Abstract OT3-26-02: A Phase 3 study of gedatolisib plus fulvestrant with and without palbociclib in patients with HR+/HER2- advanced breast cancer previously treated with a CDK4/6 inhibitor plus a non-steroidal aromatase inhibitor (VIKTORIA-1)
Authors: Hurvitz Sara , Andre Fabrice , Cristofanilli Massimo , Curigliano Giuseppe , Giordano Antonio , Han Hyo S. , Martín Miguel , Pistilli Barbara , Rugo Hope , Wesolowski Robert , Suzuki Samuel , Mutka Sarah C. , Gorbatchevsky Igor , Loibl Sibylle 
Published: March 2023

Abstract
Background: Gedatolisib is a potent reversible dual inhibitor that selectively targets all Class I isoforms of phosphoinositide 3-kinase (PI3K) and mechanistic target of rapamycin (mTOR). Two separate pivotal clinical trials demonstrated that PI3K and mTOR inhibitors are active in combination with endocrine therapy and prolong progression-free survival (PFS) among patients with hormone receptor positive (HR+)/HER2-negative (HER2-) advanced breast cancer (ABC) who had previously received endocrine therapy (SOLAR-1, BOLERO-2). CDK4/6 inhibitor (CDK4/6i) therapy has been approved in the front-line setting. However, patients eventually experience disease progression on CDK4/6i based therapy. Available data indicates that resistance to CDK4/6i is a transient adaptive mechanism that may be reversed by adding inhibitors of the PI3K/mTOR pathway (PI3K/mTORi). Thus, combination of PI3K/mTORi and CDK4/6i in patients whose disease progressed on prior CDK4/6i could potentially both restore sensitivity to CDK4/6i and prevent adaptive activation of the PI3K/mTOR pathway. This hypothesis was evaluated in a Phase 1b study (Layman SABCS 2021). Subjects with HR+/HER2- ABC who were CDK4/6i pretreated received gedatolisib (180 mg IV weekly for 3 weeks, then one week off) in combination with standard doses of palbociclib and fulvestrant. Median PFS was 12.9 months, and overall response rate was 63%. Grade 3-4 adverse events (AE) were observed at a low rate, and toxicity was overall easily managed with available standards of care, and few patients discontinued treatment due to treatment-related adverse events (4%). The most common AE was stomatitis; hyperglycemia of any grade occurred in 26% of patients. This preliminary data, dosing schedule, and study population characteristics form the basis for the Phase 3 trial, VIKTORIA-1. Trial design: This Phase 3, open-label, randomized, multinational two-part clinical trial will evaluate the efficacy and safety of gedatolisib and fulvestrant with or without palbociclib in patients with HR+/HER2- ABC previously treated with any CDK4/6i in combination with non-steroidal aromatase inhibitor therapy. Those without tumor PIK3CA mutations will be assigned to Study 1 and those with PIK3CA mutations will be assigned to Study 2. Study 1 will include up to 351 subjects randomized in a 1:1:1 ratio to Arm A (gedatolisib, palbociclib, and fulvestrant), Arm B (gedatolisib plus fulvestrant), or Arm C (fulvestrant). For subjects in Arm C whose disease progresses, crossover to Arm A or B is allowed. Study 2 will include up to 350 subjects randomized in a 3:3:1 ratio to Arm D (gedatolisib, palbociclib, and fulvestrant), Arm E (alpelisib plus fulvestrant), or Arm F (gedatolisib plus fulvestrant). Key eligibility criteria include adults with confirmed metastatic or locally advanced breast cancer, any menopausal status for females, radiologically evaluable disease, and prior CDK4/6i treatment with non-steroidal AI. Prior therapy with SERD, including fulvestrant is allowed. Key exclusion criteria include prior treatment with a PI3K, protein kinase B (Akt), or mTOR inhibitor, prior treatment with chemotherapy for advanced disease, more than two lines of prior endocrine therapy, bone only disease with no soft tissue components, active CNS metastases, and type 1 diabetes or uncontrolled type 2 diabetes. The primary endpoint is PFS assessed by blinded independent central review (BICR) per RECIST v1.1. Secondary endpoints included overall survival (OS), safety and tolerability, ORR, duration of response, time to response, CBR, quality of life, and pharmacokinetics. This trial is open for enrollment.
Citation Format: Sara Hurvitz, Fabrice Andre, Massimo Cristofanilli, Giuseppe Curigliano, Antonio Giordano, Hyo S. Han, Miguel Martín, Barbara Pistilli, Hope Rugo, Robert Wesolowski, Samuel Suzuki, Sarah C. Mutka, Igor Gorbatchevsky, Sibylle Loibl. A Phase 3 study of gedatolisib plus fulvestrant with and without palbociclib in patients with HR+/HER2- advanced breast cancer previously treated with a CDK4/6 inhibitor plus a non-steroidal aromatase inhibitor (VIKTORIA-1) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-26-02.