VIKTORIA-1 Trial of Gedatolisib Plus Fulvestrant With or Without Palbociclib in Hormone Receptor–Positive/HER2−/PIK3CA Wild-Type Advanced Breast Cancer

Author(s): Sara A. Hurvitz, MD¹; Rachel M. Layman, MD²; Giuseppe Curigliano, MD, PhD^3,4; Fabrice André, MD, PhD⁵; Massimo Cristofanilli, MD⁶; Sung-Bae Kim, MD, PhD⁷; Jorge Luis Martínez Rodríguez, MD⁸; Jorge C. Nadal, MD⁹; Gun Min Kim, MD¹⁰; Louisa Lo, MD, PhD¹¹; Yuly A. Remolina-Bonilla, MD¹²; Geronimo Rosselli, MD¹³; George Emile, MD¹⁴; Ernesto Korbenfeld, MD¹⁵; Juan Manuel Puig, MD¹⁶; Robert Wesolowski, MD¹⁷; Miguel Martin, MD, PhD¹⁸; Alistair Ring, MD¹⁹; Hyo S. Han, MD²⁰; Antonio Giordano, MD, PhD²¹; Sarah C. Mutka, PhD²²; Keren Moss, MD²²; Sam Suzuki, MS²²; Brian Sullivan, AB²²; Igor Gorbatchevsky, MD²²; Barbara Pistilli, MD⁵; for the VIKTORIA-1 Study Group;

Source: DOI: 10.1200/JCO-25-02643

Dr. Maen Hussein's Thoughts

Gedatolisib potently targets all four class I PI3K isoforms and mTORC1 and mTORC2 to comprehensively block the PI3K/AKT/mTOR pathway PFS was 9.3 m in the gedatolisib-triplet group vs 2.0 m in the fulvestrant group (hazard ratio) HR 0.24, and 7.4 m in the gedatolisib-doublet group HR 0.33 v fulvestrant. Neutropenia was worse in the triplets than doublets (62.3% vs 0.8%). The addition of gedatolisib to fulvestrant, with or without palbociclib, significantly reduced the risk of disease progression or death in patients with hormone receptor–positive/HER2−, PIK3CA WT advanced breast cancer.

PURPOSE

Gedatolisib potently targets all four class I PI3K isoforms and mTORC1 and mTORC2 to comprehensively block the PI3K/AKT/mTOR pathway and has shown compelling activity in early clinical trials with palbociclib and fulvestrant.

METHODS

This phase III randomized trial (VIKTORIA-1; ClinicalTrials.gov identifier: NCT05501886) evaluated the efficacy of gedatolisib-based therapy, comparing gedatolisib, palbociclib, and fulvestrant (gedatolisib triplet) and gedatolisib plus fulvestrant (gedatolisib doublet) with fulvestrant monotherapy in patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative (HER2−), PIK3CA wild-type (WT) advanced breast cancer. Eligible patients had disease progression during or after CDK4/6 inhibitor and aromatase inhibitor treatment. Comparison of progression-free survival as assessed by blinded independent central review for gedatolisib triplet versus fulvestrant and gedatolisib doublet versus fulvestrant was the primary objective.

RESULTS

A total of 392 patients were randomly assigned 1:1:1. The median study follow-up was 10.1 months. The median progression-free survival was 9.3 months in the gedatolisib-triplet group, 2.0 months in the fulvestrant group (hazard ratio [HR] for progression or death, 0.24 [95% CI, 0.17 to 0.35]; P < .001), and 7.4 months in the gedatolisib-doublet group (HR, 0.33 [95% CI, 0.24 to 0.48]; P < .001 v fulvestrant). Grade ≥3 treatment-related adverse events (TRAEs) reported in the gedatolisib-triplet and gedatolisib-doublet groups, respectively, included neutropenia (62.3%, 0.8%), stomatitis (19.2%, 12.3%), rash (4.6%, 5.4%), hyperglycemia (2.3%, 2.3%), and diarrhea (1.5%, 0.8%). Study treatment discontinuation because of TRAEs was reported in 2.3% (triplet) and 3.1% (doublet) of patients.

CONCLUSION

The addition of gedatolisib to fulvestrant, with or without palbociclib, significantly reduced the risk of disease progression or death in patients with hormone receptor–positive/HER2−, PIK3CA WT advanced breast cancer.

Author Affiliations

¹Fred Hutchinson Cancer Center, University of Washington, Seattle, WA; ²The University of Texas MD Anderson Cancer Center, Houston, TX; ³Istituto Europeo di Oncologia, IRCCS, Milano, Italy; ⁴University of Milano, Milano, Italy; ⁵Gustave Roussy, Villejuif, France; ⁶Weill Cornell Medical College, New York, NY; ⁷Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; ⁸Filios Alta Medicina SA de CV, Nuevo Leon, Mexico; ⁹Alexander Fleming Institute, Buenos Aires, Argentina; ¹⁰Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea; ¹¹Perth Breast Cancer Institute, Breast Cancer Research Centre-WA Hollywood Private Hospital, Nedlands, WA, Australia; ¹²Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico; ¹³Centro Medico Fleischer, Buenos Aires, Argentina; ¹⁴François Baclesse Comprehensive Cancer Center, Caen, France; ¹⁵Hospital Británico de Buenos Aires, Buenos Aires, Argentina; ¹⁶Centro Polivalente de Asistencia e Inv. Clinica CER-San Juan, San Juan, Argentina; ¹⁷The Ohio State University Comprehensive Cancer Center, Columbus, OH; ¹⁸Hospital Gregorio Marañón, Universidad Complutense, GEICAM, CIBERONC, Madrid, Spain; ¹⁹The Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom; ²⁰Moffitt Cancer Center, Tampa, FL; ²¹Dana-Farber Cancer Center, Boston, MA; ²²Celcuity Inc, Minneapolis, MN

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