Purpose: Mesothelin (MSLN) is highly expressed in high grade serous/ endometrioid ovarian cancers (HGOC). Anetumab ravtansine (AR) is an antibody drug conjugate directed at MSLN antigen with a tubulin polymerization inhibitor. We assessed safety, activity and pharmacokinetics of the combination AR/bevacizumab (Bev) (ARB) versus weekly paclitaxel (wP)/Bev (PB) in patients with platinum resistant/refractory HGOC (prrHGOC). Expiremental design: Following a run-in phase I study to assess ARB safety, prrHGOC patients with centrally confirmed MSLN positive expression were randomized to ARB or PB (wP 80mg/m2 with Bev 10mg/kg biweekly). Patients were stratified by platinum resistance/refractory and prior Bev. The primary endpoint was progression-free survival (PFS), secondary endpoints were overall response rate (ORR), safety, and blood-based angiome biomarker assessment. A futility analysis was planned after 35 PFS events. Results: The combination of Bev (10mg/kg) biweekly with AR (2.2mg/kg) weekly was well tolerated. Regarding phase II results, mesothelin positivity was 88% and 57 pts were randomized (28 ARB, 29 PB). 42% pts 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]). ORR 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 IL-6 were associated with worse PFS, and its levels decreased with PB treatment. Conclusion: Our study stopped at interim analysis highlighting the benefit of PB in prrHGOC as standard of care.

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