Perioperative nivolumab or nivolumab plus ipilimumab in resectable diffuse pleural mesothelioma: a phase 2 trial and ctDNA analyses

Our plain-English summary of Perioperative nivolumab or nivolumab plus ipilimumab in resectable diffuse pleural mesothelioma: a phase 2 trial and ctDNA analyses, by J.E. Reuss, P.K. Lee, R.J. Mehran, et al (Nature Medicine, 2025).

The study

• Authors: J.E. Reuss, P.K. Lee, R.J. Mehran, C. Hu, S. Ke, A. Jamali, M. Najjar, N. Niknafs, J. Wehr, E. Oner, Q. Meng, G. Pereira, S. Hosseini-Nami, M. Sausen, M. Zahurak, R.J. Battafarano, R.K. Hales, J. Friedberg, B. Sepesi, J.S. Deutsch, T. Cottrell, J. Taube, P.B. Illei, K.N. Smith, D.M. Pardoll, A.S. Tsao, J.R. Brahmer, V. Anagnostou, P.M. Forde
• Journal: Nature Medicine
• Published: 2025;31(12):4097-4108
• Cited by: 21 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Immune checkpoint blockade (ICB) is standard of care in advanced diffuse pleural mesothelioma (DPM), but its role in the perioperative management of DPM is unclear. In tandem, circulating tumor DNA (ctDNA) ultra-sensitive residual disease detection has shown promise in providing a molecular readout of ICB efficacy across resectable cancers. This phase 2 trial investigated neoadjuvant nivolumab and nivolumab/ipilimumab in resectable DPM along with tumor-informed liquid biopsy residual disease assessments. Patients with resectable epithelioid/biphasic DPM enrolled sequentially to nivolumab 240 mg every 2 weeks (q2w) for three cycles (Arm A, n = 16) or nivolumab 3 mg kg-1 q2w for three cycles plus ipilimumab 1 mg kg-1 on cycle 1 (Arm B, n = 14), followed by surgery, optional chemotherapy and/or radiotherapy, and nivolumab 480 mg q4w for 1 year. Co-primary endpoints included safety and feasibility; key exploratory endpoints included progression-free survival (PFS), overall survival (OS) and ctDNA analyses. The trial met its primary endpoints, and, in Arms A and B, 81.3% and 85.7% of patients proceeded to surgery, respectively. Treatment was safe, with a single dose-limiting toxicity in each arm. In Arm A, median PFS and OS were 9.6 months (95% confidence interval (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. Persistent ctDNA was detected during neoadjuvant therapy in patients who did not undergo complete surgical resection due to disease progression (Fisher's exact test, P = 0.00013). Patients with detectable ctDNA on cycle 3 and pre-surgery had shorter PFS (log-rank test, P = 0.027 and P = 0.0059, respectively); this association was more pronounced when quantitative ctDNA changes were considered (log-rank test, P = 1.8 × 10-6). Our findings support the feasibility of neoadjuvant ICB and the clinical utility of ctDNA analyses to capture residual disease in resectable DPM. ClinicalTrials.gov identifier: NCT03918252 .

© 2025. The Author(s).

In plain English

This phase 2 trial at three US centers tested immunotherapy around surgery in 30 patients with resectable epithelioid or biphasic diffuse pleural mesothelioma. The first 16 patients (Arm A) received three nivolumab doses before surgery; the next 14 (Arm B) also got one ipilimumab dose. Both arms planned up to a year of nivolumab afterward. Asbestos exposure was not studied. In Arm A, 81.3% proceeded to planned surgery, and in Arm B, 85.7%, meeting the feasibility goal. Each arm had one dose-limiting side effect. Median progression-free survival was 9.6 months (95% CI 2.5 to 27.7) in Arm A and 19.8 months (7.1 to not reached) in Arm B; median overall survival was 19.3 (14.9 to 34.7) and 28.6 months (20.4 to not reached). The arms were not formally compared. Detectable tumor DNA in blood at cycle 3 or before surgery was linked to shorter progression-free survival. The authors concluded this supports the feasibility and safety of pre-surgery immunotherapy and the potential of these blood tests. They noted it was not powered for effectiveness and sequential enrollment may have introduced confounding.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Prospective, multicenter, multiarm, non-comparative phase 2 clinical trial. Patients were enrolled sequentially to two arms, not randomized. Blood tests for circulating tumor DNA (ctDNA) were analyzed as an exploratory part of the trial.
• Who was studied: 30 previously untreated adults with epithelioid or biphasic diffuse pleural mesothelioma judged resectable: 16 in Arm A and 14 in Arm B. Patients were enrolled between 29 October 2019 and 22 January 2024 at Johns Hopkins, MD Anderson and the University of Maryland. Patients with pure sarcomatoid histology were excluded.
• Exposure: The article does not study asbestos exposure; asbestos is mentioned only in the introduction. The intervention studied was immunotherapy before surgery. Arm A received nivolumab 240 mg every 2 weeks for three doses. Arm B received nivolumab 3 mg/kg every 2 weeks for three doses plus ipilimumab 1 mg/kg on cycle 1. In both arms this was followed by surgery, optional chemotherapy and/or radiotherapy, and nivolumab 480 mg every 4 weeks for up to 1 year.
• Main results:
  • Feasibility: 81.3% of patients in Arm A (13 of 16) and 85.7% in Arm B (12 of 14) proceeded to planned surgery within 24 days of the preplanned date. Three patients in Arm A and two in Arm B had disease progression that precluded surgery.
  • Safety: one dose-limiting toxicity occurred in each arm (pneumonitis in Arm A; elevated alanine aminotransferase in Arm B). The rate was 6.3% (95% CI 0.2 to 30.2) in Arm A and 7.1% (95% CI 0.2 to 33.9) in Arm B.
  • Grade 3 or higher immunotherapy-related side effects occurred in 18.8% of patients in Arm A and 7.1% of patients in Arm B.
  • Scan response before surgery: in Arm A, 2 of 15 evaluable patients had a partial response (ORR 13.3%; 95% CI 1.7 to 40.5). In Arm B, none of 11 evaluable patients did (ORR 0.0%; 95% CI 0 to 28.5).
  • Arm A, at a median follow-up of 43.2 months: median progression-free survival was 9.6 months (95% CI 2.5 to 27.7) and median overall survival was 19.3 months (95% CI 14.9 to 34.7). These were exploratory endpoints.
  • Arm B, at a median follow-up of 24.1 months: median progression-free survival was 19.8 months (95% CI 7.1 to not reached) and median overall survival was 28.6 months (95% CI 20.4 to not reached). At data lock, 8 of 14 patients were alive, of whom 5 were recurrence free.
  • At cycle 3, ctDNA was detectable in 7% of patients who had complete macroscopic resection, compared with 100% of patients who did not complete surgery (Fisher's exact test, P = 0.00013).
  • Patients with undetectable ctDNA at cycle 3 (n = 14) had longer progression-free survival than those with detectable ctDNA (n = 7): median 19.84 versus 1.41 months (log-rank P = 0.027; HR 0.32, 95% CI 0.11 to 0.92).
  • Patients with undetectable ctDNA before surgery (n = 12) had longer progression-free survival than those with detectable ctDNA (n = 13): median 23.26 versus 2.46 months (log-rank P = 0.0059; HR 0.29, 95% CI 0.12 to 0.73).
  • Overall survival was numerically longer with undetectable ctDNA before surgery (median 27.73 versus 15 months), but the difference was not statistically significant (log-rank P = 0.16; HR 0.5, 95% CI 0.18 to 1.36).
  • Twelve patients had either a 95% or greater drop in ctDNA from cycle 1 to cycle 3 or undetectable ctDNA throughout. They had longer progression-free survival than the 6 patients with a smaller drop: median 23.26 versus 1.4 months (log-rank P = 1.8 times 10 to the minus 6).
• The authors' conclusion: The authors concluded that their findings support the feasibility and safety of immunotherapy before surgery for resectable diffuse pleural mesothelioma. They also concluded that the findings highlight the potential of ctDNA analyses to detect residual disease.
• Limitations the authors state:
  • The study was not powered to evaluate effectiveness, so progression-free and overall survival were exploratory.
  • Sequential rather than randomized enrollment may have introduced confounding. For example, more Arm A patients were male (81% versus 57% in Arm B), and male sex is a negative prognostic factor.
  • The trial was run at centers experienced in mesothelioma surgery, so the findings may apply less well to less experienced centers.
  • The ctDNA test depends on the number of informative mutations found in the tumor, which is a challenge in low-mutation tumors such as mesothelioma. Two patients' analyses were uninformative.
  • Findings on adjuvant chemotherapy in Arm A should be interpreted with caution because of small numbers and confounding.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Nivolumab (Opdivo), Ipilimumab (Yervoy), Pleural Mesothelioma, ctDNA, Liquid Biopsy, Epithelioid, Biphasic Mesothelioma, Chemotherapy.

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