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

J Clin Oncol. 2020 Jun 1;38(16):1824-1835. doi: 10.1200/JCO.19.02085. Epub 2020 Mar 26.


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.

Trial registration: NCT01439152.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents, Immunological / administration & dosage*
  • Antineoplastic Agents, Immunological / adverse effects
  • Antineoplastic Agents, Immunological / pharmacokinetics
  • Female
  • GPI-Linked Proteins / antagonists & inhibitors*
  • GPI-Linked Proteins / immunology
  • Humans
  • Immunoconjugates / administration & dosage*
  • Immunoconjugates / adverse effects
  • Immunoconjugates / pharmacokinetics
  • Male
  • Maximum Tolerated Dose
  • Maytansine / administration & dosage
  • Maytansine / adverse effects
  • Maytansine / analogs & derivatives*
  • Maytansine / pharmacokinetics
  • Mesothelin
  • Middle Aged
  • Neoplasm Metastasis
  • Neoplasm Recurrence, Local
  • Neoplasms / drug therapy*
  • Neoplasms / immunology
  • Neoplasms / mortality
  • Neoplasms / pathology
  • Progression-Free Survival


  • Antineoplastic Agents, Immunological
  • GPI-Linked Proteins
  • Immunoconjugates
  • Maytansine
  • Mesothelin
  • anetumab ravtansine

Associated data