Arginine starvation promotes OS in mesothelioma

First-line chemotherapy in combination with an investigational arginine-depleting drug improved survival in non-epithelioid pleural mesothelioma compared with chemotherapy alone, a randomized trial showed.

In the study's primary endpoint, median overall survival (OS) reached 9.3 months with the addition of pegylated arginine deiminase (ADI-PEG20; pegalgiminase) versus 7.7 months with placebo ( HR 0.71, 95% CI 0.55-0.93, P=0.02), reported Peter Slosalek, MD, of Queen Mary University of London, and his co-authors.

Addition of the first-in-class drug to pemetrexed (Alimta) and cisplatin chemotherapy similarly improved progression-free survival (6.2 months vs. 5.6 months in the placebo group; HR 0.65, 95% CI 0.46-0.90; P=0.02), according to the following findings: JAMA Oncology.

However, the standard treatment for non-epithelioid pleural mesothelioma has changed since the current trial (ATOMIC-Meso) started in 2017. Checkmate 743combination therapy of ipilimumab (Yervoy) and nivolumab (Opdivo) is currently established; approved For the initial treatment of malignant pleural mesothelioma, the non-dermoid subgroup promotes an overall survival advantage with immunotherapy (18.1 months vs. 8.8 months with chemotherapy).

Szlosarek and colleagues noted that pegalgiminase and chemotherapy do not replace the front-line approach for most patients, given the modest improvement in OS compared with pegalgiminase and chemotherapy combination therapy.

However, “pegargiminase nevertheless represents a progressive advance in chemotherapy for patients with inherently chemotherapy-resistant non-epitheloid disease. Therefore, the introduction of pegalgiminase as a second-line option alongside platinum pemetrexed” “This would be expected,” the researchers wrote. “Pegalgiminase-based chemotherapy remains a practical consideration for patients with active autoimmune disease.”

Last November, developer Polaris Group announced The company had begun a phased application to the FDA for a biologics license for pegalgiminase, an arginine-depleting agent for malignant pleural mesothelioma, but no timeline for a decision was given by the FDA.

“Cancers deficient in the tumor suppressor and urea cycle enzyme argininosuccinate synthase 1 (ASS1) are highly dependent on arginine for survival and are essentially amino acid “They are sensitive to scarcity strategies.” They added that pegalgiminase “degrades arginine to citrulline and ammonia and induces cytotoxicity in multiple ASS1-silent cancers preclinically, with evidence of single-agent activity in the clinic.”

Phase I data show that the combination of pegalgiminase and chemotherapy is associated with a favorable safety profile and high disease control rates in ASS1-deficient thoracic cancers, and that rates of neoplastic ASS1 deficiency are lower than those in non-epitheloid mesothelioma. It was three times more likely to have epithelioid mesothelioma (60% vs. 20%).

“It's really exciting to see research into arginine starvation in cancer cells come to fruition,” Dr. Slosalek said in his paper. press release. “This discovery is something I have been championing from the beginning in our lab, and our new treatment, ADI-PEG20, is now improving the lives of patients affected by mesothelioma.”

From 2017 to 2021, ATOMIC-Meso Trial At 43 centers around the world, 249 patients with nondermoid pleural mesothelioma were randomly assigned 1:1 to receive pemetrexed and cisplatin plus weekly pegalgiminase or placebo.Pegalgiminase was administered at a dose of 36.8 mg/m² Administer intramuscularly for up to 24 months until disease progression or unacceptable toxicity.

To be eligible for the trial, patients must have a documented history of unresectable, untreated disease, good performance status, adequate organ function, and expected survival of at least 3 months. was there.

The average age of participants was 69 years, 83% were male, and 93% were Caucasian. Most patients were enrolled in Europe (70%) and 21% from North America. Overall, 17% had stage I disease, 11% stage II disease, 29% stage III disease, 23% stage IV disease, and the remainder were unknown. Previous surgical history was recorded in 15% and radiotherapy in 5%.

Overall response rates between the study and placebo groups were similar (approximately 14% each).

From a safety perspective, the incidence of grade 3/4 adverse events was higher in the pegalgiminase group (28.8% vs. 16.9% in the placebo group). Drug hypersensitivity and skin reactions were seen in 2.4% and 1.6% of patients in the pegalgiminase group, respectively, but not in patients in the placebo group.