Clinical trial explores the sequencing of immunotherapy and surgery for patients with mesothelioma

A phase II clinical trial has reported that immunotherapy given before and after surgery may offer benefits for patients with operable diffuse pleural mesothelioma. Researchers from Johns Hopkins and Georgetown universities, in the United States, have tested the feasibility of combining surgery with checkpoint inhibitors and explored circulating tumour DNA analysis to guide treatment

Patients with operable diffuse pleural mesothelioma may benefit from immunotherapy before and after surgery, according to results of a clinical trial that examined treatment sequence and the role of surgery in this rare and difficult to treat disease.

Mesothelioma is an uncommon malignancy that arises in the tissue lining of many organs in the body. Approximately 30,000 cases are diagnosed worldwide each year, most in the pleura with the disease is being linked to asbestos exposure most frequently.

“Mesothelioma is a difficult tumour to treat,” said Dr. Joshua Reuss, lead author of the study and thoracic medical oncologist at Georgetown’s Lombardi Comprehensive Cancer Center.

“Our study [has] demonstrated the feasibility and safety of using immunotherapy before surgery for patients who have tumours that can potentially be removed surgically. Immunotherapy is making substantial contributions to extending the lives of patients with lung cancer and many other solid tumours.

“This is an important step in identifying mesothelioma patients who could benefit from immunotherapy in the perioperative period – right before [and] after their surgery – and in choosing patients who are actually candidates for that surgery.” Reuss added. He is also an attending physician at MedStar Georgetown University Hospital.

Reuss designed the clinical trial while in fellowship training at the Johns Hopkins Kimmel Cancer Center, where the primary site of the study was based. He presented the findings of the phase II trial, Neoadjuvant Nivolumab or Nivolumab plus Ipililumab in Resectable Diffuse Pleural Mesothelioma, at the 2025 World Conference on Lung Cancer in Barcelona on 8 September. He is also lead author of the publication.

Phase II trials are designed to assess whether innovative treatments can be delivered safely to a defined patient population and whether the benefits outweigh adverse effects.

“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.

“They don’t typically form solid masses or nodules. These tumours 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 tumour is or to measure whether a treatment is effective by standard imaging assessments,” he continued.

In this trial, clinicians worked closely with laboratory researchers to test a novel method to study circulating tumour DNA (ctDNA) in patients’ blood. Tumours often shed fragments of cancer DNA into the bloodstream. Oncologists can detect this ctDNA, although its role in clinical decision-making is still under investigation. In mesothelioma, the challenge is greater because the tumour carries relatively few detectable mutations.

“Imaging doesn’t always capture what’s happening with mesothelioma, especially during treatment,” said senior author Dr. Valsamo Anagnostou, and the Alex Grass professor of oncology and co-director of the upper aerodigestive cancers programme 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,” she said.

“This approach may give us a baseline to monitor the efficacy of treatment,” said Reuss. “If the ctDNA decreases or disappears, it is a good indication that the therapy is working. If not, it indicates that a change in therapy may be warranted.”

He added that further validation is required before this method can be adopted routinely in 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.”

Although phase II trials are not designed to determine clinical efficacy, both arms of this study showed improvements in progression-free survival and overall survival.

Reuss warned against drawing firm conclusions but acknowledged the promising indications.

“This is a small study, 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,” he concluded.

For further reading please visit: 10.1038/s41591-025-03958-3