Blood Test Predicts Immunotherapy Response in Operable Mesothelioma

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.

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. The combination arm’s median progression-free survival was 19.8 months versus 9.6 months.

Surgery: About 81% of participants in Arm A and 86% in Arm B proceeded to surgery within the planned window. Complete visible tumor removal was achieved in most surgical cases.

Safety: Grade 3 or higher immune-related side effects occurred in 19% of Arm A and 7% of Arm B. One dose-limiting toxicity was 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.

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.