PURPOSE: Mesothelin (MSLN) is highly expressed in high-grade serous/endometrioid ovarian cancers (HGOC). Anetumab ravtansine (AR) is an antibody-drug conjugate directed at the MSLN antigen with a tubulin polymerization inhibitor. We assessed the safety, activity, and pharmacokinetics of the combination AR/bevacizumab (Bev
ARB) versus weekly paclitaxel/Bev (PB) in patients with platinum-resistant/refractory HGOC (prrHGOC). PATIENTS AND METHODS: Following a run-in phase I study to assess ARB safety, patients with prrHGOC with centrally confirmed MSLN-positive expression were randomized to ARB or PB (weekly paclitaxel 80 mg/m2 with Bev 10 mg/kg biweekly). Patients were stratified by platinum resistance/refractory and prior Bev. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall response rate, safety, and blood-based angiome biomarker assessment. A futility analysis was planned after 35 PFS events. RESULTS: The combination of Bev (10 mg/kg) biweekly with AR (2.2 mg/kg) weekly was well tolerated. About phase II results, MSLN positivity was 88%, and 57 patients were randomized (28 ARB and 29 PB). Forty-two percentage of patients received prior Bev, and 23% were platinum-refractory. At futility analysis, the median PFS was 5.3 and 12.7 months for ARB and PB, respectively [P = 0.03
HR = 2.02 (1.06-3.86)]. The overall response rate was 21% with ARB and 65% with PB. The most common treatment-related grade ≥3 adverse events were anemia (18%) with ARB and neutropenia (24%) with PB. Higher baseline levels of circulating IL6 were associated with worse PFS, and its levels decreased with PB treatment. CONCLUSIONS: Our study stopped at interim analysis highlighting the benefit of PB in prrHGOC as the standard of care.