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 nonsteroidal aromatase inhibitor (VIKTORIA-1).

person Sara A. Hurvitz David Geffen School of Medicine; University of California, Los Angeles; Jonsson Comprehensive Cancer Center, Santa Monica, CA info_outline Sara A. Hurvitz, Fabrice Andre, Massimo Cristofanilli, Giuseppe Curigliano, Antonio Giordano, Hyo S. Han, Miguel Martin, Barbara Pistilli, Hope S. Rugo, Robert Wesolowski, Samuel Suzuki, Sarah Mutka, Igor Gorbatchevsky, Sibylle Loibl

Authors person Sara A. Hurvitz David Geffen School of Medicine; University of California, Los Angeles; Jonsson Comprehensive Cancer Center, Santa Monica, CA info_outline Sara A. Hurvitz, Fabrice Andre, Massimo Cristofanilli, Giuseppe Curigliano, Antonio Giordano, Hyo S. Han, Miguel Martin, Barbara Pistilli, Hope S. Rugo, Robert Wesolowski, Samuel Suzuki, Sarah Mutka, Igor Gorbatchevsky, Sibylle Loibl Organizations David Geffen School of Medicine; University of California, Los Angeles; Jonsson Comprehensive Cancer Center, Santa Monica, CA, Gustave Roussy Institute, Villejuif, France, Weill Cornell Medicine, New York, NY, European Institute of Oncology, IRCCS and University of Milano, Milan, Italy, Dana-Farber Cancer Institute, Boston, MA, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, Servicio Oncología Médica, Hospital General Universitario Gregorio Marañon, IiSGM, Universidad Complutense, Ciberonc, GEICAM, Madrid, Spain, Breast Cancer Unit, Gustave Roussy, Villejuif, France, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, Ohio State University Comprehensive Cancer Center, Columbus, OH, Celcuity, Inc., Minneapolis, MN, German Breast Group, Neu-Isenburg, Germany; Centre for Haematology and Oncology Bethanien, Frankfurt, Germany Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Celcuity, Inc Background: Patients who receive frontline CDK4/6 inhibitor (CDK4/6i) therapy eventually experience disease progression. Resistance to CDK4/6i is likely a transient adaptive mechanism that may be reversed by inhibition of the PI3K/mTOR pathway. Thus, combination of CDK4/6i and PI3K/mTORi after disease progression on CDK4/6i could restore sensitivity to CDK4/6i and prevent activation of the PI3K/mTOR pathway. This hypothesis was evaluated in a Phase 1b study (Layman SABCS 2021) of gedatolisib (geda), a potent inhibitor of PI3K and mTOR. Subjects with HR+/HER2- ABC with prior CDK4/6i received geda (180 mg IV weekly for 3 weeks, then one week off) with palbociclib (palbo) and fulvestrant (FUL). Median PFS was 12.9 months with 63% overall response rate. Efficacy was observed regardless of PIK3CA mutation status (Wesolowski SABCS 2022). Geda was well tolerated, with few discontinuations 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 (NCT05501886). Methods: This Phase 3 multinational clinical trial will evaluate geda and FULwith or without palboin patients with HR+/HER2- ABC previously treated with any CDK4/6i in combination with a non-steroidal aromatase inhibitor (AI) therapy. Those without tumor PIK3CA mutations will be assigned to Study 1 (n=351) and randomized to Arm A (geda, palbo, and FUL), Arm B (geda and FUL), or Arm C (FUL). Those with PIK3CA mutations will be assigned to Study 2 (n=350) and randomized to Arm D (geda, palbo, and FUL), Arm E (alpelisib and FUL), or Arm F (geda and FUL). Key eligibility criteria include adults with confirmed metastatic or locally advanced breast cancer, any menopausal status, radiologically evaluable disease, and prior CDK4/6i treatment in combination with a non-steroidal AI. Prior hormonal therapy, including SERDs, is allowed. Key exclusion criteria include prior treatment with a PI3K, 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 per RECIST v1.1. Secondary endpoints included overall survival, safety and tolerability, ORR, duration of response, time to response, CBR, quality of life, and pharmacokinetics. The trial is open for enrollment. Clinical trial information: NCT05501886.

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