Clinical Pearls & Morning Reports
Published September 22, 2021
Malignant pleural mesothelioma has proved to be a formidable challenge for clinicians and scientists, with the 5-year survival rate continuing to languish at 5 to 10%. Read the NEJM Review Article here.
Q: What are some of the features of malignant pleural mesothelioma?
A: Malignant mesothelioma is an aggressive tumor arising from the serosal outer linings of the lungs (pleurae), heart, abdomen, and testes. Treatment trials have focused on malignant pleural mesothelioma, which accounts for 90% of cases, is often diagnosed at an advanced stage, and invariably leads to death. By far the most important risk factor for the development of malignant mesothelioma is asbestos exposure, although other risk factors, including related minerals, are beginning to emerge. Mesothelioma has a latency period of 20 to 50 years.
Q: Name a factor that is thought to have hindered efforts to treat mesothelioma.
A: Comprehensive genomic and transcriptomic sequencing of mesothelioma has revealed extensive genomic heterogeneity among patients, which probably underpins the failure of one-size-fits-all approaches to therapy. The interpatient heterogeneity of the disease has almost certainly hindered clinical trial design and results. The mutational landscape of mesothelioma is dominated by the inactivation of tumor suppressor genes, which include BAP1, CDKN2A, NF2, and SETD2.
A: Until very recently, clinically meaningful advances in systemic treatment for advanced malignant pleural mesothelioma have been lacking. Immune checkpoint inhibition leading to tumor-suppressive T-cell activation has transformed systemic therapy for multiple solid tumors. Two important studies will imminently alter the way mesothelioma is treated in the future. On the basis of promising activity in patients with relapsed disease, combination immunotherapy with nivolumab and ipilimumab, targeting the immune checkpoints programmed cell death 1 and cytotoxic T-lymphocyte antigen 4, respectively, has shown superiority as a front-line treatment as compared with standard-of-care chemotherapy (survival, 18.1 months vs. 14.1 months). This prespecified interim analysis led to FDA approval of the combination immunotherapy in 2020, the only systemic treatment for malignant pleural mesothelioma to be approved by the FDA since 2004. Nivolumab alone is also the first drug to be associated with a significant improvement in overall survival among patients with relapsed mesothelioma.
A: For patients with mesothelioma, randomized trials targeting either PD-1 or its natural ligand, PD-L1, in combination with chemotherapy have shown potential or are ongoing. A phase 1 clinical trial exploring intrapleural delivery of CAR-T cells, combined with an immune checkpoint inhibitor, in 19 patients with pleural mesothelioma showed a disease control rate of almost 60%, an exciting finding in such an early-phase study. Epigenetic silencing of the enzyme argininosuccinate synthetase 1 (ASS1) represents the first target to undergo molecularly stratified phase 3 evaluation in patients with mesothelioma. Loss of ASS1 leads to a reliance on exogenous arginine for viability and exposes a therapeutically exploitable vulnerability with the use of arginine deprivation. Tumor-suppressor gene losses, which predominate in mesothelioma, may confer sensitivity to new small molecules, providing an opportunity for drug development.