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VIKTORIA-1 Trial of Gedatolisib Plus Fulvestrant With or Without Palbociclib in Hormone
Sara A Hurvitz1, Rachel M Layman2, Giuseppe Curigliano3,4
1Fred Hutchinson Cancer Center, University of Washington, Seattle, WA.
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.
Insights
Gedatolisib combined with fulvestrant, with or without palbociclib, significantly improved progression-free survival in advanced hormone receptor-positive, HER2-negative breast cancer patients with PIK3CA wild-type tumors. This combination therapy offers a promising new treatment option.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer remains a significant clinical challenge.
- The PI3K/AKT/mTOR pathway is frequently dysregulated in HR+ breast cancer, making it a key therapeutic target.
- Gedatolisib is a potent inhibitor of all class I PI3K isoforms and mTORC1/mTORC2, aiming to comprehensively block the PI3K/AKT/mTOR pathway.
Purpose of the Study:
- To evaluate the efficacy of gedatolisib-based therapy in patients with HR+, HER2-, PIK3CA wild-type advanced breast cancer.
- To compare the efficacy of gedatolisib plus fulvestrant (doublet) and gedatolisib, palbociclib, and fulvestrant (triplet) against fulvestrant monotherapy.
- To assess progression-free survival (PFS) as the primary endpoint in this phase III randomized trial.
Main Methods:
- The VIKTORIA-1 trial (NCT05501886) was a phase III randomized study involving 392 patients.
- Patients had disease progression during or after CDK4/6 inhibitor and aromatase inhibitor treatment.
- Treatments included gedatolisib triplet, gedatolisib doublet, or fulvestrant monotherapy, with PFS assessed by blinded independent central review.
Main Results:
- The median PFS was 9.3 months for the gedatolisib triplet and 7.4 months for the gedatolisib doublet, compared to 2.0 months for fulvestrant monotherapy.
- Gedatolisib-based therapies significantly reduced the risk of progression or death (HR 0.24 for triplet, HR 0.33 for doublet vs. fulvestrant; P < .001).
- Grade ≥3 treatment-related adverse events included neutropenia (62.3% in triplet), stomatitis (19.2% in triplet), and diarrhea, with low discontinuation rates due to TRAEs (2.3% triplet, 3.1% doublet).
Conclusions:
- Adding gedatolisib to fulvestrant, with or without palbociclib, significantly improves PFS in patients with HR+/HER2- advanced breast cancer and PIK3CA wild-type status.
- Gedatolisib-based regimens demonstrate substantial clinical activity in this patient population.
- These findings support gedatolisib as a valuable therapeutic option for advanced HR+/HER2- breast cancer.
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