Dr Hurvitz on the Rationale for Targeting PI3K and mTOR in PIK3CA Wild-Type HR+/HER2-Negative Breast Cancer

"In a phase 1b study, patients were treated with gedatolisib, fulvestrant, and palbociclib. Benefit was seen in patients regardless of whether their tumors had a PIK3CA mutation. These exciting data led to the development of the VIKTORIA-1 clinical trial."

Sara A. Hurvitz, MD, FACP, a medical oncologist, senior vice president, director of and a professor in the Clinical Research Division, the Smith Family Endowed Chair in Women’s Health, and an affiliate investigator in the Translational Science and Therapeutics Division at Fred Hutchinson Cancer Center; as well as a professor in and head of the Division of Hematology and Oncology in the Department of Medicine at the University of Washington, discussed the rationale for blocking the PI3K and mTOR pathways in hormone receptor (HR)–positive, HER2-negative breast cancer management.

Hurvitz noted that the PI3K pathway is significantly relevant in this disease setting, as it is altered in approximately 40% of HR-positive, HER2-negative breast cancers. For more than a decade, agents targeting the PI3K pathway have been available, she stated. However, many approved agents focus on only one component of the pathway because historical data have shown that targeting multiple parts of the pathway simultaneously can lead to toxicity.

Gedatolisib (PF-05212384) is an intravenous agent designed to target both PI3K and mTOR. This agent is notable because it inhibits all class IA isoforms of PI3K, in addition to inhibiting mTORC1/2. In a prior phase 1 trial (NCT02626507), gedatolisib plus palbociclib (Ibrance) and fulvestrant (Faslodex) produced an estimated 1-year progression-free survival rate of 79% (95% CI, 56%-91%) in patients with PIK3CA wild-type disease (n = 25) and 71% (95% CI, 26%-92%) in those with PIK3CA-mutated disease (n = 7). Crucially, patients experienced benefit regardless of whether patients’ tumors possessed a PIK3CA mutation.

These preliminary data were the impetus for the phase 3 VIKTORIA-1 trial (NCT05501886) evaluating gedatolisib plus fulvestrant with or without palbociclib in PIK3CA wild-type, HR-positive, HER2-negative metastatic breast cancer. The VIKTORIA-1 trial was structured into 2 distinct study parts. Study 1 focused on patients whose tumors were PIK3CA wild-type. These patients had previously received a CDK4/6 inhibitor combined with endocrine therapy. Patients in Study 1 were randomly assigned to 1 of 3 specific treatment arms: fulvestrant plus gedatolisib and palbociclib; fulvestrant plus gedatolisib; or fulvestrant alone.

Findings from study 1 of VIKTORIA-1 were presented during the 2025 ESMO Congress. Study 2 of VIKTORIA-1 evaluated patients whose tumors were PIK3CA-mutated, and the results from this study part are planned for presentation in 2026.