043: Effects of the Innate Immune System, Body Habitus & Sex on the Pharmacokinetics & Antitumor Response of Anetumab Ravtansine in Patients With Solid Tumors

Statement of Purpose, Innovation or Hypothesis: Anetumab ravtansine is an antibody-drug conjugate (ADC) targeting mesothelin and conjugated to the microtubule inhibitor DM4. ADC drugs, like anetumab ravtansine, have high interpatient variability in pharmacokinetics (PK), response, and toxicity, which raises concerns whether current dosing based on body weight (mg/kg) are optimal. Antibodies and ADCs undergo clearance via Fc gamma receptors (FcɣRs CD64, CD32, CD16) on cells of the innate immune system (IIS).  In addition, prior studies have reported that body habitus, which refers to variations in body size, can alter the PK of these agents and weight-based dosing does not fully address this issue. The objective of this study was to evaluate the relationship between patient covariates, especially biomarkers of the IIS and body habitus, and pharmacokinetics (PK) and pharmacodynamics (PD) of anetumab ravtansine.

Description of Methods & Materials: Studies were performed as part of two clinical trials: 1) patients (n=16) with platinum-resistant or platinum refractory ovarian cancer treated with anetumab ravtansine at 2.2mg/kg IV weekly plus bevacizumab and 2) patients (n=14) with pleural mesothelioma treated with anetumab ravtansine at 6.5 mg/kg IV every 3 weeks plus pembrolizumab. Serial plasma PK studies were performed after the first dose and used to calculate clearance (CL), volume of distribution (Vd), and area under the plasma concentration versus time curve (AUC_0-inf). The relationship between biomarkers of FcɣRs (CD64, CD32, CD16) on IIS cells in blood, total body weight (TBW), body surface area (BSA), sex and other covariates and PK and PD of anetumab ravtansine were evaluated.

Data & Results: In both studies, higher FcγR CD64, TBW, and BSA were associated with higher clearance CL and Vd of anetumab ravtansine (p < 0.05). Patients with the combination of higher FcγR CD64 and higher TBW or BSA had higher anetumab ravtansine CL. However, there was no relationship between FcγR CD64 and TBW or BSA, which suggests that IIS and body habitus are independent factors. The relationship between TBW and anetumab ravtansine AUC_0-inf was not flat highlighting the ineffectiveness of weight-based dosing (mg/kg). When the exposure is normalized based on per unit mass drug administrated (PUMDA; mg) there is an inverse relationship between TBW and AUC_0-inf/mg (p < 0.05), which suggests larger patients achieve less exposure per ADC administered. There were also inverse relationships between CD64 and BSA and dose normalized AUC_0-inf (AUC_0-inf/mg). Anetumab ravtansine CL was lower in female (0.030 ± 0.007L/h) compared to male (0.042 ± 0.006L/h) patients (p < 0.05). In both studies, patients with stable disease and partial response had higher anetumab ravtansine AUC_0-inf compared to patients with progressive disease.

Interpretation, Conclusion or Significance: There was high interpatient variability in PK disposition of anetumab ravtansine and a positive relationship between exposure and response. Patients with higher IIS phenotype, larger body habitus, and males compared to females had higher CL and Vd of anetumab ravtansine. Individualizing the dose of anetumab ravtansine based only on TBW is not optimal. Whereas precision dosing of antibodies and ADCs based on the use of novel metrics of body habitus, IIS biomarkers, and sex, may be more appropriate to reduce variability in PK exposure, reduce toxicity and improve response.

Disclosures: Dr. William Zamboni reports receiving funding from NIH/NCI Experimental Therapeutics-Clinical Trials Network with Phase 1 Emphasis (ET-CTN) (UM1) (UM1) Grant at Duke-UNC-Washington University and NIH/NCI Experimental Therapeutics-Clinical Trials Network with Phase 1 Emphasis (ET-CTN) (UM1) – Biomarker Supplements (n=2). Dr. William Zamboni is Founder and CSO of Glolytics, LLC, which is commercializing biomarkers of the IIS for precision medicine indications.

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