New strategy for difficult-to-treat mesothelioma: Immunotherapy and ctDNA insights

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. 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."

Joshua Reuss, MD, study's lead author, thoracic medical oncologist with Georgetown's Lombardi Comprehensive Cancer Center

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." 

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.