Tsao, Anne S.

In this 5-year follow-up from the CheckMate 743 study in patients with unresectable pleural mesothelioma (PM), we evaluated updated efficacy and safety outcomes and biomarkers and performed treatment-switching analyses with first-line nivolumab plus ipilimumab versus chemotherapy. With a median follow-up of 66.8 months, nivolumab plus ipilimumab demonstrated continued overall survival (OS) benefit versus chemotherapy in all randomly assigned patients (5-year OS rates, 14% v 6%; hazard ratio [HR], 0.74 [95% CI, 0.62 to 0.88]); similar benefit was observed regardless of tumor histology. Of biomarker-evaluable patients treated with nivolumab plus ipilimumab (n = 242), high baseline monocytic myeloid-derived suppressor cell (M-MDSC) levels correlated with worse OS versus low M-MDSC levels (HR, 1.25 [95% CI, 1.09 to 1.43]). After adjusting for 24% of patients in the chemotherapy arm who received subsequent immunotherapy, nivolumab plus ipilimumab demonstrated continued OS benefit versus chemotherapy (HR, 0.64 [95% CI, 0.53 to 0.78]). No new safety signals were observed. These results demonstrate long-term, durable clinical benefit with nivolumab plus ipilimumab versus chemotherapy, which continued to be preserved even after treatment-switching adjustment in the chemotherapy arm. Exploratory analyses suggested greater benefit with nivolumab plus ipilimumab in the low M-MDSC subgroup. These results further support first-line nivolumab plus ipilimumab as standard of care for unresectable PM.

Malignant pleural mesothelioma (MPM) is a rare malignancy with few treatment options. Recent advances have led to US Food and Drug Administration approvals and changes in the standard of care with a novel biomedical device approved for use with platinum-pemetrexed, and also for immunotherapy agents to be included as a frontline treatment option in unresectable disease. Although predictive biomarkers for systemic therapy are not currently in use in clinical practice, it is essential to correctly identify the MPM histology to determine an optimal treatment plan. Patients with nonepithelioid MPM may have a greater magnitude of benefit to dual immunotherapy checkpoint inhibitors and this regimen should be preferred in the frontline setting for these patients. However, all patients with MPM can derive benefit from immunotherapy treatments, and these agents should ultimately be used at some point during their treatment journey. There are ongoing studies in the frontline unresectable setting that may further define the frontline therapy space, but a critical area of research will need to focus on the immunotherapy refractory population. This review article will describe the new developments in the areas of biology with genomics and chromothripsis, and also focus on updates in treatment strategies in radiology, surgery, radiation, and medical oncology with cellular therapies. These recent innovations are generating momentum to find better therapies for this disease.