Pegargiminase plus chemo improves survival in nonepithelioid pleural mesothelioma

Chemotherapy with pemetrexed and cisplatin with ADI-PEG20 (pegargiminase), an arginine-depleting agent, results in better survival and demonstrates a favourable safety profile in patients with nonepithelioid pleural mesothelioma (PM), according to a study presented at AACR 2023.

“Arginine deprivation with pegargiminase alone or combined with chemotherapy displayed antitumour activity in early phase clinical trials of argininosuccinate synthase 1 (ASS1)-deficient cancers, including PM,” said the researchers, led by Peter W Szlosarek from the Cancer Research UK Barts Center, Queen Mary University of London, London, UK.

“The nonepithelioid subtype of mesothelioma is particularly aggressive and arginine-auxotrophic due to frequent ASS1 loss,” they noted.

Szlosarek and his team conducted this double-blind, placebo-controlled phase II-III trial (ATOMIC-meso) and randomized 249 patients with nonepithelioid PM (median age 71 years, 82.7 percent male; 48.2 percent biphasic and 51.8 percent sarcomatoid) from five countries between August 2017 and August 2021 in an intention-to-treat 1:1 ratio.

Participants received either chemotherapy plus pemetrexed (500 mg/m²) and cisplatin (75 mg/m²) with pegargiminase (36 mg/m²; n=125) or chemotherapy plus placebo (n=124) up to six cycles. In the phase III portion of the study, carboplatin (AUC5) was permitted instead of cisplatin. Finally, maintenance therapy with pegargiminase or placebo continued until progression, toxicity, or 24 months.

Median overall survival (OS) was the primary endpoint, while the secondary ones included median progression-free survival (PFS), safety, pharmacodynamics, and immunogenicity. Objective response rate (ORR) was assessed by blinded independent central review (BICR) during the phase II portion using modified RECIST or RECIST v1.1.

As a result, the pegargiminase-chemotherapy arm demonstrated superior median OS when compared with placebo (9.3 vs 7.7 months; hazard ratio [HR], 0.71, 95 percent confidence interval [CI], 0.55‒0.93; p=0.023). Likewise, median PFS was longer with pegargiminase than with placebo (6.2 vs 5.6 months; HR, 0.65, 95 percent CI, 0.46‒0.90; p=0.019). [AACR 2023, abstract CT007]

Stable disease

No significant difference was observed in the ORR by BICR between the pegargiminase-chemotherapy and placebo-chemotherapy groups (13.8 percent vs 13.5 percent; p=0.95), but the disease was more stable with the experimental treatment (71.3 percent vs 62.9 percent).

Notably, plasma arginine decreased with a reciprocal increase in citrulline. By week 25, 97.4 percent of patients treated with pegargiminase showed anti-ADI-PEG20 antibodies.

Grade ≥3 treatment-related adverse events occurred in 28.8 percent of patients in the pegargiminase arm compared with 16.9 percent of those in the placebo arm. In addition, grade ≥3 hypersensitivity and skin reactions developed in 3.2 percent and 1.6 percent of participants on pegargiminase, respectively, and none of those on placebo.

Drug treatment poststudy was similar between the two cohorts (45.6 percent postpegargiminase vs 46.8 percent postplacebo).

“In this first randomized trial of an arginine-depleting chemotherapy in cancer, the pegargiminase-pemetrexed-platinum triplet prolonged survival and had a favourable safety profile in patients with nonepithelioid PM,” the researchers said.