Clinical deep dive 

Mesothelioma is a cancer that forms in mesothelium, the thin layer of tissue that covers organs in the chest, abdomen and space around the heart. Mesothelioma is most commonly found in the pleura and peritoneum, but in rare instances, it can develop in the pericardium or testicles. Mesotheliomas are grouped into three main categories (epithelioid, sarcomatoid [fibrous] and mixed [biphasic]) based on their appearance.  

Symptoms of pleural mesothelioma may include shortness of breath, trouble breathing, chest pain or chronic cough due to pleural effusion. The five-year relative survival rates for pleural mesothelioma for localized, regional and distant disease are 23%, 15% and 11%, respectively. The prognosis for MPM is poor. OS is highest in patients with epithelioid MPM, followed by those with biphasic histology and lowest in those with a sarcomatoid subtype. 

Mesothelioma is a rare cancer with 2,669 cases reported in the U.S. in 2022. Most patients who develop malignant mesothelioma have lived or worked in environments where they were exposed to asbestos, the main risk factor for pleural mesothelioma. However, not all patients with asbestos exposure develop malignant mesothelioma. Asbestos, once widely used in products like automotive and construction materials, was most prevalent in the 1970s before its health risks were uncovered. Although its use has declined and asbestos-containing products have been removed from the market, exposure risk remains in older buildings and certain consumer items. As a result of reduced exposure, mesothelioma incidence has decreased. 

Mesothelioma risk also increases with age; approximately two out of three people with pleural mesothelioma are 65 years of age or older, and the cancer rarely occurs in people under 45 years of age. Mesothelioma has a higher incidence in men than in women. Other factors such as gene mutations or radiation exposure may also increase the risk of developing mesothelioma.  

Of note, pleural mesotheliomas account for more than three out of four mesotheliomas. Additionally, over half of mesotheliomas are the epithelioid subtype, which generally has a better prognosis. Sarcomatoid and mixed subtypes account for about 10% to 20% and 20% to 30% of mesotheliomas, respectively.

Mesothelioma is often difficult to treat with current treatment options generally not being curative, except in localized cases. Current treatment options include surgery, radiation therapy, chemotherapy (e.g., pemetrexed, cisplatin, carboplatin, gemcitabine, vinorelbine), immunotherapy (pembrolizumab [Keytruda], nivolumab [Opdivo], ipilimumab [Yervoy]) and targeted therapy (bevacizumab [Avastin]). Examples of first-line regimens used for biphasic or sacromatoid pleural mesothelioma histologies include Yervoy and Opdivo, carboplatin or cisplatin plus pemetrexed and Keytruda, carboplatin or cisplatin plus pemetrexed and carboplatin or cisplatin plus pemetrexed and bevacizumab. Factors such as cancer stage, patient health status and patient preferences are taken into consideration when determining a treatment strategy for malignant mesothelioma. 

Drug and clinical trial overview 

The randomized, double-blind phase 2/3 ATOMIC-Meso trial evaluated the efficacy and safety of adding pegargiminase or placebo to standard chemotherapy with pemetrexed and platinum (cisplatin or carboplatin) in patients with pleural mesothelioma. Eligible patients were 18 years of age or older with histologically proven nonresectable and treatment-naïve non-epithelioid pleural mesothelioma. Patients were randomized in a 1:1 fashion to receive either weekly pegargiminase at a dose of 36 mg/m² or placebo (until progression, toxicity or 24 months) intramuscularly and up to six cycles of standard pemetrexed and cisplatin chemotherapy. The primary efficacy endpoint was objective response rate (ORR) and OS for the phase 2 and 3 portions of the trial, respectively. A total of 249 patients were randomized with 125 patients receiving pegargiminase and chemotherapy and 124 patients receiving placebo and chemotherapy. The ORR was 13.8% in the pegargiminase group compared to 13.5% in the placebo group (P = 0.95; phase 2 portion). The median OS was 9.3 months in the pegargiminase group and 7.7 months in the placebo group (stratified hazard ratio [HR] for death, 0.71; 95% CI, 0.55-0.93; P = 0.02). The one-year OS rate was 41.4% versus 31.4% in the pegargiminase group and placebo group, respectively. At 36 months, 11.9% of patients in the pegargiminase group were alive as compared to 3.3% in the placebo group, representing a 3 to 4-fold improvement in survival. Median progression-free survival (PFS) was 6.2 months and 5.6 months in the pegargiminase and placebo groups, respectively (stratified HR for disease progression or death, 0.65; 95% CI, 0.46-0.90; P = 0.02). The number of patients who received poststudy treatments was similar between the two groups, with 57 patients (45.6%) in the pegargiminase group and 58 patients (46.8%) in the placebo group. Of note, 16.8% of patients in the pegargiminase group and 8.9% of patients in the placebo group received poststudy immune checkpoint inhibitors (P = 0.77). The incidence of treatment-emergent adverse events (TEAEs) was comparable between the groups. Most patients (98.8%) reported at least one TEAE. Nausea, fatigue and constipation were the most commonly reported TEAEs in the pegargiminase-chemotherapy group, while nausea, fatigue and anorexia were the most common in the placebo-chemotherapy group. Fatal TEAEs occurred in 7 patients (5.6%) in the pegargiminase-chemotherapy group and 12 patients (9.7%) in the placebo-chemotherapy group; 3 were possibly related to treatment (pegargiminase: n = 2, sudden death and sepsis; placebo: n = 1, sepsis). Grade 3 or higher TEAEs occurred in 36 patients (28.8%) in the pegargiminase group and in 21 patients (16.9%) in the placebo group (P = 0.03); in the pegargiminase group, anaphylactic hypersensitivity occurred in 3 patients (2.4%) and skin reactions in 2 patients (1.6%), while neither occurred in the placebo group.