting arginine, specifically in non-epithelioid mesothelioma,” said Peter Szlosarek, MD, PhD, the principal investigator of this study and a medical oncologist and researcher at the Cancer Research UK Barts Cancer Institute in London, England.
“[These results] come after more than 5 decades since the first clinical use of asparaginase – the paradigm for amino acid depletion in cancer – namely childhood leukemia. ATOMIC-Meso has now set the bar for future studies of arginine deprivation in tumors requiring arginine as an essential amino acid on account of low expression of argininosuccinate synthetase 1 (ASS1),” he added.
The ADI-PEG 20 agent is an enzyme targeted at non-epithelioid pleural mesotheliomas with low ASS1 expression (a feature seen in approximately 75% of mesotheliomas in this subgroup) that degrades the arginine fueling mesothelioma cells. Mesotheliomas with this deficiency have been found to require arginine to grow, therefore Dr. Szlosarek and colleagues hypothesized that using this drug to restrict arginine would destroy the mesothelioma cells thus prolonging patient survival.
Sarcomatoid mesothelioma, and biphasic mesothelioma that is predominantly sarcomatoid, has traditionally been more difficult to control compared to its counterpart, epithelioid mesothelioma. Unlike epithelioid mesothelioma, sarcomatoid doesn’t respond well to chemotherapy. For this reason, the results of this study in this particular subgroup are even more pronounced.
“The results show a near 2-month median survival improvement for ADIPemCis (ADI-PEG 20 + Alimta + cisplatin) versus PlaceboPemCis (placebo + Alimta + cisplatin), which for a chemorefractory (chemo-resistant) subtype of mesothelioma represents a 30% reduction in the risk of death,” added Dr. Szlosarek.
Recent clinical trials have shown that patients with this more aggressive type of disease tend to respond significantly better to treatment with nivolumab + ipilimumab (Opdivo/Yervoy) than the current standard chemotherapy of Alimta + cisplatin alone.
“Further studies will be needed to determine the most effective deployment of ADI-PEG20-based chemotherapy in light of the approval of nivolumab plus ipilimumab for mesothelioma, however, there are survivors from ATOMIC-Meso beyond 3 years who have not required immunotherapy pointing to arginine deprivation as a viable alternative treatment for a subgroup of patients,” explained Dr. Szlosarek.
“As Chief Investigator I would like to thank all the patients and their families who participated in ATOMIC-meso, all the staff at research sites and Polaris Pharmaceuticals Inc., for their unwavering support. We look forward to further data being presented in 2023 with publication of the study in full,” he added.
