Diffuse pleural mesothelioma remains a uniquely challenging malignancy. Its growth pattern undermines conventional imaging, its biology yields scant circulating tumor signal, and debate exists around the value and timing of surgery. Against this backdrop, we asked two simple questions of central practical importance and clinical significance. First, can immune checkpoint blockade be given before and after surgery without derailing the operative plan or compromising safety in patients with resectable pleural mesothelioma? Second, can an ultra-sensitive, tumor-informed liquid biopsy provide a clinically meaningful molecular read-out of peri-operative immunotherapy outcomes, early enough to guide therapeutic decision making?
Patients with good performance status and multidisciplinary confirmation of operability received either neoadjuvant nivolumab alone or combined with a single dose of ipilimumab. All patients who underwent resection also received post-operative therapy, including adjuvant nivolumab for one year per protocol. The co-primary endpoints were feasibility, defined a priori as proceeding to surgery without protocol-defined delay, and safety, captured by dose-limiting toxicities during the neoadjuvant window. Progression-free and overall survival were evaluated as exploratory outcomes alongside tumor-informed, whole-genome sequencing liquid biopsy, measuring circulating tumor DNA (ctDNA) at baseline, through neoadjuvant therapy, immediately pre-operatively, and again post-operatively.
The clinical verdict on feasibility and safety was clear. More than four-in-five patients in each arm reached the operating room as planned, and complete macroscopic resection was achieved in most cases. Immune-related toxicities aligned with expectations for immunotherapy agents, and adjuvant nivolumab was generally well-tolerated. These findings address the core, practical anxiety that neoadjuvant immunotherapy might derail operability, which it did not.
Efficacy signals, while exploratory in this phase 2 clinical trial setting, were encouraging and coherent. Median progression-free and overall survival favored the combination of nivolumab with ipilimumab over nivolumab alone, and a meaningful fraction of patients in the combination arm remained alive and recurrence-free at the time of data analysis. One should avoid over-interpreting arm-to-arm contrasts in this small, sequentially-accrued study, but the pattern – durable control in a subset without dramatic radiographic responses – foreshadows the central translational lesson of this work.
That lesson is that, in mesothelioma, cell-free tumor DNA detection in the bloodstream is a more reliable indicator of treatment effect than tumor measurements on imaging. Conventional response rates by modified RECIST were modest, as expected in this pleural surface-spreading cancer type, which often thins rather than shrinks; yet the ctDNA assay drew a much sharper picture. By leveraging genome-wide mutation profiles from each patient’s tumor, and utilizing a machine learning framework to suppresses technical noise in cell-free DNA, we were able to detect extraordinarily low tumor levels and track ctDNA dynamics over time. Two clinically intelligible patterns emerged.
First, detectable ctDNA during the neoadjuvant window correlated with the feasibility endpoint at the heart of this trial. Patients who ultimately could not complete surgery – either because their disease progressed between planning and incision, or because the tumor proved unresectable intraoperatively – showed persistent or rising ctDNA levels, while still being nominally eligible on imaging. This is the kind of actionable information that can promptly redirect specific patients to alternative treatment strategies.
Second, ctDNA served as an indicator of long-term progression-free survival. Patients with undetectable ctDNA by the end of neoadjuvant therapy and immediately before surgery experienced substantially longer progression-free survival than those with residual ctDNA; this same pattern held, often more strongly, when one looked at two-timepoint dynamics. Significant drops in tumor fraction from baseline, or persistently undetectable ctDNA throughout the neoadjuvant course, were observed in patients most likely to attain durable control after surgery; additionally, post-operative re-emergence of ctDNA predicted disease recurrence. Importantly, these molecular trajectories frequently diverged from scan-based impressions. In other words, ctDNA captured the direction and velocity of disease progression and therapy response when imaging techniques could not.
It is worth pausing on what, precisely, we can and cannot claim based on these data. The notion that ctDNA is prognostic, i.e., that it stratifies patients by risk independent of treatment choice – is strongly supported here, since those without detectable ctDNA at key junctures attained better outcomes. Whether ctDNA is also predictive, i.e., whether its clearance specifically marks benefit from neoadjuvant checkpoint blockade, is a more nuanced claim in a non-randomized phase 2 study without a non-immunotherapy control arm. The temporal coupling of ctDNA reduction to neoadjuvant dosing, and the association with improved clinical outcomes, together make a persuasive case that the ctDNA signal is treatment-linked. However, definitive proof will require larger, prospective trials, adequately powered to prove the clinical benefit of a ctDNA-guided adaptive therapy.
Two practical implications follow immediately. First, the trial establishes that neoadjuvant checkpoint blockade can be considered among curative-intent therapy options for resectable mesothelioma without jeopardizing surgery. Second, ctDNA residual disease after neoadjuvant immunotherapy and prior to surgery – offers a crisp, quantitative, molecular read-out that may refine individual care. Clear molecular response supports proceeding to resection, while a persistent ctDNA signal should trigger a re-consideration of medical management. After resection, reappearance of ctDNA should prompt intensified surveillance and the swift deployment of systemic therapy.
No early-phase study is without limitations. Arms were accrued sequentially, and the participating sites brought deep surgical expertise that not all centers can immediately replicate. Mesothelioma’s low mutational burden and locoregional spread will always challenge liquid biopsy analytical and clinical sensitivity. Yet even within these constraints, the core conclusions hold; perioperative immunotherapy is feasible and safe, and ctDNA provides an accurate and timely account of tumor burden dynamics and therapeutic response – something imaging alone has not reliably delivered in this setting.
Taken together, the purpose of this trial was to determine whether perioperative immune checkpoint blockade is practical in resectable mesothelioma, and whether an ultra-sensitive tumor-informed ctDNA assay can serve as an early, clinically-useful biomarker. The result is yes on both counts. The therapy was feasible and safe, and the liquid biopsies were not merely measurable, but clinically informative, identifying patients likely to attain clinical benefit, signaling those at risk of surgical attrition or early recurrence, and offering a path to more adaptive, individualized, and precise perioperative care. As the field moves to larger studies, these findings provide a clear blueprint; keep immunotherapy in the perioperative conversation, and let ctDNA, measured carefully and interpreted judiciously, guide the rhythm of that dialogue.
Dive deeper and read the full study here: https://www.nature.com/articles/s41591-025-03958-3