Malignant pleural mesothelioma (MPM) and thymoma are rare tumor types with limited treatment options.^1,2 Chemotherapy regimens with platinum agents plus folate antimetabolites were the only approved first-line MPM treatment from 2004 until last year.¹ New treatments and diagnosis are anticipated to foster survival benefit for MPM and thymoma patients.³ More innovative diagnostic and therapeutic techniques for MPM and thymoma were discussed by thoracic oncological experts at the virtual event of World Conference on Lung Cancer 2021.³

Dr. Jennifer Sauter, MD, Assistant Attending Pathologist of the Memorial Sloan Kettering Cancer Center in New York of the United States, first shared the findings from the study of comprehensive integrative analysis, as part of The Cancer Genome Atlas (TCGA) published in 2018.³ This study confirmed that BRCA1-associated protein 1 (BAP1) was the most frequent alternation and regarded as a candidate predictive biomarker for MPM immunotherapy.³ Methylthioadenosine phosphorylase (MTAP) was also identified as a surrogate marker for detecting cyclin-Dependent Kinase Inhibitor 2A (CDKN2A) homozygous deletion by immunohistochemistry (IHC) in difficult malignancy cases.³ In addition to the landscape of gene mutations, a novel genomic near haploidization (GNH) subtype accounting for approximately 5% of MPM was observed, characterized by recurrent TP53 and SETB1 mutations, younger age at diagnosis, poor overall survival (OS), abundant tumor infiltrating lymphocytes (TILs), and necrosis compared with non-GNH subtypes.³ Of note, V-domain Ig-containing suppressor of T-cell activation (VISTA), a remarkable checkpoint gene was found in TCGA.³ “VISTA is a novel immune checkpoint inhibitor suppressing T-cell activation, which indicates a potential immunotherapy target in MPM ,” said Dr. Sauter. She stated that the emerging anti-VISTA agents were currently tried as the second-line treatment in patients with epithelioid and programmed cell death ligand-1 (PD-L1) negative MPM.³

Professor Arnaud Scherpereel of Pulmonary and Thoracic Oncology Department in the University Hospital of Lille in France introduced the application of immune checkpoint inhibitors (ICIs) to unresectable MPM.⁴ For salvage treatment, relapsed MPM patients who received nivolumab, an anti-programmed cell death protein-1 (PD-1) antibody, achieved 12-month OS at 39.5%, which was significantly higher than 26.9% for placebo group in the phase 3 CONFIRM trial.⁴ For the first-line treatment, Professor Scherpereel highlighted the findings from the phase 3 CHECKMATE 743 trial, with notable longer duration of response, OS improvement for all MPM subtypes and risk reduction of disease-related symptoms in unresectable MPM patients receiving nivolumab + ipilimumab, an anti-cytotoxic T-lymphocyte 4 (CTLA-4) antibody, versus chemotherapy.⁴ “Chemotherapy is still useful in MPM patients experiencing fast disease progression. Yet, in general, nivolumab + ipilimumab is favorable over chemotherapy in all patients based on patient-reported outcome measures, and has become the new standard of first-line treatment for unresectable MPM,” said Professor Scherpereel. He stated that more ongoing trials have been underway to test the feasibility of combining chemotherapy or alternative strategies with immunotherapy combo.⁴

As to alternative approaches, Professor Joachim Aerts, head of the Department of Pulmonary Medicine at the Erasmus University Medical Center in Rotterdam of the Netherlands, illustrated the crucial role of cellular therapies in immunotherapy for MPM and thymoma.⁵ Mesothelin (MSLN), a broad-presented tumor associated antigen, is the most frequently used chimeric antigen receptor (CAR) T-cell target in MPM thymic cancer.⁵ “There are different combination strategies underway with CAR T-cell therapy, like PD-1 inhibitor, in the aim to optimizing cellular therapy and activating innate immunity,” said Professor Aerts. Moreover, autologous monocyte-derived dendritic cells (DCs) are loaded with autologous tumor lysate, which contains broad spectrum of tumor associated antigens to activate T-cells.⁵ The clinical trials conducted by Professor Aerts and his team manifested that DC therapy was efficacious in activating tumor-directed CD8 T-cells and favorable to progression-free survival (PFS) in MPM.⁵

Dr. Meinoshin Okumura, MD, PhD, who is currently President of National Hospital Organization (NHO) at the Osaka Toneyama Medical Center of Japan, dived deep into the thymic tumor management.⁶ He mentioned that lenvatinib was approved as the first-and-ever molecular target drug for thymic carcinoma in Japan this year, with significantly higher overall response rate (ORR) at 38.1% and longer median PFS at 9.2 months compared with previous targeted therapies.⁶ Besides, Dr. Okumura pointed out that total thymectomy resulted in significantly better relapse-free survival than partial thymectomy in early-stage thymoma without myasthenia gravis (MG).⁶ “Because of the slow growing nature of thymoma, debulking surgery is widely accepted for unresectable thymoma with improved OS compared to biopsy alone,” said Dr. Okumura. He added that post-operative radiotherapy (PORT) was recommended for patients with completely resected stage II or III thymoma in recent meta-analysis, while intensity-modulated radiation therapy (IMRT) + chemotherapy and proton-beam therapy were suggested for thymic carcinoma.⁶

To sum up, novel treatments and diagnosis in recent years have optimized regimens for patients with MPM and thymoma, in spite of the small dataset and limited long-term results from various interventions, including immunotherapy and risk-reducing surgery. Further research on the combinations of different innovative treatments is necessary for providing more diversified options and promoting survival benefits for patients with MPM and thymoma.