Novel mesothelin antibody-drug conjugates: current evidence and future role in the treatment of ovarian cancer

Our plain-English summary of Novel mesothelin antibody-drug conjugates: current evidence and future role in the treatment of ovarian cancer, by D. Mauricio, J. Harold, J.R. Tymon-Rosario, et al (Expert Opinion on Biological Therapy, 2021).

The study

• Authors: D. Mauricio, J. Harold, J.R. Tymon-Rosario, B. Zeybek, A.D. Santin
• Journal: Expert Opinion on Biological Therapy
• Published: 2021;21(8):1087-1096
• Type of article: Review
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction: Ovarian cancer is the deadliest gynecologic malignancy in the United States, and effective therapies for recurrent, advanced, and progressive disease are limited. Mesothelin is known to be expressed in ovarian cancers, and antibody-drug conjugates targeting mesothelin are a promising novel therapeutic agent.Areas Covered: This article reviews the currently available literature of anti-mesothelin antibody-drug conjugates as a novel treatment for ovarian cancer. Preclinical in vitro and in vivo data as well as clinical results are reviewed for each available agent. Additionally, adverse effects are covered.Expert Opinion: Anti-mesothelin antibody-drug conjugates and their combination with chemotherapeutic agents have undergone phase II trials with encouraging results and demonstrated favorable adverse effect profiles. Phase III data will be necessary to establish its role in ovarian cancer, particularly in recurrent, advanced, or progressive disease.

In plain English

This article was a review, not a new study. The authors, from Yale University School of Medicine, summarized published laboratory, animal and clinical research on antibody-drug conjugates. These are drugs that link an antibody to a cell-killing agent. The ones reviewed target mesothelin, a protein highly expressed in several cancers, including mesothelioma and ovarian cancer. The review is about treating ovarian cancer and did not look at asbestos exposure. Most of it covered anetumab ravtansine. In mice, the drug reduced ovarian tumor weight by 81% compared with an inactive control. The authors described a first-in-human trial by other researchers in 148 patients with tumors including mesothelioma and ovarian cancer. That trial set the maximum tolerated dose at 6.5 mg/kg once every 3 weeks and reported eye side effects. In a Phase Ib study that combined the drug with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer, the response rate was 27.7% (95% CI 17.3 to 40.2). A second drug, DMOT4039A, was also reviewed. The authors concluded that Phase III data and further trials are needed.

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: Narrative review of published preclinical (laboratory and animal) and clinical studies
• Who was studied: No population of its own. The review covered cell-line, mouse xenograft and patient-derived tumor model studies, plus clinical trials by other researchers, including a phase I trial of 148 patients with mesothelin-overexpressing tumors (mesothelioma, breast, pancreatic, non-small-cell lung and ovarian cancers).
• Exposure: Not an asbestos exposure. The 'exposure' is drug treatment with antibody-drug conjugates aimed at mesothelin, a protein highly expressed in solid tumors including mesothelioma and ovarian cancer. The main drug reviewed was anetumab ravtansine; DMOT4039A was also covered.
• Main results:
  • In a mouse study by Golfier and colleagues (an orthotopic ovarian cancer model using OVCAR-3-s-05 cells), anetumab ravtansine was reported to reduce ovary tumor weight by 81% compared with vehicle treatment (P < 0.05).
  • In the first-in-human phase I trial by Hassan and colleagues, the maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg once every 3 weeks.
  • In the same phase I trial, the objective response rates across all tumor types were 16%, 9% and 6% for the 6.5 mg/kg every-3-weeks, 1.8 mg/kg weekly and 2.2 mg/kg weekly cohorts, respectively.
  • Among ovarian cancer patients given 6.5 mg/kg every 3 weeks in that trial, grade 3 or worse blurred vision occurred in 5% and grade 3 or worse keratitis in 10%.
  • In a Phase Ib study of anetumab ravtansine plus pegylated liposomal doxorubicin in 65 patients with platinum-resistant ovarian, fallopian tube or primary peritoneal cancer, the objective response rate in the modified intent-to-treat analysis was 27.7% (95% CI 17.3, 40.2), with one complete and 17 partial responses. Median progression-free survival was 5.1 months.
  • In a phase I trial of DMOT4039A in unresectable pancreatic or platinum-resistant ovarian cancer, 3 of 10 ovarian cancer patients had confirmed partial responses.
• The authors' conclusion: The authors concluded that anti-mesothelin antibody-drug conjugates showed encouraging results in phase II trials, and that additional clinical trials with anetumab ravtansine are warranted.
• Limitations the authors state:
  • The authors state that Phase III data are still needed to establish the role of these drugs in ovarian cancer.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelin, Ovarian Cancer.

Related studies

• 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)
• Preclinical Efficacy of an Antibody-Drug Conjugate Targeting Mesothelin Correlates with Quantitative 89Zr-ImmunoPET — A.G. Terwisscha van Scheltinga, A. Ogasawara, et al. (2017)
• Antibody-Drug Conjugates (ADCs) for Personalized Treatment of Solid Tumors: A Review — J.M. Lambert, C.Q. Morris (2017)
• Targeting Multiple EGFR-expressing Tumors with a Highly Potent Tumor-selective Antibody-Drug Conjugate — M.G. Anderson, H.D. Falls, et al. (2020)
• Antibody drug conjugates in thoracic malignancies — J.M. Pacheco, D.R. Camidge (2018)
• 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)

Browse more research in Expert Opinion on Biological Therapy, or return to medical research.