Evaluation of Innate Immune System, Body Habitus, and Sex on the Pharmacokinetics and Pharmacodynamics of Anetumab Ravtansine in Patients With Cancer

Our plain-English summary of Evaluation of Innate Immune System, Body Habitus, and Sex on the Pharmacokinetics and Pharmacodynamics of Anetumab Ravtansine in Patients With Cancer, by L. Chen, A.T. Lucas, A.S. Mansfield, et al (Clinical and Translational Science, 2025).

The study

• Authors: L. Chen, A.T. Lucas, A.S. Mansfield, S. Lheureux, C. O'Connor, B.A. Zamboni, K. Patel, T. McKee, J. Moscow, W.C. Zamboni
• Journal: Clinical and Translational Science
• Published: 2025;18(3):e70178
• Type of article: Randomized trial
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Anetumab ravtansine, like other ADC drugs, has high inter-patient variability in its pharmacokinetic (PK) and pharmacodynamic (PD) outcomes, which raises concerns about whether current dosing regimens are optimal for patients. The objective of this study was to evaluate covariates, especially body habitus and the innate immune system (IIS), which may affect anetumab ravtansine PK and PD as part of two clinical trials in patients with ovarian cancer and mesothelioma. Biomarkers of Fcγ receptors(FcγR) CD64 on IIS cells, total body weight (TBW), body surface area (BSA), and other covariates, such as sex and age, were analyzed for an association with anetumab ravtansine PK. Higher FcγR CD64, TBW, and BSA were associated with higher clearance (CL) of anetumab ravtansine (p < 0.05). However, there was no relationship between TBW or BSA and FcγR CD64. Female patients had a lower anetumab ravtansine CL (0.030 ± 0.007 L/h) compared to male patients (0.042 ± 0.006 L/h) (p < 0.05). In both studies, patients with stable disease (SD) and partial response (PR) had higher anetumab ravtansine AUC0-inf compared to patients with progressive disease (PD). Individualizing the dose of anetumab ravtansine and potentially other ADCs based only on TBW is not optimal, whereas precision dosing of an ADC based on the inclusion of novel metrics of IIS biomarkers, body habitus, and sex may be more appropriate to reduce variability in PK exposure, reduce toxicity, and improve response.

© 2025 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

In plain English

This study looked at how patients from two National Cancer Institute trials cleared the cancer drug anetumab ravtansine. The analysis included 16 women with platinum-resistant or platinum-refractory high-grade ovarian cancer from one trial (study 10150). It also included 14 patients with pleural mesothelioma from the other trial (study 10107): 10 men and 4 women. The study did not examine asbestos exposure. The authors compared blood drug levels after the first dose with body weight, body surface area, sex, age, and levels of the immune-cell receptor CD64. Across both trials, higher CD64, body weight and body surface area were each associated with faster clearance of the drug. CD64 was not related to body size. Female patients cleared the drug more slowly than male patients (0.030 plus or minus 0.007 L/h versus 0.042 plus or minus 0.006 L/h). Patients with partial response or stable disease had higher average drug exposure than those whose disease progressed; these differences were not statistically significant. The authors concluded that dosing by body weight alone is not optimal. They named the small number of patients as a limitation.

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: Pharmacokinetic and biomarker analysis carried out within two NCI clinical trials (Experimental Therapeutics Clinical Trials Network), using noncompartmental analysis and correlation and regression statistics
• Who was studied: Patients with pharmacokinetic and immune biomarker results from two trials: 16 patients with platinum-resistant or platinum-refractory high-grade ovarian cancer (study 10150, all female) and 14 patients with pleural mesothelioma (study 10107; 10 male, 4 female). Total enrollment of the parent trials, years and locations are not stated
• Exposure: No asbestos exposure was studied. The exposure was the drug anetumab ravtansine: 2.2 mg/kg weekly with bevacizumab in ovarian cancer; 6.5 mg/kg with pembrolizumab 200 mg every 3 weeks in mesothelioma, with the dose capped at 650 mg for patients weighing 100 kg or more
• Main results:
  • Both trials combined: higher CD64 on cycle 1 day 1 was associated with higher drug clearance (r = 0.48, p = 0.028)
  • Mesothelioma patients: higher CD64 was associated with higher clearance (r = 0.67, p = 0.024) and higher volume of distribution (r = 0.66, p = 0.026); in ovarian cancer patients similar relationships were not statistically significant
  • Both trials combined: higher total body weight was associated with higher clearance (r = 0.48, p = 0.0076), as was higher body surface area (r = 0.54, p = 0.0021)
  • CD64 was not associated with body weight or body surface area in the combined studies (p = 0.95 and p = 0.92)
  • Both trials combined: female patients had lower clearance (0.030 plus or minus 0.007 L/h) than male patients (0.042 plus or minus 0.006 L/h), p = 0.00008
  • Drug exposure per mg administered was inversely related to body weight (r = −0.50, p = 0.0045)
  • Ovarian cancer patients with partial response had higher mean drug exposure (AUC) than those with stable or progressive disease, not statistically significant (p = 0.12)
  • Mesothelioma patients with partial response or stable disease had higher mean drug exposure (AUC) than those with progressive disease, not statistically significant (p = 0.27)
  • Anti-drug antibodies were detected in 1 of 12 patients in study 10107 and 1 of 11 in study 10150
• The authors' conclusion: The authors concluded that individualizing the dose of these antibody drugs based on total body weight is not optimal, and that dosing that also takes into account immune-system biomarkers, body habitus and sex may be more appropriate
• Limitations the authors state:
  • Low overall number of patients with pharmacokinetic and biomarker studies
  • Low number of patients with matched pharmacokinetic and antitumor response data

Topics

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

Medical terms in this study, explained in our Lexicon: Clinical Trial, Ovarian Cancer, Mesothelioma, Biomarker.

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