VIKTORIA-1 Trial of Gedatolisib Plus Fulvestrant With or Without Palbociclib in Hormone Receptor-Positive/HER2-/PIK3CA Wild-Type Advanced Breast Cancer

Clinical Snapshot

Key Findings

• P Value: Both comparisons P < 0.001

• Effect Size: Triplet vs fulvestrant: median PFS 9.3 vs 2.0 months; Doublet vs fulvestrant: median PFS 7.4 vs 2.0 months

• Primary Outcome: Progression-free survival by blinded independent central review

• Nnt Or Sensitivity: Based on median PFS improvement, approximately 2-3 patients need treatment to prevent one progression event at 6 months

• Confidence Interval: Triplet HR 0.24 (95% CI 0.17-0.35); Doublet HR 0.33 (95% CI 0.24-0.48)

Clinical Application

Requires access to gedatolisib (investigational agent), established infrastructure for PI3K/mTOR inhibitor monitoring, and expertise in managing associated toxicities including neutropenia and stomatitis Relevant to Australian practice where CDK4/6 inhibitors are PBS-subsidised first-line therapy. Would require TGA approval and PBS listing. Fits within Cancer Australia guidelines for advanced breast cancer management Patients with HR+/HER2- advanced breast cancer who have progressed on CDK4/6 inhibitor plus aromatase inhibitor therapy, representing a common clinical scenario in Australian oncology practice

Abstract

PURPOSE: 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. METHODS: This phase III randomized trial (VIKTORIA-1; ClinicalTrials.gov identifier: NCT05501886) evaluated the efficacy of gedatolisib-based therapy, comparing gedatolisib, palbociclib, and fulvestrant (gedatolisib triplet) and gedatolisib plus fulvestrant (gedatolisib doublet) with fulvestrant monotherapy in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HER2-), PIK3CA wild-type (WT) advanced breast cancer. Eligible patients had disease progression during or after CDK4/6 inhibitor and aromatase inhibitor treatment. Comparison of progression-free survival as assessed by blinded independent central review for gedatolisib triplet versus fulvestrant and gedatolisib doublet versus fulvestrant was the primary objective. RESULTS: A total of 392 patients were randomly assigned 1:1:1. The median study follow-up was 10.1 months. The median progression-free survival was 9.3 months in the gedatolisib-triplet group, 2.0 months in the fulvestrant group (hazard ratio [HR] for progression or death, 0.24 [95% CI, 0.17 to 0.35]; P < .001), and 7.4 months in the gedatolisib-doublet group (HR, 0.33 [95% CI, 0.24 to 0.48]; P < .001 v fulvestrant). Grade ≥3 treatment-related adverse events (TRAEs) reported in the gedatolisib-triplet and gedatolisib-doublet groups, respectively, included neutropenia (62.3%, 0.8%), stomatitis (19.2%, 12.3%), rash (4.6%, 5.4%), hyperglycemia (2.3%, 2.3%), and diarrhea (1.5%, 0.8%). Study treatment discontinuation because of TRAEs was reported in 2.3% (triplet) and 3.1% (doublet) of patients. CONCLUSION: 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-, PIK3CA WT advanced breast cancer.

References

1. 1.Hurvitz, S. A., Layman, R. M., Curigliano, G., André, F., Cristofanilli, M., Kim, S. B., Martínez Rodríguez, J. L., Nadal, J. C., Kim, G. M., Lo, L., Remolina-Bonilla, Y. A., Rosselli, G., Emile, G., Korbenfeld, E., Puig, J. M., Wesolowski, R., Martin, M., Ring, A., Han, H. S., Giordano, A., Mutka, S. C., Moss, K., Suzuki, S., Sullivan, B., Gorbatchevsky, I., & Pistilli, B. (2026). VIKTORIA-1 Trial of Gedatolisib Plus Fulvestrant With or Without Palbociclib in Hormone Receptor-Positive/HER2-/PIK3CA Wild-Type Advanced Breast Cancer. Journal of Clinical Oncology. https://doi.org/10.1200/JCO-25-02643