Perioperative use of nivolumab with or without ipilimumab may prove to be of benefit for patients with resectable diffuse pleural mesothelioma, according to the findings of a phase II study published in Nature Medicine. Findings from the study were also presented during the International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer (WCLC; Abstract OA12.03).
“This is the first published clinical trial to show that perioperative combination immune checkpoint blockade is not only feasible but potentially beneficial in resectable mesothelioma,” stated senior study author Valsamo “Elsa” Anagnostou, MD, PhD, the Alex Grass Professor of Oncology, Co-Director of the Upper Aerodigestive Cancers Program, Sidney Kimmel Cancer Center, Johns Hopkins Medicine. “The approach mirrors what we’ve seen succeed in lung cancer and opens a door for patients with mesothelioma, where very few options exist.”
Rationale and Study Methods
Immunotherapy is already a standard of care for patients with advanced diffuse pleural mesothelioma. This phase II study was initiated to explore the use of immune checkpoint inhibition in the perioperative setting.
The study enrolled patients with resectable epithelioid or biphasic diffuse pleural mesothelioma to a nivolumab monotherapy arm (arm A) or a nivolumab/ipilimumab combination arm (arm B) followed by surgery, optional chemotherapy and/or radiotherapy, and then nivolumab monotherapy for a year. In arm A, 16 patients received nivolumab at 240 mg every 2 weeks for three cycles. In arm B, 14 patients received nivolumab at 3 mg/kg every 2 weeks for three cycles plus ipilimumab at 1 mg/kg on cycle 1.
Researchers also looked at circulating tumor DNA (ctDNA) residual disease detection with a whole-genome sequencing liquid biopsy as a molecular readout of the efficacy of the immunotherapy.
Key Study Findings
A total of 81.3% of patients in arm A and 85.7% of those in arm B proceeded to surgery. The median progression-free survival in arm A was 9.6 months (95% confidence interval [CI] = 2.5‒27.7 months), and the median overall survival was 19.3 months (95% CI = 14.9‒34.7 months). In arm B, the median progression-free survival was 19.8 months (95% CI = 7.1 months to not reached), and the median overall survival was 28.6 months (95% CI = 20.4 months to not reached).
Patients who had undetectable ctDNA levels after neoadjuvant immunotherapy and before surgery, or who showed significant changes in ctDNA levels during treatment, were more likely to experience longer event-free and overall survival.
Persistent ctDNA was found during neoadjuvant therapy in patients who did not undergo complete surgical resection as a result of disease progression (P = .00013). Shorter progression-free survival was observed for patients with detectable ctDNA on cycle 3 (P = .027) and prior to surgery (P = .0059).
“Imaging doesn’t always capture what’s happening with mesothelioma, especially during treatment,” said Dr. Anagnostou. “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.”
“Mesotheliomas have historically also been difficult to track using mutation-based liquid biopsies, largely due to these tumors’ low numbers of somatic mutations,” added co-first author Paul Lee, an investigator in the Molecular Oncology Laboratory at the Kimmel Cancer Center. “Our progress in characterizing mesothelioma-derived ctDNA may pave the way for more clinically meaningful, minimally invasive residual disease tracking.”
Disclosure: The study was sponsored by Bristol Myers Squibb. For full disclosures of the study authors, visit nature.com.
