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

Joshua E Reuss^#^{1

2}, Paul K Lee^#², Reza J Mehran³, Chen Hu², Suqi Ke², Amna Jamali², Mimi Najjar², Noushin Niknafs², Jaime Wehr², Ezgi Oner², Qiong Meng², Gavin Pereira², Samira Hosseini-Nami², Mark Sausen⁴, Marianna Zahurak², Richard J Battafarano², Russell K Hales², Joseph Friedberg⁵, Boris Sepesi⁶, Julie S Deutsch^{2

7}, Tricia Cottrell⁸, Janis Taube^{2

9}, Peter B Illei², Kellie N Smith^{2

7

9}, Drew M Pardoll^{2

7

9}, Anne S Tsao³, Julie R Brahmer², Valsamo Anagnostou^{10

11

12}, Patrick M Forde^{13

14

15}

Affiliations

¹ Georgetown University, Department of Hematology/Oncology, Washington, DC, USA.
² Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴ Labcorp, Baltimore, MD, USA.
⁵ Fox Chase Cancer Center, Philadelphia, PA, USA.
⁶ Swedish Medical Center, Englewood, CO, USA.
⁷ Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁸ Queen's University, Kingston, Ontario, Canada.
⁹ Mark Foundation Center for Advanced Genomics and Imaging, Baltimore, MD, USA.
¹⁰ Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. vanagno1@jhmi.edu.
¹¹ Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. vanagno1@jhmi.edu.
¹² Lung Cancer Precision Medicine Center of Excellence, Johns Hopkins University School of Medicine, Baltimore, MD, USA. vanagno1@jhmi.edu.
¹³ Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. fordep1@tcd.ie.
¹⁴ Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. fordep1@tcd.ie.
¹⁵ Trinity St. James's Cancer Institute, Trinity College Dublin, Dublin, Ireland. fordep1@tcd.ie.

^# Contributed equally.

PMID: 40921804
DOI: 10.1038/s41591-025-03958-3

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

Joshua E Reuss et al. Nat Med. 2025.

. 2025 Sep 8.

doi: 10.1038/s41591-025-03958-3. Online ahead of print.

Authors

Affiliations

¹ Georgetown University, Department of Hematology/Oncology, Washington, DC, USA.
² Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴ Labcorp, Baltimore, MD, USA.
⁵ Fox Chase Cancer Center, Philadelphia, PA, USA.
⁶ Swedish Medical Center, Englewood, CO, USA.
⁷ Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁸ Queen's University, Kingston, Ontario, Canada.
⁹ Mark Foundation Center for Advanced Genomics and Imaging, Baltimore, MD, USA.
¹⁰ Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. vanagno1@jhmi.edu.
¹¹ Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. vanagno1@jhmi.edu.
¹² Lung Cancer Precision Medicine Center of Excellence, Johns Hopkins University School of Medicine, Baltimore, MD, USA. vanagno1@jhmi.edu.
¹³ Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. fordep1@tcd.ie.
¹⁴ Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. fordep1@tcd.ie.
¹⁵ Trinity St. James's Cancer Institute, Trinity College Dublin, Dublin, Ireland. fordep1@tcd.ie.

^# Contributed equally.

PMID: 40921804
DOI: 10.1038/s41591-025-03958-3

Abstract

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 neoadjuvant therapy in patients who did not undergo complete surgical resection due to disease progression (Fisher's exact test, P = 0.00013). Patients with detectable ctDNA on cycle 3 and pre-surgery had shorter PFS (log-rank test, P = 0.027 and P = 0.0059, respectively); this association was more pronounced when quantitative ctDNA changes were considered (log-rank test, P = 1.8 × 10^-6). Our findings support the feasibility of neoadjuvant ICB and the clinical utility of ctDNA analyses to capture residual disease in resectable DPM. ClinicalTrials.gov identifier: NCT03918252 .

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Conflict of interest statement

Competing interests: J.E.R. receives research funding to his institution from Genentech/Roche, Verastem, Nuvalent, Arcus, Revolution Medicines, Regeneron, Amgen, DualityBio and AstraZeneca and serves in a consultant/advisory role for AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Seagen, Gilead, Janssen, Novocure, Regeneron, Summit Therapeutics, Pfizer, Eli Lilly, Natera, Merck, EMD Serono, Roche Diagnostics and OncoHost. C.H. serves in a consultant/advisory role for Belay Diagnostics and Johnson & Johnson. N.N. is an inventor on patent application 17/598,690 submitted by Johns Hopkins University related to genomic features of response to immunotherapy. M.S. is employed by and owns stock in Labcorp. J.S.D. receives research funding to the institution from Bristol Myers Squibb and is a consultant for NextPoint Therapeutics. J.T. has participated on advisory boards for AstraZeneca, Bristol Myers Squibb, Merck, Regeneron, Elephas, Lunaphore, Roche and Moderna and has received research grants from Bristol Myers Squibb and Akoya Biosciences. T.R.C. reports research funding received by the institution from Janssen; receiving honoraria from AstraZeneca, the Society for Immunotherapy of Cancer and TotalCME; and being named on a patent for a machine learning algorithm for immune-related pathologic response criteria. P.B.I. reports consulting/advisory board membership for AstraZeneca, Bristol Myers Squibb, Roche, Sanofi, AbbVie, Merus and Agilent. K.N.S. has received honoraria from Adaptive Biotechnologies and Illumina; has received research support from AbbVie, Bristol Myers Squibb and AstraZeneca; holds several patents related to the MANAFEST technology and TCR discovery; and is a scientific founder of Clasp Therapeutics. D.M.P. holds equity in Aduro Biotech, DNAtrix, Ervaxx, Five Prime Therapeutics, Immunomic, Potenza and Trieza Therapeutics. D.M.P. is a member of scientific advisory boards for Bristol Myers Squibb, Camden Nexus II, Five Prime Therapeutics and WindMIL. D.M.P. is a member of the board of directors for Dracen Pharmaceuticals. A.S.T. receives research funding to the institution from Ariad, Bristol Myers Squibb, Eli Lilly, Genentech, Millennium, Polaris, AstraZeneca, Boehringer Ingelheim, Epizyme, Merck, Novartis and Seattle Genetics and receives consulting fees from Ariad, Bristol Myers Squibb, Eli Lilly, Genentech, Merck, Pfizer, Seattle Genetics, AstraZeneca, Boehringer Ingelheim, EMD Serono, GlaxoSmithKline, Novartis and Roche. J.R.B. receives research funding to Johns Hopkins University from AstraZeneca and Bristol Myers Squibb; serves in a consultant/advisory role for AstraZeneca, RAPT Therapeutics, Mestag, GlaxoSmithKline, Amgen, Sanofi Aventis, Summit Therapeutics, Genentech and Bayer; and is on the Data Safety and Monitoring Board (DSMB) for Genmab. P.M.F. has received research funding (directly to the institution) from AstraZeneca, Bristol Myers Squibb, Novartis, Regeneron, Kyowa and BioNTech; has served in a consultant/advisory role for AstraZeneca, AbbVie, Amgen, Ascendis, BioNTech, Bristol Myers Squibb, ChromaCode, Daiichi Sankyo, F-Star, Genelux, Gilead, iTeos, Novartis, Novocure, Regeneron, Tavotek, Teva, Genentech, Sanofi, Surface, Janssen, G1 and Merck; and has served on DSMBs for Polaris and Flame. V.A. receives research funding to Johns Hopkins University from AstraZeneca and Personal Genome Diagnostics; has received research funding to Johns Hopkins University from Bristol Myers Squibb and Delfi Diagnostics in the past 5 years; is an advisory board member for AstraZeneca and NeoGenomics (compensated); and receives honoraria from Foundation Medicine, Guardant Health, Roche and Personal Genome Diagnostics. These arrangements have been reviewed and approved by Johns Hopkins University in accordance with its conflict of interest policies. V.A. is an inventor on patent applications (63/276,525, 17/779,936, 16/312,152, 16/341,862, 17/047,006 and 17/598,690) submitted by Johns Hopkins University related to cancer genomic analyses, ctDNA therapeutic response monitoring and immunogenomic features of response to immunotherapy that have been licensed to one or more entities. Under the terms of these license agreements, the university and inventors are entitled to fees and royalty distributions. The other authors declare no competing interests.

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

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

Authors

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Conflict of interest statement

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