Systemic Chemotherapy for Unresectable Pleural Mesothelioma from Front Line to Salvage Treatment: How Can We Treat the Patients Failed to PD-1/PD-L1 Inhibitors?

There are a limited number of randomized clinical trials on systemic chemotherapy for malignant pleural mesothelioma (MPM). The combination of platinum/pemetrexed is considered a standard front-line treatment. There is no established treatment option for those who progressed after initial treatment with platinum/pemetrexed. In recent years, immune checkpoint inhibitors (ICIs), such as pembrolizumab and nivolumab, demonstrated a favorable response, disease control, and survival in phase II trials. In 2018, nivolumab was approved for advanced or metastatic MPM patients who were resistant or intolerant to previous chemotherapy in Japan. Combinations of ICIs or an ICI and conventional chemotherapy are under investigation to further improve response and survival. If these combination regimens that include anti-program death-1 (PD1)/PD-ligand1 (PD-L1) antibodies demonstrate high enough activity, safety, and tolerability as front-line treatments, the standard regimen with platinum/pemetrexed might be replaced. The best treatment regimen to use for patients who failed PD-1/PD-L1 inhibitors has not yet been elucidated. Based on the possible immunotherapy-induced chemosensitization effect that was recently reported, cytotoxic agents, such as pemetrexed, vinorelbine, or gemcitabine, would be the ideal choice. For patients who experienced a certain time to progression after first-line chemotherapy that included pemetrexed, a pemetrexed-based rechallenge might be administered. Combination treatment with immunotherapy and antiangiogenic agents with/without chemotherapy may offer hope, though there are only preclinical studies to support this strategy so far.