This study evaluates the feasibility and safety of perioperative immunotherapy in resectable diffuse malignant pleural mesothelioma (DPM) and explores the clinical application value of circulating tumor DNA (ctDNA) in assessing disease response and residual disease.
Literature Overview
This article, titled 'Perioperative nivolumab or nivolumab plus ipilimumab in resectable diffuse pleural mesothelioma: a phase 2 trial and ctDNA analyses', published in the journal Nature Medicine, reviews and summarizes the potential application of immune checkpoint blockade (ICB) therapy in resectable diffuse pleural mesothelioma (DPM), and evaluates the role of ctDNA in monitoring treatment response and residual disease. The study enrolled 30 patients divided into two groups: Arm A received nivolumab monotherapy, while Arm B received combination therapy with nivolumab and ipilimumab, followed by surgery and adjuvant therapy. The primary endpoints were safety and feasibility of treatment. Exploratory endpoints included progression-free survival (PFS), overall survival (OS), and ctDNA analysis.Background Knowledge
DPM is a rare and aggressive pleural malignancy often associated with asbestos exposure. Although surgery remains a potentially curative option, DPM exhibits a low response rate to systemic therapies and lacks effective molecular markers for evaluating residual disease and treatment response. Traditional imaging modalities (e.g., RECIST) are limited in DPM due to its growth pattern, which often does not form measurable lesions. Thus, ctDNA, as an ultrasensitive liquid biopsy tool, provides a molecular-level method to assess the efficacy of ICB. In recent years, ctDNA detection technologies, particularly those based on tumor mutation profiles and machine learning, have significantly enhanced its application in resectable cancers. This study aims to validate the safety and feasibility of ICB in perioperative settings for DPM and to assess the clinical utility of ctDNA in disease monitoring.
Research Methods and Experiments
The study employed a multicenter, multi-cohort, non-controlled phase 2 clinical trial design, enrolling 30 treatment-naïve patients with resectable DPM. Sixteen patients were assigned to Arm A to receive nivolumab monotherapy, and 14 patients were assigned to Arm B to receive combination therapy with nivolumab and ipilimumab. Both groups received three cycles of neoadjuvant treatment before surgery, followed by surgical resection and adjuvant therapy, and continued to receive nivolumab maintenance therapy for one year. The primary endpoint was the feasibility and safety of treatment. Secondary endpoints included treatment response rate and toxicity of adjuvant therapy. Exploratory endpoints included progression-free survival (PFS), overall survival (OS), and dynamic monitoring of ctDNA. ctDNA analysis was based on tumor-informed whole-genome sequencing (WGS) and machine learning models to evaluate the relationship between ctDNA clearance and disease progression.Key Conclusions and Perspectives
Research Significance and Prospects
The study supports the feasibility of perioperative ICB in resectable DPM and highlights the clinical value of ctDNA in residual disease assessment. Future research should further optimize ctDNA analysis methods and validate their predictive capacity in larger randomized trials. Additionally, integrating more personalized treatment strategies, such as targeted therapy or combination chemotherapy, may improve long-term survival in DPM patients. The application of ctDNA analysis in other tumor types with low mutation burden also warrants further investigation.
Conclusion
This study is the first systematic evaluation of the feasibility and safety of perioperative immunotherapy in resectable DPM, confirming the high sensitivity of ctDNA in monitoring residual disease and treatment response. The results demonstrate that dynamic changes in ctDNA can serve as an early biomarker for treatment response in the perioperative setting, providing a critical foundation for future personalized treatment decisions. Although the study had a small sample size and did not directly compare efficacy between Arm A and Arm B, the data support the potential of ICB in perioperative treatment of DPM. The ultrasensitive nature of ctDNA analysis offers a unique advantage in postoperative disease monitoring, enabling earlier detection of recurrence and optimizing follow-up strategies. Future research should further explore ctDNA applications in other cancers with low mutation burden and integrate more precise imaging evaluation methods to improve long-term survival outcomes in resectable DPM.
