Blood Test Predicts Immunotherapy Response in Meso
Georgetown-Hopkins Phase 2 trial shows ctDNA blood test predicts which people with mesothelioma benefit from immunotherapy before surgery.
A Phase 2 clinical trial led by Georgetown and Johns Hopkins researchers has found that a blood-based biomarker called circulating tumor DNA (ctDNA) can predict which people with operable pleural mesothelioma will benefit from immunotherapy before surgery.
The study, published in Nature Medicine in September 2025, tested two immunotherapy regimens before surgical resection in 30 people with resectable disease. The combination of nivolumab and ipilimumab produced a median overall survival of 28.6 months, exceeding the historical average of about 18 months for this cancer.
What the Trial Tested
The study, registered as NCT03918252, enrolled 30 adults with resectable epithelioid or biphasic pleural mesothelioma across three academic cancer centers: Johns Hopkins, MD Anderson, and the University of Maryland.
Participants were assigned to one of two treatment arms before surgery:
- Arm A (16 patients): Three cycles of nivolumab alone
- Arm B (14 patients): Three cycles of nivolumab plus ipilimumab
After surgery, all participants received up to one year of maintenance nivolumab, with optional chemotherapy and radiation.
Key Findings
The combination immunotherapy arm showed stronger results across multiple measures. On survival, people in the combination arm (nivolumab plus ipilimumab) had a median overall survival of 28.6 months, compared with 19.3 months for nivolumab alone, and median progression-free survival of 19.8 months versus 9.6 months. On surgery, about 81% of participants in Arm A and 86% in Arm B proceeded to operation within the planned window, and most surgical cases achieved complete visible tumor removal. On safety, Grade 3 or higher immune-related side effects occurred in 19% of Arm A and 7% of Arm B, with one dose-limiting toxicity reported in each arm.
Why the ctDNA Results Matter
The most significant finding may be what the blood tests revealed.
Researchers used an ultra-sensitive method to detect tiny fragments of tumor DNA circulating in the blood. This ctDNA measurement turned out to be far more accurate than imaging scans at predicting who would do well after treatment.
People whose ctDNA became undetectable before surgery had a median progression-free survival of 23.3 months. Those with persistent ctDNA had a median of just 2.5 months before their cancer progressed.
The pattern was striking: people who achieved a 95% or greater reduction in ctDNA levels had a median progression-free survival of 23.3 months, while those with less than 95% reduction had just 1.4 months.
Circulating tumor DNA consists of small fragments of DNA that tumors shed into the bloodstream. When treatment is working, ctDNA levels drop. When the cancer is growing or coming back, ctDNA levels rise. Unlike imaging scans, which show tumor size, ctDNA can detect microscopic residual disease that scans miss.
What This Changes for Patients
This trial is the first to demonstrate that perioperative immunotherapy (treatment given both before and after surgery) is safe and feasible in operable mesothelioma. Previous major trials, including CheckMate 743, established immunotherapy as standard of care for inoperable disease, but the role of immunotherapy alongside surgery has been unclear.
The ctDNA findings could change how treatment decisions are made. If validated in larger studies, ctDNA monitoring could help oncologists identify early whether immunotherapy is working, and potentially escalate treatment for people whose ctDNA remains detectable.
Dr. Joshua Reuss, who designed the trial during his fellowship at Johns Hopkins and now practices at Georgetown’s Lombardi Comprehensive Cancer Center, noted that the study was not powered to definitively measure clinical efficacy. The ctDNA methodology needs further validation before routine clinical use.
Limitations
The trial enrolled 30 people, a small number that limits the strength of its conclusions. The study design was non-comparative, meaning the two arms were not directly pitted against each other in a head-to-head comparison. All participants were from academic cancer centers with high-volume mesothelioma programs, which may not reflect outcomes at community hospitals.
Additionally, the study included only people with resectable disease, a subset that tends to have better outcomes regardless of treatment.
The Broader Picture
This trial joins a growing body of research exploring immunotherapy before surgery for mesothelioma. A separate trial at Baylor College of Medicine and Duke University (the NEMO trial, NCT05932199) is currently enrolling people to test durvalumab and tremelimumab with and without chemotherapy before surgery.
Together, these studies reflect a shift in mesothelioma treatment strategy: from giving immunotherapy only when surgery is no longer an option, to integrating it into the surgical pathway to potentially improve long-term outcomes.
References
Nature Medicine. Perioperative Nivolumab or Nivolumab Plus Ipilimumab in Resectable Diffuse Pleural Mesothelioma: A Phase 2 Trial and ctDNA Analyses.
https://www.nature.com/articles/s41591-025-03958-3
Georgetown Lombardi Comprehensive Cancer Center. Clinical Study Deepens Understanding of Mesothelioma.
https://lombardi.georgetown.edu/news-release/clinical-study-deepens-understanding-of-mesothelioma-and-opens-the-door-to-potential-treatment-options/
ClinicalTrials.gov. NCT03918252: Perioperative Immunotherapy for Mesothelioma.
https://clinicaltrials.gov/study/NCT03918252
ScienceDaily. Blood Test Spots Hidden Mesothelioma After Treatment.
https://www.sciencedaily.com/releases/2025/09/250910000314.htm
Reader Q&A
Frequently Asked Questions
What is perioperative immunotherapy?
Perioperative immunotherapy refers to immune checkpoint inhibitor treatment given both before (neoadjuvant) and after (adjuvant) surgery. The goal is to shrink tumors before the operation and then continue treatment afterward to reduce the risk of recurrence.
What is ctDNA and why does it matter for mesothelioma?
Circulating tumor DNA (ctDNA) consists of fragments of tumor DNA found in the bloodstream. In this study, ctDNA levels predicted which people would benefit from immunotherapy far more accurately than imaging scans. People whose ctDNA became undetectable before surgery had significantly longer progression-free survival.
Is this treatment available now?
The specific combination tested in this trial (perioperative nivolumab plus ipilimumab for operable mesothelioma) is not yet standard of care. However, nivolumab and ipilimumab are individually approved for inoperable mesothelioma. People with resectable disease may want to ask their oncologist about clinical trials testing perioperative approaches.
Who led this research?
The trial was led by Dr. Joshua Reuss at Georgetown’s Lombardi Comprehensive Cancer Center and Dr. Valsamo Anagnostou at Johns Hopkins. It was presented at the 2025 World Conference on Lung Cancer in Barcelona and published in Nature Medicine.
How much does a ctDNA cost?
Studies report varying costs for circulating tumor DNA (ctDNA) testing. A budget impact analysis assumed a weighted total cost of $3500 per patient for tumor-informed ctDNA testing in colorectal cancer surveillance. Another analysis estimated ctDNA at $500 per test for posttreatment surveillance across cancers. Budget-neutral thresholds reached $16,202 for commercial payers and $5793 for Medicare Advantage payers in a first-year model. These figures include testing, treatment, and surveillance costs but exclude mesothelioma-specific data.
Can a ctDNA test be wrong?
ctDNA tests can produce false positive results due to clonal hematopoiesis of indeterminate potential (CHIP), where somatic mutations in hematopoietic cells contaminate plasma cell-free DNA, particularly in older adults with advanced cancers like metastatic castration-resistant prostate cancer (mCRPC). In one analysis of mCRPC patients without BRCA co-mutations, 25% of ATM detections and 38% of CHEK2 detections by ctDNA were negative on tumor tissue tests, suggesting CHIP-related false positives, yet PARP inhibitor efficacy remained low even in tissue-confirmed cases. ctDNA assays also risk false negatives from low tumor shedding or assay limitations, as noted in colorectal cancer evaluations. Evidence indicates pairing ctDNA with tumor tissue testing improves accuracy.
Where does mesothelioma cancer usually start?
Mesothelioma most commonly starts in the pleura, the thin membrane lining the lungs, accounting for the majority of cases. The cancer can also develop in the peritoneum, the lining of the abdominal cavity, or more rarely in the pericardium (heart lining) or tunica vaginalis testis. Asbestos fibers that are inhaled travel to the ends of small air passages and reach the pleura, where they can cause inflammation, scarring, and DNA damage that leads to uncontrolled cell growth. If asbestos fibers are swallowed, they can reach the abdominal lining and contribute to peritoneal mesothelioma.
What is the most common cancer caused by asbestos?
Lung cancer is the most common cancer caused by asbestos, followed by mesothelioma as the second-most diagnosed asbestos-related cancer. Asbestos exposure increases lung cancer risk across all forms of asbestos, with greater exposure generally correlating to higher risk. Mesothelioma, while less common than lung cancer overall, is the cancer most specifically associated with asbestos and accounts for approximately 80% of cases in the pleura (lung lining). Among occupationally exposed workers, 5% to 7% of all lung cancers are potentially related to asbestos exposure.