In a phase III trial (VIKTORIA-1) reported in the Journal of Clinical Oncology, Hurvitz et al found that gedatolisib and fulvestrant both with and without palbociclib improved progression-free survival vs fulvestrant alone in patients with hormone receptor–positive, HER2-negative, PIK3CA wild-type advanced breast cancer.
As related by the investigators, “Gedatolisib potently targets all four class I PI3K isoforms and mTORC1 and mTORC2 to comprehensively block the PI3K/AKT/mTOR pathway and has shown compelling activity in early clinical trials with palbociclib and fulvestrant.”
Study Details
In the open-label trial, 392 patients from sites in 23 countries were randomly assigned 1:1:1 between December 2022 and January 2025 to receive gedatolisib, palbociclib, and fulvestrant (n = 131), gedatolisib plus fulvestrant (n = 130), or fulvestrant monotherapy (n = 131). Eligible patients had disease progression during or after CDK4/6 inhibitor and aromatase inhibitor treatment. Treatments consisted of gedatolisib at 180 mg on days 1, 8, and 15 for 3 weeks with 1 week off; palbociclib at 125 mg once daily for 21 days with 1 week off; and fulvestrant at 500 mg every 2 weeks during cycle 1 (days 1 and 15) and then once every 4 weeks beginning with cycle 2. The primary outcome measures of the trial were progression-free survival for the gedatolisib triplet and the gedatolisib doublet groups vs fulvestrant monotherapy on blinded independent central review.
Key Findings
Median follow-up was 10.1 months (interquartile range = 6.6–15.1 months). Compared with a median progression-free survival of 2.0 months (95% confidence interval [CI] = 1.8–2.3 months) in the fulvestrant group, median progression-free survival was 9.3 months (95% CI = 7.2–16.6 months) in the gedatolisib triplet group (hazard ratio [HR] = 0.24, 95% CI = 0.17–0.35, P < .001) and 7.4 months (95% CI = 5.5–9.9 months) in the gedatolisib doublet group (HR = 0.33, 95% CI = 0.24–0.48, P < .001).
The most common treatment-related grade 3 or 4 adverse events were: neutropenia (62%) and stomatitis (19%) in the triplet group; stomatitis (12%) and rash (5%) in the doublet group; and neutropenia and thrombocytopenia (both 0.8%) in the fulvestrant monotherapy group. Treatment-related adverse events led to a discontinuation of treatment in 2.3% of patients in the triplet group and 3.1% of the doublet group. Death considered related to treatment occurred in two patients in the triplet group, due to pneumonia and hepatic failure, respectively.
The investigators concluded: “The addition of gedatolisib to fulvestrant, with or without palbociclib, significantly reduced the risk of disease progression or death in patients with hormone receptor–positive/HER2[-negative], PIK3CA wild-type advanced breast cancer.”
Sara A. Hurvitz, MD, of Fred Hutchinson Cancer Center, University of Washington, Seattle, is the corresponding author for the Journal of Clinical Oncology article.
DISCLOSURE: The study was supported by Celcuity Inc. For full disclosures of the study authors, visit ascopubs.org.
