Efficacy and safety of luveltamab tazevibulin in patients with recurrent platinum-resistant ovarian cancer: Results from the dose-optimization stage of the REFRalphaME-O1 (GOG-3086, ENGOT-79ov, and APGOT-OV9) phase II/III study

Abstract

Objectives: Despite current advances in targeted therapy, patients who have platinum-resistant ovarian cancer (PROC) with low/medium levels of folate receptor alpha (FRalpha) expression have limited treatment options. Luveltamab tazevibulin (luvelta), a novel antibody-drug conjugate designed to target cancers with a broad range of FRalpha expression, led to an overall response rate (ORR) of 37.5 % in recurrent ovarian cancer with FRalpha expression >25 % by tumor proportion score (TPS) in a phase I study. Luvelta is being studied in the REFRalphaME-O1 pivotal trial in PROC. Herein, we report outcomes from the phase II (dose-optimization) portion of the study. Method(s): Global, randomized, open-label, phase II/III trial designed as a dose-ranging study to select an optimized dose (phase II) and randomized controlled (chemotherapy) registration study (phase III). Eligibility criteria included patients with high-grade serous PROC, 1-3 prior lines of therapy, measurable disease, ECOG performance status =25 % (VENTANA FOLR1 FOLR1-2.1] RxDx Assay; Ventana Medical Systems, Roche Labs). Patients with primary platinum-refractory disease are excluded. In the phase II portion, patients were randomized 1:1 to receive IV luvelta Q3W at 4.3 mg/kg (starting dose level DL] 1) or 5.2 mg/kg (starting DL2) with prophylactic G-CSF for two cycles followed by 4.3 mg/kg for cycles >=3. Analysis was planned for completion when 25 patients/arm had been enrolled and had a 12-week follow-up. Primary outcomes are safety evaluations, ORR (RECIST v1.1) per investigator and pharmacokinetic analysis. Subanalyses were completed for FRalpha expression levels by positive staining (PS) 2+ of =75 %. No formal statistics were specified for phase II analysis. Result(s): A total of 57 patients were enrolled in the phase II portion (29 DL1; 28 DL2); the median age was 60 years (range: 41-81) and the median number of prior lines of therapy was two (range: 1-3), with 84 % of patients having prior bevacizumab and 54 % prior PARPi. The safety profile was similar between the two dose groups. The most common any-grade treatment-emergent adverse events (TEAEs) were arthralgia (66 % DL1; 75 % DL2), nausea (62 % DL1; 61 % DL2), constipation (66 % DL1; 43 % DL2) and neutropenia (48 % DL1; 43 % DL2). Grade 3+ TEAEs occurred in 66 % (DL1) and 79 % (DL2), with the most common being arthralgia, nausea and constipation. Neutropenia grade 3+ occurred in 28 % (DL1) versus 29 % (DL2), with no febrile neutropenia and no grade 5 TEAEs. There were no ocular or interstitial lung disease safety signals. Three patients (10 %) and one patient (3.6 %) in DL1 and DL2, respectively, discontinued treatment due to a TEAE. Efficacy outcomes are shown in the table. There was one complete response in DL2. Conclusion(s): The luvelta starting dose of 5.2 mg/kg Q3W showed encouraging antitumor activity with an ORR of 33.3 % in patients with low/medium FRalpha expression and no additional safety signals. This starting dose was selected as the optimal regimen for evaluation in phase III, which is currently open and enrolling globally. These luvelta activity data represent a significant advancement in targeted therapy for this patient population. Formula presented] Formula presented]Copyright © 2025