Abstract RF7-04: 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

Abstract ***This abstract is an updated version of the previously submitted shell abstract (#286), which was accepted for a rapid-fire oral presentation (RF4-03). Background: Second-line treatment for HR+/HER2- ABC after endocrine therapy (ET) + a CDK4/6 inhibitor (CDK4/6i) is associated with a poor clinical outcome. Treatment resistance likely involves the PAM pathway; therefore, adding a PAM inhibitor (PAMi) to ET + CDK4/6i after progression on CDK4/6i may restore sensitivity and prevent adaptive PAM pathway activation. Gedatolisib is a highly potent multitarget inhibitor of all Class I PI3K isoforms plus mTORC1 and mTORC2 that provides comprehensive PAM blockade. In preclinical studies, gedatolisib demonstrated superior potency and cytotoxicity compared to alpelisib, capivasertib, and everolimus, regardless of PI3K-pathway mutation status, and combinations of gedatolisib + fulvestrant, with and without palbociclib, were active in treatment-naive and resistant cell lines. The phase 3 VIKTORIA-1 trial was designed to evaluate the safety and efficacy of gedatolisib-based therapy in patients with HR+/HER2- ABC that progressed during or following CDK4/6i and aromatase inhibitor therapy. Based on the PIK3CA screening result, patients are enrolled to Study 1 (PIK3CA-WT) or Study 2 (PIK3CA-mutated disease). Herein, we report updated results from Study 1. Methods: VIKTORIA-1 is a randomized, open-label, phase 3 trial. Eligible patients must have HR+/HER2- ABC, disease progression during or after a CDK4/6i + nonsteroidal aromatase inhibitor, no chemotherapy for ABC, no prior PAMi, and radiologically evaluable disease (per RECIST v1.1). Study 1 patients (PIK3CA WT) were randomized 1:1:1 to: gedatolisib + palbociclib + fulvestrant (triplet), gedatolisib + fulvestrant (doublet), or fulvestrant, stratified by presence of visceral metastasis, time to radiological disease progression on immediate prior therapy, and geographic region. Treatment was administered in 28-day cycles as follows: gedatolisib 180 mg IV weekly for 3 weeks on/1 week off; palbociclib 125 mg po daily for 21 days; fulvestrant 500 mg IM every 2 weeks (cycle 1) then every 4 weeks. Co-primary endpoints were progression-free survival (PFS) assessed by blinded independent central review comparing the triplet to fulvestrant, then, if positive, the doublet to fulvestrant. Statistical comparisons were performed by stratified log-rank test. Additional endpoints include overall survival, response, safety, and quality of life (QOL). Results: At data cut-off (May 30,2025), 392 patients with PIK3CA WT disease had been randomized, and median study follow-up was 10.1 mos. The trial met its primary endpoints, 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