Safety and activity of anti-mesothelin antibody-drug conjugate anetumab ravtansine in combination with pegylated-liposomal doxorubicin in platinum-resistant ovarian cancer: multicenter, phase Ib dose escalation and expansion study

Abstract

Objectives: Anetumab ravtansine is an antibody-drug conjugate consisting of a fully human anti-mesothelin monoclonal antibody conjugated to cytotoxic maytansinoid tubulin inhibitor DM4. Mesothelin is highly expressed in ovarian cancer. This phase Ib study determines the safety, pharmacokinetics, and anti-tumor activity of anetumab ravtansine and pegylated liposomal doxorubicin in mesothelin-expressing platinum-resistant ovarian cancer.

Methods: Anetumab ravtansine (5.5 or 6.5 mg/kg) and pegylated liposomal doxorubicin (30 mg/m²) were administered intravenously every 3 weeks to 65 patients with platinum-resistant epithelial ovarian cancer. Mesothelin expression was assessed by central immunohistochemistry. Adverse events, tumor response (RECIST 1.1), and progression-free survival were determined. Biomarker samples were assessed by ELISA and next-generation sequencing.

Results: In dose escalation, nine patients received anetumab ravtansine across two doses (5.5 or 6.5 mg/kg). The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg every 3 weeks and no dose-limiting toxicities were observed. In dose expansion, 56 patients were treated at the maximum tolerated dose. The most common treatment-emergent adverse events of any grade were nausea (47.7%), decreased appetite (43.1%), fatigue (38.5%), diarrhea (32.3%), and corneal disorder (29.2%). In all treated patients the objective response rate was 27.7% (95% CI 17.3% to 40.2%), including one complete (1.5%) and 17 partial responses (26.2%), with median duration of response of 7.6 (95% CI 3.3 to 10.2) months and median progression-free survival of 5.0 (95% CI 3.2 to 6.0) months. In an exploratory analysis of a sub-set of patients (n=19) with high mesothelin expression who received ≤3 prior lines of systemic therapy, the objective response rate was 42.1% (95% CI 20.3% to 66.5%) with a median duration of response of 8.3 (95% CI 4.1 to 12.0) months and median progression-free survival of 8.5 (95% CI 4.0 to 11.4) months.

Conclusions: Anetumab ravtansine and pegylated liposomal doxorubicin showed tolerability and promising clinical activity. These results established the dose schedule and the mesothelin-positive target population of this combination for a phase III study in platinum-resistant ovarian cancer.

Trial registration number: NCT02751918.

Keywords: ovarian cancer.

Figure 1

Study design.

Figure 2

Anti-tumor activity of anetumab ravtansine plus pegylated liposomal doxorubicin. (A) Best change in tumor size in target lesions from baseline and level of mesothelin expression in patients with ovarian cancer. High and low mesothelin expression were defined as either ≥70% or <70%, respectively, of tumor cells membrane staining for mesothelin at the intensity level of 2+/3+. The solid line indicates the cut-off for a partial response (−30%). Data from eight patients were not included as they were not evaluable. Responses were categorized according to RECIST (1.1). (B) Duration of treatment in all treated patients including in patients with high mesothelin expression and ≤3 prior lines of therapy. Each bar represents one patient (n=65). (C) Kaplan–Meier estimates of progression-free survival in all treated patients (n=65). Censored patients are indicated by an open circle. (D) Kaplan–Meier estimates of progression-free survival in patients who received ≤3 prior lines of therapy and with high or low mesothelin (MSLN) expression (n=28). Censored patients are indicated by an open circle. *Value cannot be estimated. (E) Kaplan–Meier estimates of progression-free survival in patients who received ≤3 or >3 prior lines of therapy (n=58). Censored patients are indicated by an open circle.