Perioperative nivolumab or nivolumab plus ipilimumab in resectable diffuse pleural mesothelioma: a phase 2 trial and ctDNA analyses

作者：Joshua E. Reuss, Paul K. Lee, Reza J. Mehran, Chen Hu, Suqi Ke, Amna Jamali, Mimi Najjar, Noushin Niknafs, Jaime Wehr, Ezgi Öner, Qiong Meng, Gavin Pereira, Samira Hosseini-Nami, Mark Sausen, Marianna Zahurak, Richard J. Battafarano, Russell K. Hales, Joseph S. Friedberg, Boris Sepesi, Julie S. Deutsch, Tricia R. Cottrell, Janis M. Taube, Peter B. Illei, Kellie N. Smith, Drew M. Pardoll, Anne S. Tsao, Julie R. Brahmer, Valsamo Anagnostou, Patrick M. Forde · 发表于：Nature Medicine · 年份：2025 · DOI：10.1038/s41591-025-03958-3 · 被引用次数：19 · 研究领域：Occupational and environmental lung diseases、Pleural and Pulmonary Diseases、Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis

Immune checkpoint blockade (ICB) is standard of care in advanced diffuse pleural mesothelioma (DPM), but its role in the perioperative management of DPM is unclear. In tandem, circulating tumor DNA (ctDNA) ultra-sensitive residual disease detection has shown promise in providing a molecular readout of ICB efficacy across resectable cancers. This phase 2 trial investigated neoadjuvant nivolumab and nivolumab/ipilimumab in resectable DPM along with tumor-informed liquid biopsy residual disease assessments. Patients with resectable epithelioid/biphasic DPM enrolled sequentially to nivolumab 240 mg every 2 weeks (q2w) for three cycles (Arm A, n = 16) or nivolumab 3 mg kg−1 q2w for three cycles plus ipilimumab 1 mg kg−1 on cycle 1 (Arm B, n = 14), followed by surgery, optional chemotherapy and/or radiotherapy, and nivolumab 480 mg q4w for 1 year. Co-primary endpoints included safety and feasibility; key exploratory endpoints included progression-free survival (PFS), overall survival (OS) and ctDNA analyses. The trial met its primary endpoints, and, in Arms A and B, 81.3% and 85.7% of patients proceeded to surgery, respectively. Treatment was safe, with a single dose-limiting toxicity in each arm. In Arm A, median PFS and OS were 9.6 months (95% confidence interval (CI): 2.5–27.7) and 19.3 months (95% CI: 14.9–34.7), respectively. In Arm B, median PFS and OS were 19.8 months (7.1–not reached) and 28.6 months (20.4–not reached), respectively. Persistent ctDNA was detected during neo...