Introduction AXL expression in PROC is associated with a poor prognosis, a mesenchymal (Mes) gene expression molecular subtype (GEMS) and resistance to platinum chemotherapy. Pre-clinically, the function-blocking antibody tilvestamab binds and inhibits AXL tyrosine kinase, reducing AXL expression and downstream signalling.

Methods Patients (pts) with PROC and ≥2 previous lines of therapy were enrolled at 8 sites in Singapore, South Korea, UK and Norway in a multiple ascending-dose phase 1 study of safety, tolerability and pharmacokinetics, receiving 2-weekly intravenous tilvestamab at 1, 3 or 5 mg/kg, as monotherapy. RECIST responses were evaluated by CT scan and serum CA-125 by GCIG criteria. Exploratory tissue-based pharmacodynamics were evaluated on 2 sequential biopsies (pre-treatment and 28 days on treatment).

Results Of sixteen pts enrolled, 10 had tumors of Mesenchymal subtype pre-treatment. Mean (SD) duration on therapy was 10.5 (±6.3) weeks. No adverse clinical or laboratory signals were noted; tilvestamab exhibited dose-proportional PK. Best RECIST response was stable disease (median 35 days duration), in 5 evaluable patients; no CA-125 responses were observed but 1 patient with Mes PROC experienced a 44% reduction in CA125 from baseline (at 5 mg/kg). Reverse phase protein array revealed a significant reduction in AXL expression on treatment (log2Fc=-0.4, p=0.01, n=8 pairs). A tissue GEMS switch from Mesenchymal (pre-treatment) to Epithelial-B (on-treatment) was observed in 2 cases.

Conclusion/Implications Tilvestamab was well-tolerated with some evidence of on-target pharmacodynamic changes as well as phenotypic change - from mesenchymal to epithelial - in 2/16 PROC tumours. Further studies are warranted, including drug combinations, in biomarker selected cohorts of OC.