Immunotherapy for Pleural Mesothelioma.

Abstract

Immune checkpoint inhibitors (ICIs) have changed the treatment landscape of pleural mesothelioma (PM) over the past decade. This review summarizes the history of immunotherapy in PM, covering studies of single-agent immunotherapy, combination checkpoint blockade, the integration of ICIs into frontline therapeutic strategies, and ICI-VEGF combinations. Also discussed are the emerging role of biomarkers in guiding first-line therapy selection for patients with PM and novel therapeutic approaches. Dual checkpoint blockade targeting PD-1 and CTLA-4 demonstrated clinical efficacy in early-phase studies and led to the pivotal phase III CheckMate 743 trial, which established nivolumab and ipilimumab as a standard first-line systemic therapy for PM, particularly in patients with nonepithelioid histology. Since that time, other combination therapy approaches have been explored. For example, chemoimmunotherapy studies have evaluated ICIs, including pembrolizumab and durvalumab, in combination with platinum chemotherapy, with pembrolizumab plus platinum-doublet chemotherapy expanding the approved frontline treatment options for PM. VEGF inhibition, validated in the phase III MAPS study, provided a biologic rationale for combining antiangiogenic agents with ICIs. This prompted investigation of bevacizumab in combination with atezolizumab and chemotherapy in the BEAT-meso study. Unfortunately, this combination did not provide meaningful benefit in this setting. Optimal patient selection and treatment sequencing remain undefined. Although robust data support the use of second-line immunotherapy after first-line chemotherapy, there is a paucity of evidence regarding the efficacy of chemotherapy following frontline ICI. Despite advancements in therapeutic options in PM, biomarker-driven treatment selection remains limited at this time. Future large clinical studies must incorporate validated and standardized biomarker subanalyses, including approaches such as circulating tumor DNA and multiomics, for biomarkers to become clinically relevant in this heterogeneous malignancy. Finally, novel therapeutic strategies, including bispecific antibodies, targeted therapies, perioperative immunotherapy, vaccines, and cellular therapies, are under active investigation and may further expand treatment options for patients with PM.