Malignant mesothelioma is a rare but highly aggressive cancer associated with exposure to asbestos fibers (Bibby et al., 2016). Due to its insidious onset and non-specific clinical manifestations, it is mostly diagnosed in the advanced stage, leading to poor prognosis. The median OS is about 12 months, and the 5-year OS rate is about 10 % (Taioli et al., 2015).

Treatment with platinum agents plus pemetrexed has been the standard first-line systemic treatment recommendation for unresectable malignant mesothelioma since 2004 based on the EMPHASIS trial (Popat et al., 2022, Vogelzang et al., 2003). Another phase III clinical trial (IFCT-GFPC-0701 MAPS) (Zalcman et al., 2016) found that bevacizumab and doublet chemotherapy significantly increased OS and PFS, compared to cisplatin plus pemetrexed. In 2021, the CheckMate 743 trial reported that nivolumab plus ipilimumab significantly prolonged patients’ survival compared to the platinum plus pemetrexed treatment, especially in patients with biphasic or sarcomatoid histology (Peters et al., 2022) who present worse prognosis and limited benefits from chemotherapy (Billé et al., 2016). In 2023, the phase III clinical trial IND 227 reported that pembrolizumab combined with doublet chemotherapy showed significant improvement in OS and PFS compared to doublet chemotherapy only. Subgroup analysis revealed that the non-epithelioid subtype is more likely to benefit from pembrolizumab plus cisplatin and pemetrexed (Chu et al., 2023). Recently, the ATOMIC-Meso trial evaluated the efficacy and safety of adding pegargiminase, an arginine-depleting agent, or placebo to pemetrexed and platinum in patients with treatment naïve non-epithelioid mesothelioma. This trial demonstrated significantly improved OS with pegargiminase-chemotherapy compared with chemotherapy alone, providing a new option for patients with non-epithelioid mesothelioma (Szlosarek et al., 2024). The efficacy and safety of some other drugs, such as cediranib, nintedanib, and CBP501 (a synthetic duodecapeptide), have been explored in the first-line setting, but only showed limited benefits compared with standard chemotherapy (Tsao et al., 2022).

As to salvage therapies for patients with relapsed unresectable malignant mesothelioma, the efficacy and safety of immune checkpoint inhibitors (ICIs), including single-agent nivolumab, pembrolizumab, tremelimumab, and a combination of nivolumab and ipilimumab, were explored in different RCTs (Maio et al., 2017, Fennell et al., 2021, Popat et al., 2020, Scherpereel et al., 2019). Because different treatments were set as control arms in different RCTs, it is still unclear whether ICIs should be recommended as optimal treatments for relapsed malignant mesothelioma. The efficacy and safety of target therapy including ramucirumab (Pinto et al., 2021), NGR-hTNF (Gregorc et al., 2018) (anti-angiogenic treatments), and anetumab ravtansine (Kindler et al., 2022) (an antibody-drug conjugate of anti-mesothelin antibody) have been explored. Among these, only the treatment with ramucirumab and chemotherapy significantly prolongs OS compared to chemotherapy alone.

Despite the increasing number of RCTs comparing different systemic therapies for unresectable malignant mesothelioma in both first-line and salvage settings, it is still unclear what can be indicated as the optimal treatment. Clinicians also realized that malignant mesothelioma with different histological subtypes should be treated diversely. Here we aimed to evaluate different first-line and salvage systemic therapies that have been investigated in RCTs for unresectable malignant mesothelioma and performed subgroup analyses of different pathological subtypes and clinical characteristics.