A novel treatment approach using combination immunotherapy before and after surgery shows promise for patients with operable mesothelioma, according to a new study led by investigators at the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Institute for Cancer Immunotherapy.
The study, published Sept. 8 in Nature Medicine, is the first to test perioperative (pre- and post-surgery) combination immune checkpoint blockade in mesothelioma and the first to pair it with ultra-sensitive liquid biopsy analyses to detect residual disease and link circulating tumor DNA, known as ctDNA, with clinical outcomes.
Diffuse pleural mesothelioma is a rare, aggressive cancer typically caused by asbestos exposure. For decades, few treatment advances have improved outcomes. Immunotherapy has been integrated into the standard of care for patients with inoperable mesothelioma; however, its value in the management of operable mesothelioma remains unknown. In this new study, preoperative (neoadjuvant) nivolumab, alone or in combination with ipilimumab, followed by surgery and postoperative nivolumab, was feasible and safe, with manageable side effects, and showed encouraging survival outcomes, the researchers say.
"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," says Valsamo "Elsa" Anagnostou, M.D., Ph.D., the Alex Grass Professor of Oncology, co-director of the upper aerodigestive cancers program and the study's senior author. "The approach mirrors what we've seen succeed in lung cancer, and opens a door for patients with mesothelioma, where very few options exist."
In the phase 2 trial, over 80% of patients successfully underwent surgery within the preplanned window after receiving neoadjuvant immunotherapy. Patients treated with the combination regimen (nivolumab and ipilimumab) lived a median of 28.6 months, with nearly 36% alive and recurrence-free at follow-up. Average survival for mesothelioma is 18 months.
A groundbreaking feature of the study was the implementation of a tumor-informed ultra-sensitive whole genome sequencing liquid biopsy that identifies the presence of ctDNA. This is the first time this method has been used in operable mesothelioma.
"Imaging doesn't always capture what's happening with mesothelioma, especially during treatment," says 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," says Paul Lee, a young investigator in the Molecular Oncology laboratory at the Kimmel Cancer Center and a co-first author on the study. "Our progress in characterizing mesothelioma-derived ctDNA may pave the way for more clinically meaningful, minimally invasive residual disease tracking."
Patients who had undetectable ctDNA levels after neoadjuvant immunotherapy and before surgery, or who showed a 95% or greater drop in ctDNA during treatment, experienced significantly longer event-free and overall survival. In contrast, persistent ctDNA was linked with early disease progression, even when imaging results appeared stable.
"This adds a new level of precision to treatment decision-making," says Julie Brahmer, M.D., co-director of the upper aerodigestive cancers program. "It helps distinguish patients who may need additional therapy from those who do not."
The clinical and molecular findings of the study were presented at a concurrent oral presentation at the 2025 World Conference on Lung Cancer by Joshua Reuss, M.D., assistant professor at Georgetown University's Lombardi Comprehensive Cancer Center and the study's first co-author, and Patrick Forde, M.D., professor at the Trinity St. James's Cancer Institute in Dublin, Ireland, and the study's co-senior author. Both Reuss and Forde are adjunct faculty at the Johns Hopkins University School of Medicine.
In addition to Anagnostou, Lee, Reuss, Forde and Brahmer, other researchers on the study were Reza Mehran, Chen Hu, Suqi Ke, Amna Jamali, Mimi Naijar, Noushin Niknafs, Jaime Wehr, Ezgi Oner, Qiong Meng, Gavin Pereira, Samira Hosseini-Nami, Mark Sausen, Mariana Zahurak, Richard Battafarano, Russell Hales, Joseph Friedberg, Boris Sepesi, Julie Deutsch, Tricia Cottrell, Janis Taube, Peter Illei, Kellie Smith, Drew Pardoll, Anne Tsao, and Patrick Forde.
The study was conducted across multiple academic cancer centers. The trial was sponsored by Bristol Myers Squibb. The research was supported in part by the Department of Defense Congressionally Directed Medical Research Programs grant CA190755, the Johns Hopkins Kimmel Cancer Center NCI Support Grant NCI CCSG P30 CA006973, the U.S. Food and Drug Administration grant U01FD005942-FDA, National Institutes of Health grant CA1211113, the Bloomberg~Kimmel Institute for Cancer Immunotherapy, the ECOG-ACRIN Thoracic Malignancies Integrated Translational Science Center Grant UG1CA233259, the Robyn Adler Fellowship Award, the Commonwealth Foundation, the Mark Foundation for Cancer Research, and the Florence Lomax Eley Fund.
