Gedatolisib plus fulvestrant with or without palbociclib improved progression-free survival versus fulvestrant monotherapy in advanced breast cancer.
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Key Takeaway
Consider gedatolisib plus fulvestrant with or without palbociclib for advanced breast cancer, noting increased Grade ≥3 adverse events with triplet therapy.
This phase III randomized trial enrolled 392 patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HER2-), wild-type (WT) advanced breast cancer who had disease progression during or after CDK4/6 inhibitor and aromatase inhibitor treatment. The study compared gedatolisib plus fulvestrant with or without palbociclib against fulvestrant monotherapy. The primary outcome was progression-free survival as assessed by blinded independent central review, with a follow-up of 10.1 months.
In the triplet group, median progression-free survival was 9.3 months versus 2.0 months in the fulvestrant group, with a hazard ratio of 0.24 (95% CI, 0.17 to 0.35; p < .001). In the doublet group, median progression-free survival was 7.4 months versus 2.0 months in the fulvestrant group, with a hazard ratio of 0.33 (95% CI, 0.24 to 0.48; p < .001). Both regimens demonstrated a reduced risk of progression or death compared with monotherapy.
Safety analysis revealed that Grade ≥3 treatment-related adverse events occurred in 62.3% of patients in the triplet group versus 0.8% in the doublet group for neutropenia. Stomatitis occurred in 19.2% of the triplet group and 12.3% of the doublet group. Other Grade ≥3 events included rash (4.6% triplet, 5.4% doublet), hyperglycemia (2.3% triplet, 2.3% doublet), and diarrhea (1.5% triplet, 0.8% doublet). Discontinuations due to adverse events occurred in 2.3% of the triplet group and 3.1% of the doublet group. Serious adverse events were not reported. Tolerability was not reported.
Limitations include that the setting was not reported, funding or conflicts were not reported, and practice relevance was not reported. The study design is a randomized trial, but the specific location and broader applicability remain unclear based on the available data.
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View Original 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-), 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]; < .001), and 7.4 months in the gedatolisib-doublet group (HR, 0.33 [95% CI, 0.24 to 0.48]; < .001 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-, WT advanced breast cancer.
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