Results from an early phase clinical trial, presented at the recent World Conference on Lung Cancer Meeting in Barcelona, Spain, and published in Nature Medicine, show that patients with mesothelioma who received combination neoadjuvant immunotherapy had successful surgeries and encouraging early outcomes.
Prof Patrick Forde, Trinity St James’s Cancer Institute (TSJCI) and School of Medicine, Trinity College Dublin, led the first clinical trial of combination immunotherapy before surgery for mesothelioma, a rare lung cancer that affects about 30,000 patients globally each year, with increased incidence in regions with high asbestos exposure.
While surgery is a potential option for some patients with mesothelioma, it rarely cures the cancer as tumour tends to infiltrate around the lungs making it difficult to remove completely. Immune checkpoint inhibitors, in particular those that block PD-1 and CTLA4 receptors, have led to improved survival for patients with advanced mesothelioma.
However, up until now, no study has examined their combined use before surgery for mesothelioma. This phase 2 trial investigated the use of neoadjuvant nivolumab and nivolumab/ipilimumab in resectable diffuse pleural mesothelioma (DPM) along with tumour-informed liquid biopsy residual disease assessments.
Patients received either a single immunotherapy drug (Arm A) or combination immunotherapy (Arm B) for six weeks before mesothelioma surgery followed by up to one year of immunotherapy after the operation.
The trial met its primary endpoints, and, in Arms A and B, 81.3 per cent and 85.7 per cent of patients proceeded to surgery, respectively. Treatment was safe, with a single dose-limiting toxicity in each arm.
In Arm A, median progression-free survival (PFS) and overall survival (OS) were 9.6 months [95% CI: 2.5–27.7] and 19.3 months [95% CI: 14.9–34.7], respectively. In Arm B, median PFS and OS were 19.8 months (7.1–not reached) and 28.6 months (20.4–not reached), respectively. Follow-up of patients who received combination immunotherapy showed improved survival compared to previous clinical trials that did not use immunotherapy.
In collaboration with colleagues at Johns Hopkins University, US, analysis of blood samples taken before and during treatment showed that tracking fragments of circulating tumour DNA (ctDNA) could help predict benefit from the treatment, including the likelihood of a successful surgery and avoiding relapse of cancer.
Together, the study findings support the feasibility and safety of neoadjuvant immune checkpoint blockade for patients with resectable DPM and highlight the potential of ctDNA analyses to detect residual disease and further optimise precision therapeutic interventions.
“We are excited to make progress for patients with mesothelioma, which is a rare and serious cancer that affects about 50 people annually in Ireland,” said Prof Forde.
“The use of immunotherapy to treat different cancers is expanding across stages of the disease, and allied to our recent work in lung cancer this study shows the potential benefits of leveraging the patient’s own immune system prior to surgery in order to recognise and kill cancer cells at the earliest timepoint possible. At TSJCI we have clinical trials ongoing and planned across different types and stages of cancer that aim to apply cutting edge research to maximise benefit for patients.”
In 2024 Prof Forde joined the TSJCI, Ireland’s first internationally accredited Comprehensive Cancer Centre, as Prendergast Professor of Immuno-Oncology with the goal of working with colleagues across Ireland and Europe to improve access for patients to cutting edge cancer clinical trials. Prof Forde leads immunotherapy clinical trials at TSJCI and internationally, particularly those focused on delivering treatment before surgery and increasing the long-term survival after surgery for lung cancer and other cancers.
Reference
Reuss JE, Lee PK, Mehran RJ, et al. Perioperative nivolumab or nivolumab plus ipilimumab in resectable diffuse pleural mesothelioma: A phase 2 trial and ctDNA analyses. Nat Med. 2025 Sep 8. The paper is available at: www.nature.com/articles/s41591-025-03958-3
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