Sara A. Hurvitz, Rachel M. Layman, Giuseppe Curigliano, Fabrice André, Massimo Cristofanilli, Sung-Bae Kim, J. Martinez Rodriguez, Jorge Nadal, G. Kim, Louisa L. Lo, Yuly A. Remolina-Bonilla, Geronimo Rosselli, George Emile, Ernesto Korbenfeld, Juan Manuel Puig, Robert Wesolowski, Miguel Martin, Alistair Ring, Hyo S. Han, Antonio Giordano, Sarah C. Mutka, Keren Moss, Sam Suzuki, Brian Sullivan, Igor Gorbatchevsky, Barbara Pistilli, for the VIKTORIA-1 Study Group, Rachel M. Layman, Robert Wesolowski, Erica Stringer-Reasor, Rena D. Callahan, Hyo S. Han, William Irvin, Issam Makhoul, Jennifer Specht, Massimo Cristofanilli, Hiba Jabbour, David Chan, Antonio Giordano, Ritesh Parajuli, Andrea Silber, Hema Vankayala, Delia Guaqueta, Tayyaba Bashir, Gerburg Wulf, Ricardo Alvarez, Sibel Blau, Jennifer M. Suga, Sunil G. Babu, Amanda Gillespie-Twardy, Kathryn Elizabeth Hudson, Urszula Sobol, Wederson M. Claudino, Cynthia Osborne, Jose Guimaraes, Danielle Charpentier, Jeffrey Sulpher, Cameron Phillips, Daniel Egle, Martin Wiesholzer, Renate Pusch, Sonja Heibl, Laure Nuytemans, Francois Duhoux, Patrick Neven, Sevilay Altıntaş, Nicolás Isambert, Barbara Pistilli, Marie Meurer, Mónica Arnedos, Youssef Tazi, Frank Priou, George Emile, Christoph Mundhenke, Marcus Schmidt, M. Hackenthal, Toralf Reimer, Mustafa Deryal, Joke Tio, Marina Cazzaniga, Giuseppe Tonini, Marco Angelo Colleoni, Giampaolo Tortora, Laura Biganzoli, Daniela Boggiani, Y. Izarzugaza Perón, Alba Gonzalez-Haba Martinez, Noelia Martínez Jáñez, Carmela Rodríguez López, José Luis Alonso Romero, Santiago González Santiago, Agostina Stradella Trucco, Cristina Saavedra Serrano, Sarah Khan, Alistair Ring, Ciara O’Brien, Simon Waters, Alistair Ring, Davide Mauri, Grigorios Rallis
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.