Pleural mesothelioma (PM) - The status of systemic therapy

Pleural mesothelioma (PM) remains a malignancy with poor prognosis. Despite initial disappointing response rates to single-agent chemotherapy, upfront platinum and anti-folate-based combination chemotherapy has remained the backbone of treatment for PM for the last three decades. The role of maintenance chemotherapy remains unclear; switch-maintenance gemcitabine has shown improvements in progression-free but not overall survival. The addition of antiangiogenic agents to chemotherapy yielded modest improvements in survival, both upfront in combination with platinum-pemetrexed, and in the relapsed setting. Immunotherapy, particularly PD-(L)1 inhibitors, has shown important but variable effectiveness in relapsed PM when used as monotherapy, and is an important salvage treatment after first-line chemotherapy. Furthermore, the randomized phase 3 trial of ipilimumab-nivolumab versus platinum-pemetrexed chemotherapy demonstrated improved overall survival favouring ipilimumab-nivolumab (HR 0.74, 96.6% CI 0.60-0.91; p = 0.0020), establishing this regimen as the new standard first-line treatment for PM, particularly in those with non-epithelioid histology. Increased interest in PM genomics has led to development of novel personalized therapeutics, such as those targeting DNA repair and EZH2 pathways, however with variable outcomes in trials. Targeting the membrane glycoprotein mesothelin and arginine deprivation are other important strategies under ongoing investigation. The field of PM is changing and new treatments bring hope to a largely lethal and poor prognostic malignancy. Despite these developments, current challenges include understanding the role of combination and multimodality treatments, drivers of resistance to treatment, and establishing predictive biomarkers to improve patient selection and treatment sequencing.