Abstract CT258: A randomized, open-label, phase 3 study of fulvestrant and CDK4/6 inhibitors with or without gedatolisib as first-line treatment in patients with HR+/HER2- advanced breast cancer (VIKTORIA-2)

Abstract Background: For patients with HR+/HER2- advanced breast cancer (ABC), first-line treatment typically includes a CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) combined with endocrine therapy (ET). For patients whose disease was sensitive to adjuvant ET, the expected mPFS is 25 to 28 months. However, patients with HR+/HER2- early BC whose disease recurs while receiving or within 12 months of completing adjuvant ET are considered to have ET-resistant disease and significantly worse clinical outcomes than those with endocrine sensitive disease. To improve outcomes for these patients, the addition of a PI3K-AKT-mTOR (PAM) inhibitor to standard-of-care CDK4/6 inhibitor and fulvestrant is being explored. Gedatolisib, a potent multi-node PAM inhibitor, has demonstrated superior potency and cytotoxicity in BC cell lines compared to approved single-node PAM inhibitors such as alpelisib, everolimus, and capivasertib (Rosetti S, et al. Cancer Res. 2023). In a Phase 1b study, gedatolisib combined with palbociclib and letrozole as a 1L treatment for patients with endocrine sensitive HR+/HER2- ABC reported an overall response rate (ORR) of 85.2%, mPFS of 48.4 months, and a median OS of 77.3 months in treatment-naïve patients (Layman R, et al. Lancet Oncol. 2024; Rugo HS, et al. SABCS 2024). Based on these findings, the VIKTORIA-2 phase 3 clinical trial was initiated. Methods: VIKTORIA-2 (NCT06757634) is a randomized, open-label phase 3 clinical trial evaluating the efficacy and safety of gedatolisib + investigator’s choice CDK4/6 inhibitor + fulvestrant (Arm A) compared with investigator’s choice CDK4/6 inhibitor + fulvestrant (Arm B) as first-line therapy in patients with ET-resistant HR+/HER2- ABC. After a run-in confirming safety of the combination of gedatolisib + ribociclib + fulvestrant, patients will be randomized 1:1 to either of two cohorts stratified by their tumor PIK3CA mutational status. To be eligible, patients must have confirmed HR+, HER2- ABC; disease that progressed during or within 12 months of completing neo(adjuvant) ET; provide a sample for central assessment of PIK3CA mutation status; radiologically evaluable disease according to RECIST v1.1; and ECOG performance status of 0-2. The dual primary endpoints are: PFS of Arm A vs Arm B for each cohort (PIK3CA mutant and PIK3CA mutation not detected). Secondary endpoints will evaluate OS, safety, and tolerability between treatment arms. Enrollment is ongoing. Citation Format: Sara Hurvitz, Barbara Pistilli, Virginia Kaklamani, Rachel M. Layman, Javier Cortés, Kyong Hwa Park, Massimo Cristofanilli, Brian Sullivan, Elizabeth C. Moser, Igor Gorbatchevsky, Giuseppe Curigliano. A randomized, open-label, phase 3 study of fulvestrant and CDK4/6 inhibitors with or without gedatolisib as first-line treatment in patients with HR+/HER2- advanced breast cancer (VIKTORIA-2) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT258.