Gedatolisib (pan-PI3K/mTORC1/2 inhibitor) + fulvestrant ± palbociclib doubles PFS vs alpelisib in PIK3CA-mut HR+/HER2− ABC

Gedatolisib (IV, comprehensive PI3Kα/β/δ/γ + mTORC1/2 inhibitor) was tested in the randomized, open-label Phase 3 VIKTORIA-1 Study 2 (NCT05501886) in HR+/HER2− PIK3CA-mutant advanced breast cancer after progression on CDK4/6 inhibitor + aromatase inhibitor, with no prior PI3K/AKT/mTOR inhibitor and no chemo for advanced disease (N=362; geda+palbo+fulvestrant n=155; alpelisib+fulvestrant n=155; geda+fulvestrant n=52; data cut-off March 9, 2026). Median PFS by blinded independent central review was 11.1 months with geda+palbo+fulv vs 5.6 months with alpelisib+fulv (HR 0.50, 95% CI 0.37–0.68; P<0.0001), and 11.3 vs 5.6 months for geda+fulv vs alpelisib+fulv (HR 0.51, 95% CI 0.33–0.79; P<0.0013)—a substantially larger post–CDK4/6 PFS than the ~7.3-month benchmark seen with capivasertib+fulvestrant in PIK3CA/AKT1/PTEN-altered disease. Safety favored gedatolisib on metabolic toxicity: hyperglycemia all-grade/grade 3 was 15.0%/2.6% (geda triplet) and 11.5%/0% (geda doublet) vs 57.9%/13.8% (alpelisib+fulv), while stomatitis was higher with gedatolisib (all-grade/grade 3: 61.4%/16.3% triplet; 61.5%/5.8% doublet) vs 34.2%/5.3% on alpelisib+fulv; discontinuation due to TRAEs remained low (2.6%, 3.8%, 7.1%, respectively).