First-in-human study of a thorium-227-labeled mesothelin-targeting antibody-chelator conjugate (MSLN-TTC), in patients with malignant mesothelioma and other solid tumors

Our plain-English summary of First-in-human study of a thorium-227-labeled mesothelin-targeting antibody-chelator conjugate (MSLN-TTC), in patients with malignant mesothelioma and other solid tumors, by A. Minchom, O. Lindén, D.G. Knapen, et al (ESMO Open, 2025).

The study

• Authors: A. Minchom, O. Lindén, D.G. Knapen, R. Hassan, F.I. Lin, K. Jalkanen, V. Subbiah, A. Tafuri, D. Ferreira, V. Jardine, A. Cleton, J. Pinkert, F. Bladt, H. Hennekes, E.F. Smit
• Journal: ESMO Open
• Published: 2025;10(12):105905
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: BAY 2287411 [227Th-anetumab corixetan; mesothelin-targeting antibody-chelator conjugate (MSLN-TTC)] is a targeted alpha therapy consisting of a fully human mesothelin-targeting monoclonal antibody conjugated with a 3,2-hydroxypyridinone (3,2-HOPO) chelator radiolabeled with the alpha particle-emitting radionuclide thorium-227. This phase I study determined the safety, pharmacokinetics, and antitumor activity of MSLN-TTC in mesothelin-expressing mesothelioma and serous ovarian cancer.

Methods: MSLN-TTC was administered i.v. 1.5, 2.5, or 3.5 MBq of thorium-227 and with a total antibody dose of 10, 30, 50, or 150 mg every 6 weeks to 36 patients included in the intention-to-treat population. Adverse events, tumor response according to RECIST 1.1 and mRECIST criteria, and progression-free survival were determined. Tumor mesothelin expression was assessed retrospectively.

Results: In dose escalation, 35 patients (30 with malignant pleural mesothelioma) received MSLN-TTC across three thorium-227 dose levels and four total antibody doses. No dose-limiting toxicities were observed, and the maximum tolerated dose was not reached due to treatment discontinuations following 45.7% of the patients developing neutralizing antibodies. The most common treatment-emergent adverse events of any grade were fatigue (10/36, 27.8%), decreased lymphocyte count (7/36, 19.4%), nausea (7/36, 19.4%), anemia (6/36, 16.7%), and infusion-related reaction (6/36, 16.7%). The disease control rate was 34.3%, including 12 stable diseases (12/36, 34.3%). No complete or partial responses were observed. The median progression-free survival was 70 days (95% confidence interval 29-161 days).

Conclusions: MSLN-TTC showed good tolerability, but the maximum tolerated dose could not be determined due to discontinuations after antidrug antibody formation. Stable disease was observed in 12 out of 36 patients.

Copyright © 2025 The Author(s). Published by Elsevier Ltd.. All rights reserved.

In plain English

This first-in-human phase I dose-escalation trial at seven sites in Europe and the USA tested MSLN-TTC, an antibody against the protein mesothelin carrying radioactive thorium-227, injected every 42 days. Of 36 patients assigned to treatment, 30 had pleural mesothelioma, 2 had peritoneal mesothelioma and 4 had serous ovarian cancer; 35 received the radioactive drug. No dose-limiting toxicities occurred in the first 42 days, but the maximum tolerated dose could not be defined. Twenty-one of 36 patients (58.3%) stopped after the first cycle, 12 because their disease progressed and 6 because of antibodies against the drug. Neutralizing antibodies developed in 45.7% of the 35 treated patients. Fatigue was the most common adverse event (10 of 36, 27.8%); investigators judged it drug-related in 8 (22.2%). No drug-related event was worse than grade 3. No patient had a complete or partial response. Twelve of 35 treated patients (34.3%) had stable disease. Median progression-free survival was 70 days (95% confidence interval 29 to 161 days). The authors concluded that the drug was unlikely to bring meaningful benefit and would not be pursued further.

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: Multicenter, open-label, phase I first-in-human dose-escalation trial (NCT03507452), sponsored by Bayer AG
• Who was studied: 36 adult patients assigned to treatment, of whom 35 received thorium-227, at seven sites in Finland, the Netherlands, Sweden, the UK and the USA. They had advanced epithelioid mesothelioma, either pleural (n = 30) or peritoneal (n = 2), or serous ovarian cancer, either high-grade (n = 3) or low-grade (n = 1). All had progressed after prior treatment. Study dates are not given in the text.
• Exposure: Not an asbestos exposure study. The treatment was MSLN-TTC (BAY 2287411), a mesothelin-targeting antibody linked to the alpha emitter thorium-227. It was given intravenously on day 1 of each 42-day cycle at 1.5, 2.5 or 3.5 MBq of thorium-227, with total antibody doses of 10, 30, 50 or 150 mg.
• Main results:
  • No dose-limiting toxicities were reported in any of the seven dose cohorts during the 42-day observation period.
  • One patient (3.5 MBq, 10 mg antibody) had grade 3 thrombocytopenia in cycle 3, which was classified as a multiple dose DLT.
  • 21 of 36 patients (58.3%) stopped after the first cycle: 12 for progressive disease, 6 for antidrug antibody formation, 2 for an adverse event and 1 who withdrew.
  • Among the 35 treated patients, 51.5% had at least one antidrug-antibody-positive sample after dosing, and 45.7% had neutralizing antibodies.
  • Among the 36 patients, the most frequent treatment-emergent adverse events were fatigue (n = 10, 27.8%) and decreased lymphocyte count (n = 7, 19.4%).
  • Investigators judged fatigue drug-related in 8 of 36 patients (22.2%).
  • The highest grade of drug-related adverse event was grade 3.
  • One patient in the 3.5 MBq plus 10 mg antibody group died during treatment from a grade 5 deterioration in general physical health. The death was attributed to disease progression and considered unrelated to study treatment.
  • No deaths were due to drug-related adverse events. 20 patients died during the 12-month follow-up, 16 of them from disease progression.
  • Among the 35 patients treated with thorium-227, none had a complete or partial response.
  • Among the 35 treated patients, 12 (34.3%) had stable disease and 17 (48.6%) had progressive disease.
  • Of the 12 patients with stable disease, 11 had pleural mesothelioma and 1 had peritoneal mesothelioma.
  • Median progression-free survival was 70 days (95% CI 29-161 days).
  • Response was not correlated with the tumor's mesothelin level (H-score).
• The authors' conclusion: The authors concluded that MSLN-TTC was well tolerated at the low cumulative doses given. Because there was no clinical response and antidrug antibodies were common, they judged it unlikely to give meaningful benefit, and it will not be developed further.
• Limitations the authors state:
  • Many patients stopped treatment early, so the cumulative thorium-227 doses given were lower than planned.
  • Antidrug antibodies sped up removal of the drug from the blood in several patients, which may explain the lack of response in some. Testing higher antibody doses to reduce antibody formation did not appear to work.
  • Overall tumor response was not available for six patients.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelin, Mesothelioma, Monoclonal Antibody, Ovarian Cancer, Progression-Free Survival, Pleural Mesothelioma, confidence interval.

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• Advances in Precision Oncology: Targeted Thorium-227 Conjugates As a New Modality in Targeted Alpha Therapy — U.B. Hagemann, K. Wickstroem, et al. (2020)
• Anetumab ravtansine: a novel mesothelin-targeting antibody-drug conjugate cures tumors with heterogeneous target expression favored by bystander effect — S. Golfier, C. Kopitz, et al. (2014)
• Synergistic Effect of a Mesothelin-Targeted 227Th Conjugate in Combination with DNA Damage Response Inhibitors in Ovarian Cancer Xenograft Models — K. Wickstroem, U.B. Hagemann, et al. (2019)
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