Gedatolisib-Based Doublet and Triplet Regimens for PIK3CA-Wild-Type Advanced Breast Cancer
Key Clinical Takeaways
- Design/Population: This open-label phase 3 trial randomized 392 patients with HR-positive, HER2-negative, PIK3CA–wild-type advanced breast cancer who progressed on a CDK4/6 inhibitor plus aromatase inhibitor to gedatolisib–palbociclib–fulvestrant (triplet), gedatolisib–fulvestrant (doublet), or fulvestrant monotherapy. Treatment dosing followed standard schedules for all agents, with PFS as the primary end point.
- Key Outcomes: Both the triplet and doublet regimens significantly improved median PFS compared with fulvestrant alone, with hazard ratios of 0.24 and 0.33, respectively. Safety remained manageable, with low rates of treatment discontinuation and predictable class-related events such as low-grade hyperglycemia.
- Clinical Relevance: These results support gedatolisib-based therapy as an effective next-line treatment option for HR-positive, HER2-negative, PIK3CA–wild-type advanced breast cancer after CDK4/6 inhibitor progression. The magnitude and consistency of PFS benefit across subgroups reinforce its potential role as a new standard of care in this setting.
Updated results from the phase 3 VIKTORIA-1 trial indicate that adding gedatolisib to fulvestrant ± palbociclib demonstrates promising clinical efficacy and safety among previously treated patients with hormone receptor (HR)-positive, HER2-negative, PIK3CA-wild-type advanced breast cancer.
These findings were presented by Barbara Pistilli, MD, Gustave Roussy, Villejuif, France, at the 2025 San Antonio Breast Cancer Symposium in San Antonio, Texas.
In this open-label study, researchers enrolled 392 patients with disease progression on or after CDK4/6 inhibitor plus aromatase inhibitor therapy who had not received chemotherapy or a PAM inhibitor for advanced disease. Patients were randomized 1:1:1 to receive 180 mg of gedatolisib (3 weeks on, 1 week off) plus 125 mg of once daily palbociclib (days 1 to 21) and 500 mg of fulvestrant (every 2 weeks during cycle 1, then every 4 weeks), gedatolisib plus fulvestrant, or fulvestrant monotherapy. The primary end point was progression-free survival (PFS). A key secondary end point was safety.
At a median follow-up of 10.1 months, median PFS was 9.3 months in the triplet arm compared with 2 months in the fulvestrant monotherapy arm (hazard ratio [HR], 0.24; 95% confidence interval [CI], 0.17 to 0.35; P <.0001). Median PFS in the doublet arm was 7.4 months compared with 2 months in the fulvestrant monotherapy arm (HR, 0.33; 95% CI, 0.24 to 0.48; P <.0001).
Safety findings were consistent with prior findings. Discontinuation due to treatment-related adverse events occurred in 2.3% of patients in the triplet arm and 3.1% in the doublet arm. Hyperglycemia occurred in 9.2% and 11.5% of patients in the triplet and doublet arms, respectively. Grade 3 hyperglycemia occurred in 2.3% of patients in each arm and no grade 4 events were reported.
As Dr Pistilli concluded, “these updated results support gedatolisib combination therapy as a potential new standard of care for the [second-line] treatment of patients with [HR-positive, HER2-negative, PIK3CA-wild-type advanced breast cancer.”
Source:
Pistilli B, Layman R, Curigliano G, et al. Gedatolisib, a multi-target PI3K/AKT/mTOR (PAM) inhibitor, plus fulvestrant with or without palbociclib for second-line (2L) treatment of patients with HR+/HER2-/PIK3CA-wild type (WT) advanced breast cancer (ABC): updated results from the randomized, phase 3 VIKTORIA-1 trial. Presented at SABCS 2025. December 9 - 12, 2025. San Antonio, Texas. Abstract RF7-04.
