Treatment with the folate receptor α–directed antibody-drug conjugate luveltamab tazevibulin led to a 37.5% overall response rate in Frα-selected patients with advanced ovarian cancer, defined by a tumor proportion score above 25%.
R. Wendel Naumann, MD
Treatment with the folate receptor α (Frα)–directed antibody-drug conjugate luveltamab tazevibulin (STRO-002; Luvelta) led to a 37.5% overall response rate (ORR) in Frα-selected patients with advanced ovarian cancer, defined by a tumor proportion score above 25%, according to findings from a phase 1 dose-expansion study (NCT03748186).1
Results also demonstrated that the agent induced a median duration of response (DOR) of 5.5 months (n = 12) and a median progression-free survival (PFS) of 6.1 months (n = 35), regardless of starting dose.
In keeping with prior safety data, the most common adverse effect from the dose-expansion phase was asymptomatic neutropenia, and no meaningful ocular toxicity signals or complications were reported.
“Today, patients with this form of heavily pre-treated ovarian cancer have extremely limited treatment options available to them, and unfortunately, experience poor outcomes,” said R. Wendel Naumann, MD, professor and director of Gynecologic Oncology Research; and Associate Medical Director of Clinical Trials at the Levine Cancer Institute, Atrium Health in Charlotte, North Carolina, and a co-lead principal investigator in the STRO-002-GM1 studies.
“To date, luvelta continues to demonstrate encouraging efficacy data, which was further supported by results from the dose-expansion cohort,” he added. “The safety profile was shown to be manageable and notably devoid of ocular complications across a broad spectrum of patients with FolRα-selected ovarian cancer.”
Frα-selected patients represent approximately 80% of all patients with advanced ovarian cancer, making Frα an ideal target for treatment selection and evaluation.
This study employed a modified 3+3 dose-escalation study with a dose-expansion phase.2 The dose-escalation phase enrolled patients with advanced ovarian cancer patients with relapsed/refractory disease to standard therapy. Patients with ovarian cancer and endometrial cancer were enrolled in the dose-expansion portion.
The ovarian cancer expansion cohort (cohort A) consists of a dose-finding design with randomization into 2 dose levels of STRO-002: 4.3 mg/kg and 5.2 mg/kg. Dose expansion in the endometrial cancer population (cohort B) comprises a single dose cohort design of 5.2 mg/kg of STRO-002. Thirty-two patients who were FolRα-selected, defined as a tumor proportion score (TPS) greater than 25%, were included in the findings.
Additional findings from the phase 1 study illustrated a FRα-dependent response, with an ORR of 11.1% (n = 9) in patients who had a Frα TPS of 25% or less, a median DOR of 2.9 months (n = 1) and a median PFS of 3.8 months (n = 9).
Moreover, the higher starting dose of 5.2 mg/kg provided greater benefit compared with the lower dose of 4.3 mg/kg in Frα-selected patients. With the higher dose, the ORR was 43.8% (n = 16), and the median DOR and PFS was 5.4 months (n = 7) and 6.6 months (n = 16), respectively. In the lower dose cohort, the ORR, median DOR and PFS was 31.3% (n = 16), 13 months (n = 5), and 6.1 months (n = 19), respectively.
In cohort C, an additional 15 patients with advanced ovarian cancer were enrolled and treated with prophylactic pegfilgrastim on day 8 after each 5.2 mg/kg administration of luveltamab tazevibulin. Among 10 patients who were evaluable for safety, substantial decreases in neutropenia and potential increases in dose intensity due to decreased dose delays were reported.
Specifically, grade 3 or greater neutropenia was reduced from 66.7% to 10.0%, reflecting an 85.0% decrease in the rate of grade 3 or greater neutropenia at the first cycle of treatment (P = .006). Additionally, dose delays at the second cycle of treatment were reduced by 60.6% (P = .021).
Based on these results, the developer of the agent, Sutro, expects to launch the registrational, phase 2/3 REFRaME study in the second quarter of 2023.
In the run-in, dose-confirmation phase of REFRaME, 50 patients will be randomly assigned 1:1 to receive 5.2 mg/kg of luveltamab tazevibulin plus prophylactic pegfilgrastim for 2 cycles followed by a step-down dose to 4.3 mg/kg or 4.3 mg/kg of luveltamab tazevibulin alone.
After this portion of the study, additional patients will be randomly assigned to the two dose levels, and standard chemotherapy. Upon agreement with FDA on the recommended dose vs standard of care, the other dose level will be dropped. After the trial has accumulated data on approximately 110 patients with the recommended dose of luveltamab tazevibulin, Sutro is expected to apply for accelerated approval based on the primary end point of ORR.
Following completion of the phase 3 portion of the trial, the company can seek full approval based on the primary end point of PFS between the luveltamab tazevibulin arm (n = 160) and the standard of care arm (n = 160).
“We are pleased with our phase 1 dose-expansion efficacy data, which are generally consistent with previously reported results and demonstrate luvelta’s potential in a difficult-to-treat patient population,” Bill Newell, chief executive officer of Sutro, said. “Through the addition of cohort C, we were able to evaluate patients at the higher dose of luvelta at 5.2 mg/kg with the use of prophylactic pegfilgrastim and determined that the rates of asymptomatic neutropenia and dose delays could be diminished.”