Background
The PAM pathway drives breast cancer growth and mediates resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i). Combining PAM inhibition with ET plus CDK4/6i after progression may restore sensitivity. However, most approved agents that target single components of this pathway require direct PI3K-pathway alteration for clinical benefit. Gedatolisib, a highly potent multitarget inhibitor of all class I PI3K isoforms plus mTORC1 and mTORC2, comprehensively blocks PAM regardless of PIK3CA status. The phase 3 VIKTORIA-1 trial was designed to evaluate the safety and efficacy of gedatolisib-based therapy in patients with hormone receptor–positive (HR+)/HER2-negative (HER2–) advanced breast cancer that progressed during or after standard therapy. Patients are enrolled to study 1 or study 2 based on PIK3CA status (wild type [WT] vs mutated, respectively). Herein, we encore study 1 top-line safety and efficacy data.
Methods
This randomized, open-label, phase 3 trial enrolled patients with HR+/HER2– advanced breast cancer that progressed on/after CDK4/6i plus nonsteroidal aromatase inhibitor and had radiologically evaluable disease (per RECIST v1.1), no prior chemotherapy for advanced breast cancer, and no prior PAMi. Study 1 patients were randomized to gedatolisib plus palbociclib plus fulvestrant (triplet), gedatolisib plus fulvestrant (doublet), or fulvestrant alone, stratified by visceral metastasis, time to radiological disease progression on immediate prior therapy, and geographic region. Treatment was given in 28-day cycles of gedatolisib 180 mg IV weekly for 3 weeks on/1 week off; palbociclib 125 mg by mouth daily for 21 days; fulvestrant 500 mg intramuscularly every 2 weeks (cycle 1) then every 4 weeks. Patients in the fulvestrant arm could cross-over to gedatolisib treatment upon progression. Co-primary end points were progression-free survival (PFS) assessed by blinded independent central review for the triplet vs fulvestrant and the doublet vs fulvestrant. Statistical comparisons were performed by stratified log-rank test. Additional end points include overall survival (OS), response, and safety.
Results
At data cut-off (May 30, 2025), 392 patients with PIK3CA WT disease had been randomized. Median study follow-up was 10.1 months. The trial met its primary end points, with median PFS for the triplet vs fulvestrant of 9.3 vs 2.0 months (HR, 0.24; 95% CI, 0.17-0.35; P < .0001) and doublet (7.4 vs 2.0 months; HR, 0.33; 95% CI, 0.24-0.48; P < .0001), with consistent benefit across prespecified subgroups. OS data were immature but favored the gedatolisib arms. Safety profiles were generally consistent with the individual agents. Rates of discontinuation of assigned therapy due to treatment-related adverse events were low (2.3% for triplet; 3.1% for doublet). Detailed safety data will be presented.
Conclusions
These data support gedatolisib combination therapy as a potential new standard of care for the second-line treatment of patients with HR+/HER2– PIK3CA WT advanced breast cancer.
