ASBESTOS
Clinical study deepens understanding of mesothelioma and opens the door to potential treatment options
Georgetown University Medical Center
WASHINGTON – People with operable diffuse pleural mesothelioma may benefit from immunotherapy before and after surgery, based on results of a clinical trial exploring the sequence of treatment and the role of surgery for this difficult to treat cancer.
Mesothelioma is a rare cancer that affects the tissue that lines many organs of the body. Approximately 30,000 cases are diagnosed every year worldwide, most of them in the pleura, or lining of the lungs. It occurs most often in people who have been exposed to asbestos.
“Mesothelioma is a difficult tumor to treat,” said the study’s lead author Joshua Reuss, MD, a thoracic medical oncologist with Georgetown’s Lombardi Comprehensive Cancer Center. “Our study demonstrated the feasibility and safety of using immunotherapy before surgery for patients who have tumors that can potentially be removed surgically.
“Immunotherapy is making substantial contributions to extending the lives of patients with lung cancer and many other solid tumors. This is an important step in identifying mesothelioma patients who could benefit from immunotherapy in the perioperative period, meaning right before or after their surgery and in choosing patients who are actually candidates for that surgery,” said Reuss, who is also an attending physician at MedStar Georgetown University Hospital.
Reuss designed the clinical trial during fellowship training at the Johns Hopkins Kimmel Cancer Center, the primary site where the study was conducted. He presented the results of the phase II study, Neoadjuvant Nivolumab or Nivolumab plus Ipililumab in Resectable Diffuse Pleural Mesothelioma, at the 2025 World Conference on Lung Cancer in Barcelona, Spain on September 8 and is lead author of the study published concurrently in the journal Nature Medicine (DOI 10.1038/s41591-025-03958-3).
Phase II clinical trials are designed to assess whether it is possible to deliver innovative treatments to specific patient populations, and whether the potential benefits of the therapy outweigh any adverse effects that patients experience.
“When looking at patient outcomes to date, the issue of whether any mesothelioma is truly resectable is controversial,” said Reuss. “Several major studies have not shown improvement in survival when surgery is incorporated into systemic therapy for mesothelioma. This study incorporates immunotherapy into the treatment of patients who might benefit from surgery.
“Since they occur in the tissue that lines the lungs, mesotheliomas don’t grow and spread like other cancers.” Reuss said. “They don’t typically form solid masses or nodules. These tumors are more fluid, or diffuse throughout the lining of the lung. That makes it more difficult to use our usual methods to determine how extensive a tumor is or to measure whether a treatment is effective by standard imaging assessments.”
In this study, the clinical team worked closely with scientists in the laboratory to test a novel approach studying circulating tumor DNA (ctDNA) in their patient’s blood. Tumors frequently shed cancer DNA into the blood stream. Oncologists can test the blood to detect the presence of this ctDNA, but their role in clinical decision-making is an evolving area of interest. This is particularly challenging in mesothelioma, a tumor type that has a low number of cancer mutations that can be detected by traditional ctDNA techniques.
“Imaging doesn’t always capture what’s happening with mesothelioma, especially during treatment,” said the study’s senior author, Valsamo Anagnostou, MD, PhD, the Alex Grass professor of oncology and co-director of the upper aerodigestive cancers program at Johns Hopkins. “By using an ultra-sensitive genome-wide ctDNA sequencing method, we were able to detect microscopic signs of cancer that imaging missed and predict which patients were most likely to benefit from treatment or experience relapse.”
“This approach may give us a baseline to monitor the efficacy of that treatment,” Reuss said. “If the ctDNA decreases or disappears, it is a good indication that the therapy is working, If not, it indicates a change in therapy may be warranted.” Reuss added that further validation of this methodology is required before it can routinely be incorporated into clinical practice.
“These analyses contribute to our understanding of which patients with mesothelioma may be candidates for surgery,” Reuss said. “Up until now, ctDNA assessments have not been part of the clinical landscape in the management of diffuse pleural mesothelioma, but our analyses suggest this may be nearing a change in the future.”
Phase II clinical trials are not designed to measure the clinical efficacy of treatment options but both arms of this trial showed improvements in the time from treatment to when the tumors began to grow again and overall length of survival.
Reuss cautions against drawing conclusions about that data, but notes that the results do provide positive signals about the potential value of neoadjuvant immunotherapy for mesothelioma patients with tumors that can be surgically removed and point the way to future studies.
“This is a small study,” he said, “and it does not tell us whether neoadjuvant immunotherapy will improve outcomes for these patients, but it does open windows of opportunity. We need to take what we learned and do further studies, dig deeper so that we can develop better therapies for patients with mesothelioma.”
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The study was conducted across multiple academic cancer centers. The trial was sponsored by Bristol Myers Squibb. The research was supported in part by the Department of Defense Congressionally Directed Medical Research Programs grant CA190755, the Johns Hopkins Kimmel Cancer Center NCI Support Grant NCI CCSG P30 CA006973, the US Food and Drug Administration grant U01FD005942-FDA, National Institutes of Health grant CA1211113, the Bloomberg~Kimmel Institute for Cancer Immunotherapy, the ECOG-ACRIN Thoracic Malignancies Integrated Translational Science Center Grant UG1CA233259, the Robyn Adler Fellowship Award, the Commonwealth Foundation, the Mark Foundation for Cancer Research, and the Florence Lomax Eley Fund.
Reuss reports receives research funding through Georgetown University 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, Lilly, Natera, Merck, EMD Serono, Roche Diagnostics, and OncoHost. Anagnostou reports receiving research funding from Astra Zeneca and Personal Genome Diagnostics, Bristol-Myers Squibb, and Delfi Diagnostics, is an advisor to Astra Zeneca and Neogenomics and receives honoraria from Foundation Medicine, Guardant Health, Roche and Personal Genome Diagnostics. Other author disclosures are included in the manuscript.
Additional authors include Paul K. Lee, Reza J. Mehran, Chen Hu, Suqi Ke, Amna Jamali, Mimi Najjar, Noushin Niknafs, Jaime Wehr, Ezgi Oner, Qiong Meng, Gavin Pereira, Samira Hosseini-Nami, Mark Sausen, Marianna Zahurak, Richard J. Battafarano, Russell K. Hales, Joseph Friedberg, Boris Sepesi, Julie S. Deutsch, Tricia Cottrell, Janis Taube, Peter B. Illei, Kellie N. Smith, Drew M. Pardoll, Anne S. Tsao, Julie R. Brahmer, and Patrick M. Forde.
Journal
Nature Medicine
Article Title
Perioperative nivolumab or nivolumab plus ipilimumab in resectable diffuse pleural mesothelioma: phase 2 trial results and ctDNA analyses
Article Publication Date
8-Sep-2025
COI Statement
Reuss reports receives research funding through Georgetown University 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, Lilly, Natera, Merck, EMD Serono, Roche Diagnostics, and OncoHost. Anagnostou reports receiving research funding from Astra Zeneca and Personal Genome Diagnostics, Bristol-Myers Squibb, and Delfi Diagnostics, is an advisor to Astra Zeneca and Neogenomics and receives honoraria from Foundation Medicine, Guardant Health, Roche and Personal Genome Diagnostics. Other author disclosures are included in the manuscript.
First-ever clinical trial demonstrates safety, molecular readout and promise of pre- and post-surgery immunotherapy combination for patients with operable mesothelioma
A novel treatment approach using combination immunotherapy before and after surgery shows promise for patients with operable mesothelioma, according to a new study led by investigators at the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Institute for Cancer Immunotherapy.
The study, published Sept. 8 in Nature Medicine, is the first to test perioperative (pre- and post-surgery) combination immune checkpoint blockade in mesothelioma and the first to pair it with ultra-sensitive liquid biopsy analyses to detect residual disease and link circulating tumor DNA, known as ctDNA, with clinical outcomes.
Diffuse pleural mesothelioma is a rare, aggressive cancer typically caused by asbestos exposure. For decades, few treatment advances have improved outcomes. Immunotherapy has been integrated into the standard of care for patients with inoperable mesothelioma; however, its value in the management of operable mesothelioma remains unknown. In this new study, preoperative (neoadjuvant) nivolumab, alone or in combination with ipilimumab, followed by surgery and postoperative nivolumab, was feasible and safe, with manageable side effects, and showed encouraging survival outcomes, the researchers say.
“This is the first published clinical trial to show that perioperative combination immune checkpoint blockade is not only feasible but potentially beneficial in resectable mesothelioma,” says Valsamo “Elsa” Anagnostou, M.D., Ph.D., the Alex Grass Professor of Oncology, co-director of the upper aerodigestive cancers program and the study’s senior author. “The approach mirrors what we’ve seen succeed in lung cancer, and opens a door for patients with mesothelioma, where very few options exist.”
In the phase 2 trial, over 80% of patients successfully underwent surgery within the preplanned window after receiving neoadjuvant immunotherapy. Patients treated with the combination regimen (nivolumab and ipilimumab) lived a median of 28.6 months, with nearly 36% alive and recurrence-free at follow-up. Average survival for mesothelioma is 18 months.
A groundbreaking feature of the study was the implementation of a tumor-informed ultra-sensitive whole genome sequencing liquid biopsy that identifies the presence of ctDNA. This is the first time this method has been used in operable mesothelioma.
“Imaging doesn’t always capture what’s happening with mesothelioma, especially during treatment,” says Anagnostou. “By using an ultra-sensitive genome-wide ctDNA sequencing method, we were able to detect microscopic signs of cancer that imaging missed and predict which patients were most likely to benefit from treatment or experience relapse.”
“Mesotheliomas have historically also been difficult to track using mutation-based liquid biopsies, largely due to these tumors’ low numbers of somatic mutations,” says Paul Lee, a young investigator in the Molecular Oncology laboratory at the Kimmel Cancer Center and a co-first author on the study. “Our progress in characterizing mesothelioma-derived ctDNA may pave the way for more clinically meaningful, minimally invasive residual disease tracking.”
Patients who had undetectable ctDNA levels after neoadjuvant immunotherapy and before surgery, or who showed a 95% or greater drop in ctDNA during treatment, experienced significantly longer event-free and overall survival. In contrast, persistent ctDNA was linked with early disease progression, even when imaging results appeared stable.
“This adds a new level of precision to treatment decision-making,” says Julie Brahmer, M.D., co-director of the upper aerodigestive cancers program. “It helps distinguish patients who may need additional therapy from those who do not.”
The clinical and molecular findings of the study were presented at a concurrent oral presentation at the 2025 World Conference on Lung Cancer by Joshua Reuss, M.D., assistant professor at Georgetown University’s Lombardi Comprehensive Cancer Center and the study’s first co-author, and Patrick Forde, M.D., professor at the Trinity St. James’s Cancer Institute in Dublin, Ireland, and the study’s co-senior author. Both Reuss and Forde are adjunct faculty at the Johns Hopkins University School of Medicine.
In addition to Anagnostou, Lee, Reuss, Forde and Brahmer, other researchers on the study were Reza Mehran, Chen Hu, Suqi Ke, Amna Jamali, Mimi Naijar, Noushin Niknafs, Jaime Wehr, Ezgi Oner, Qiong Meng, Gavin Pereira, Samira Hosseini-Nami, Mark Sausen, Mariana Zahurak, Richard Battafarano, Russell Hales, Joseph Friedberg, Boris Sepesi, Julie Deutsch, Tricia Cottrell, Janis Taube, Peter Illei, Kellie Smith, Drew Pardoll, Anne Tsao, and Patrick Forde.
The study was conducted across multiple academic cancer centers. The trial was sponsored by Bristol Myers Squibb. The research was supported in part by the Department of Defense Congressionally Directed Medical Research Programs grant CA190755, the Johns Hopkins Kimmel Cancer Center NCI Support Grant NCI CCSG P30 CA006973, the U.S. Food and Drug Administration grant U01FD005942-FDA, National Institutes of Health grant CA1211113, the Bloomberg~Kimmel Institute for Cancer Immunotherapy, the ECOG-ACRIN Thoracic Malignancies Integrated Translational Science Center Grant UG1CA233259, the Robyn Adler Fellowship Award, the Commonwealth Foundation, the Mark Foundation for Cancer Research, and the Florence Lomax Eley Fund.
Johns Hopkins researchers report these competing interests: Reuss receives research funding from Genentech/Roche, Verastem, Nuvalent, Arcus, Revolution Medicines, Regeneron, Amgen, Duality Bio, and Astra Zeneca, and is an advisory board member for Astra Zeneca, BMS, Daiichi Sankyo, Seagen, Gilead, Janssen, Novocure, Regeneron, Summit Therapeutics, Pfizer, Lilly, Natera, Merck, EMD Serono, Roche Diagnostics and OncoHost. Hu serves as a consultant/adviser for Belay Diagnostics LLC and Johnson & Johnson Enterprise Innovation Inc. Niknafs is an inventor on patent application 17/598,690 submitted by Johns Hopkins University Taube is adviser for AstraZeneca, Bristol Myers Squibb, Merck, Regeneron, Elephas, Lunaphore, Roche, and Moderna and has received research grants from Bristol Myers Squibb and Akoya Biosciences. Illei is a consultant/adviser for AstraZeneca, Bristol Myers Squibb, Roche, Sanofi, AbbVie, Merus, and Agilent. Smith has received honoraria from Adaptive Biotechnologies and Illumina, Inc., and research support from AbbVie, Bristol Myers Squibb and AstraZeneca. She also holds several patents related to the MANAFEST technology and TCR discovery, and is a scientific founder of Clasp Therapeutics. Pardoll holds equity in Aduro Biotech, DNAtrix, Ervaxx, Five Prime therapeutics, Immunomic, Potenza, Trieza Therapeutics and is a scientific adviser for Bristol Myers Squibb, Camden Nexus II, Five Prime Therapeutics, and WindMil and is a member of board of directors of Dracen Pharmaceuticals. Tsao receives research funding 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. Brahmer receives research funding from Astra Zeneca and BMS, is a consultant/adviser to Astra Zeneca, RAPT Therapeutics, Mestag, GSK, Amgen, Sanofi Aventis, Summit therapeutics, Genentech and Beyer and is on the Data Safety and Monitoring Board for Genmab. Forde has received research funding from AstraZeneca, Bristol Myers Squibb, Novartis, Regeneron, Kyowa and BioNTech, and is a consultant/adviser to AstraZeneca, Abbvie, Amgen, Ascendis, BioNTech, BMS, Chromacode, Daiichi Sankyo Company, F-Star, Genelux, Gilead, Iteos, Novartis, Novocure, Regeneron, Tavotek, Teva, Genentech, Sanofi, Surface, Janssen, G1 and Merck, and has served on a data safety and monitoring board for Polaris and Flame. Anagnostou receives research funding from Astra Zeneca and Personal Genome Diagnostics, Bristol-Myers Squibb, and Delfi Diagnostics, is an adviser to Astra Zeneca and Neogenomics and receives honoraria from Foundation Medicine, Guardant Health, Roche and Personal Genome Diagnostics. Anagnostou 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 The Johns Hopkins University 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 terms of all these arrangements are being managed by The Johns Hopkins University in accordance with its conflict-of-interest policies.
Journal
Nature Medicine
