First-in-Human, Multicenter, Phase I Dose-Escalation and Expansion Study of Anti-Mesothelin Antibody-Drug Conjugate Anetumab Ravtansine in Advanced or Metastatic Solid Tumors

Our plain-English summary of First-in-Human, Multicenter, Phase I Dose-Escalation and Expansion Study of Anti-Mesothelin Antibody-Drug Conjugate Anetumab Ravtansine in Advanced or Metastatic Solid Tumors, by R. Hassan, G.R. Blumenschein, K.N. Moore, et al (Journal of Clinical Oncology, 2020).

The study

• Authors: R. Hassan, G.R. Blumenschein, K.N. Moore, A.D. Santin, H.L. Kindler, J.J. Nemunaitis, S.M. Seward, A. Thomas, S.K. Kim, P. Rajagopalan, A.O. Walter, D. Laurent, B.H. Childs, N. Sarapa, C. Elbi, J.C. Bendell
• Journal: Journal of Clinical Oncology
• Published: 2020;38(16):1824-1835
• Cited by: 157 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Purpose: This phase I study, which to our knowledge is the first-in-human study of this kind, investigates the safety, tolerability, pharmacokinetics, and clinical activity of anetumab ravtansine, an antibody-drug conjugate of anti-mesothelin antibody linked to maytansinoid DM4, in patients with advanced, metastatic, or recurrent solid tumors known to express the tumor-differentiation antigen mesothelin.

Patients And Methods: This phase I, open-label, multicenter, dose-escalation and dose-expansion study of anetumab ravtansine enrolled 148 adult patients with multiple solid tumor types. Ten dose-escalation cohorts of patients with advanced or metastatic solid tumors (0.15-7.5 mg/kg) received anetumab ravtansine once every 3 weeks, and 6 expansion cohorts of patients with advanced, recurrent ovarian cancer or malignant mesothelioma received anetumab ravtansine at the maximum tolerated dose once every 3 weeks, 1.8 mg/kg once per week, and 2.2 mg/kg once per week.

Results: Forty-five patients were enrolled across the 10 dose-escalation cohorts. The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg once every 3 weeks or 2.2 mg/kg once per week. Thirty-two patients were enrolled in the 6.5 mg/kg once-every-3-weeks, 35 in the 1.8 mg/kg once-per-week, and 36 in the 2.2 mg/kg once-per-week expansion cohorts. The most common drug-related adverse events were fatigue, nausea, diarrhea, anorexia, vomiting, peripheral sensory neuropathy, and keratitis/keratopathy. There were no drug-related deaths. Anetumab ravtansine pharmacokinetics were dose proportional; the average half-life was 5.5 days. Among 148 patients with mesothelioma or ovarian, pancreatic, non-small-cell lung, and breast cancers, 1 had a complete response, 11 had partial responses, and 66 had stable disease. High levels of tumor mesothelin expression were detected in patients with clinical activity.

Conclusion: Anetumab ravtansine exhibited a manageable safety and favorable pharmacokinetic profile with encouraging preliminary antitumor activity in heavily pretreated patients with mesothelin-expressing solid tumors. The results allowed for the determination of recommended doses, schedules, and patient populations for anetumab ravtansine in phase II studies.

In plain English

This was a phase I, open-label, nonrandomized trial of anetumab ravtansine, an experimental drug that joins an antibody against the tumor protein mesothelin to a cell-killing agent called DM4. Between September 2011 and June 2015, 148 adults at 8 centers were treated. They had advanced solid tumors that no longer responded to standard therapy, mostly pleural or peritoneal mesothelioma or ovarian cancer. Doses were raised step by step from 0.15 to 7.5 mg/kg every 3 weeks. The 7.5 mg/kg dose was not tolerated. The recommended dose for phase II trials was set at 6.5 mg/kg every 3 weeks or 2.2 mg/kg weekly. The most frequent severe drug-related side effects were fatigue, keratitis/keratopathy (an eye problem) and nausea. Eighteen patients died, all from disease progression, and none of these deaths was considered drug related. Of 138 patients whose tumors were evaluated, 1 had a complete response, 11 a partial response and 66 stable disease. Among 16 mesothelioma patients given 6.5 mg/kg every 3 weeks, 5 (31%) had a partial response. The authors concluded the drug was well tolerated. They noted the study was not designed or statistically powered to assess effectiveness.

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: Phase I, open-label, nonrandomized, multicenter dose-escalation and dose-expansion drug trial
• Who was studied: 148 adult patients at 8 centers, enrolled September 2011 to June 2015. All had advanced, metastatic or recurrent solid tumors refractory to standard therapy. Most had mesothelioma (pleural or peritoneal) or ovarian cancer; a few had pancreatic, non-small-cell lung, breast or other cancers.
• Exposure: The study drug anetumab ravtansine (an anti-mesothelin antibody linked to DM4) was given by intravenous infusion. In the escalation phase, 10 dose levels from 0.15 to 7.5 mg/kg were given every 3 weeks. Expansion cohorts received 6.5 mg/kg every 3 weeks, 1.8 mg/kg weekly, or 2.2 mg/kg weekly. The article does not study asbestos exposure.
• Main results:
  • The maximum tolerated dose was 6.5 mg/kg every 3 weeks; 1 of 6 patients in that escalation cohort had a dose-limiting toxicity.
  • The 7.5 mg/kg every-3-weeks dose was not tolerated, with dose-limiting toxicities in 2 of 4 patients.
  • The recommended phase II dose and schedule was 6.5 mg/kg every 3 weeks or 2.2 mg/kg once per week.
  • The most frequent grade 3 or higher drug-related adverse events were fatigue, keratitis/keratopathy, and nausea.
  • Eighteen deaths were reported in all; all resulted from disease progression and none was considered drug related.
  • Tumor response was evaluated in 138 of 148 patients. Among them, 66 had stable disease and 11 had a partial response.
  • One complete response occurred, in the 2.2 mg/kg once-per-week ovarian cancer cohort.
  • In the mesothelioma subgroup treated at 6.5 mg/kg every 3 weeks, 5 of 16 patients (31%) had a partial response. It lasted 174 days in 1 patient and at least 600 days in the other 4.
  • As of February 2019, 2 patients with malignant peritoneal mesothelioma were still on treatment, with partial responses lasting longer than 1,700 days.
  • Median progression-free survival was 2.8 months in each expansion cohort.
  • All patients with a partial or complete response had at least 60% tumor mesothelin expression by immunohistochemistry.
• The authors' conclusion: The authors concluded that anetumab ravtansine was well tolerated, with manageable adverse effects and favorable pharmacokinetics, in patients with advanced solid tumors.
• Limitations the authors state:
  • The study was not designed or statistically powered to assess clinical efficacy; antitumor activity was described as preliminary.
  • A link between mesothelin expression and antitumor activity showed a positive trend, but its significance could not be established from these preliminary data.

Topics

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

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)
• Anetumab ravtansine versus vinorelbine in patients with relapsed, mesothelin-positive malignant pleural mesothelioma (ARCS-M): a randomised, open-label phase 2 trial — H.L. Kindler, S. Novello, et al. (2022)
• Antibody-Drug Conjugates (ADCs) for Personalized Treatment of Solid Tumors: A Review — J.M. Lambert, C.Q. Morris (2017)
• 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 — A. Minchom, O. Lindén, et al. (2025)
• Phase 1b Multicenter Study of SG001, a Humanized Anti-PD-1 Antibody, in Patients with Advanced Solid Tumors — J. Fang, O. Jiang, et al. (2025)
• Phase I study of ABBV-428, a mesothelin-CD40 bispecific, in patients with advanced solid tumors — J.J. Luke, F. Barlesi, et al. (2021)

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