Novel ADC Generates Responses in Difficult-to-Treat Ovarian Cancer

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Findings from the phase 2/3 REFRαME-O1 trial (NCT05870748) evaluating the antibody-drug conjugate (ADC) luveltamab tazevibulin demonstrated encouraging responses, particularly in patients with ovarian cancer with low to medium FRα expression. The therapy also delivered a manageable safety profile, offering hope for a patient population with limited treatment options.

Data from the study’s phase 2 portion presented at the 2025 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer showed that patients treated with the ADC at 5.2 mg/kg plus prophylactic granulocyte colony-stimulating factor (G-CSF) for the first 2 cycles, then 4.3 mg/kg (n = 25), experienced an overall response rate (ORR) of 32% (95% CI, 17%-50%) and a disease control rate (DCR) of 96% (95% CI, 80%-99.9%). Best responses included complete response (4.0%), partial response (PR; 28.0%), stable disease (SD; 68.0%), and progressive disease (PD; 4.0%). The median time to response was 6.0 weeks (range, 4.7-11).

Notably, in this cohort, patients with low to medium FRα expression (n = 12), defined as an FRα level of at least 25% and less than 75%, had an ORR of 33.3% (95% CI, 12.3%-60.9%) with a DCR of 91.7% (95% CI, 61.5%-99.8%).

In those with high FRα expression of at least 75% (n = 13), the ORR and DCR were 30.8% (95% CI, 9.1%-61.4%) and 100% (95% CI, 75.3%-100%), respectively.

Patients treated at the dose of 4.3 mg/kg in cycle 1 and beyond (n = 29) achieved an ORR of 13.8% (95% CI, 3.9%-32%) and a DCR of 69% (95% CI, 49%-85%). Best responses comprised PR (13.8%), SD (55.2%), and PD (31.0%). The median time to response was 6.4 weeks (range, 5.4-11.9).

“[Luveltamab tazevibulin] demonstrated clinical activity with an ORR over 30% in patients with platinum-resistant ovarian cancer and an FRα expression greater than 25% by tumor proportion score, which comprises 80% of all high-grade serous carcinoma,” lead study author Jung-Yun Lee, MD, PhD, associate professor in the Department of Obstetrics and Gynecology at Yonsei University College of Medicine in Seoul, South Korea, said in a presentation of the data.

Trial Design

REFRαME-O1 is currently enrolling patients for the trial’s phase 3 portion. In this portion, investigators will randomly assign patients 1:1 to receive luveltamab tazevibulin or investigator’s choice of chemotherapy.

In the study’s phase 2 portion, investigators enrolled patients with platinum-resistant ovarian cancer with an FRα expression of at least 25% at any staining intensity. One to 3 prior lines of therapy were required, as was an ECOG performance status of 0 or 1. Patients with primary platinum-refractory disease were excluded.

Patients enrolled in phase 2 were randomly assigned 1:1 to receive either luveltamab tazevibulin once every 3 weeks at a starting dose of 5.2 mg/kg with prophylactic G-CSF for the first 2 cycles, then 4.3 mg/kg in subsequent cycles, or luveltamab tazevibulin at 4.3 mg/kg once every 3 weeks starting in cycle 1.

The primary end points of phase 2 were safety, investigator-assessed ORR per RECIST 1.1 criteria, and pharmacokinetics.

Lee noted that the baseline characteristics were well balanced between the phase 2 arms. The median age was 60.5 years (range, 41-81) in the 5.2-mg/kg cohort (n = 28) and 59.0 years (range, 42-81) in the 4.3-mg/kg cohort (n = 29). Most patients had an ECOG performance status of 0 (5.2 mg/kg, 50.0%; 4.3 mg/kg, 58.6%), had received prior bevacizumab (Avastin; 89.3%; 79.3%), had received a prior PARP inhibitor (53.6%; 55.2%), and had an FRα expression of at least 75% (57.1%; 62.1%). Patients in both arms had received a median of 2 prior lines of therapy (range, 1-3).

At data cutoff, 79% of patients in the 5.2-mg/kg cohort had discontinued treatment due to PD (71.4%) and adverse effects (AEs; 3.6%); 86% of patients in the 4.3-mg/kg cohort had discontinued study treatment due to PD (65.5%) and AEs (10.3%).

Safety Data

Lee explained that the safety profile of luveltamab tazevibulin was similar between the 2 doses. Additionally, rates of neutropenia were lower than those in prior studies following updated management and G-CSF prophylaxis guidelines.

In the overall population between both doses (n = 57), all patients experienced at least 1 treatment-emergent AE (TEAE), and 71.9% had grade 3 or higher TEAEs. The most common TEAEs included arthralgia (any-grade, 70.2%; grade ≥3, 12.3%), nausea (61.4%; 3.5%), constipation (54.4%; 7.0%), neutropenia (45.6%; 28.1%), fatigue (45.6%; 3.5%), myalgia (43.9%; 8.8%), abdominal pain (38.6%; 8.8%), neuropathy (38.6%; 1.8%), decreased appetite (38.6%; 0%), vomiting (35.1%; 1.8%), insomnia (29.8%; 3.5%), increased alanine aminotransferase levels (26.3%; 5.3%), and alopecia (24.6%; 0%).

Based on the phase 2 data, investigators selected the optimal dose of luveltamab tazevibulin as 5.2 mg/kg once every 3 weeks plus G-CSF prophylaxis for the first 2 cycles, then 4.3 mg/kg once every 3 weeks.

REFERENCE:

Lee JY, Oaknin A, Lorusso D, et al. Efficacy and safety of luveltamab tazevibulin in patients with recurrent platinum-resistant ovarian cancer: results from the dose-optimization stage of the REFRαME-O1 (GOG-3086, ENGOT-79OV, and APGOT-OV9) phase 2/3 study. Presented at: 2025 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer; March 14-17, 2025; Seattle, WA. Abstract 922978.