Exploring the Role of Gedatolisib in HR+/HER2-Negative Breast Cancer

In a conversation with CancerNetwork® at the European Society for Medical Oncology (ESMO) Congress 2025, Sara A. Hurvitz, MD, FACP, discussed the mechanistic properties of gedatolisib (PKI-587) among patients with stage III or IV hormone receptor (HR)–positive HER2-negative breast cancer, as well as factors that influence its use in doublet or triplet therapies. She spoke in the context of findings from the phase 3 VIKTORIA-1 trial (NCT05501886) that she presented at the congress.

Hurvitz expressed that gedatolisib was unique in its targeting of the Phosphatidylinositol 3-kinase/AKT/mTOR (PAM) pathway. Additionally, she explained that its intravenous administration reduces the dosing frequency, which may contrast with oral therapies, which are associated with higher occurrences of toxicity.

Furthermore, when considering whether to add palbociclib (Ibrance) to gedatolisib and fulvestrant (Faslodex), Hurvitz suggested that would be a question that would “stimulate much debate.” She concluded by explaining that an evaluation of subgroups in VIKTORIA-1 appeared to show a benefit with the triplet among patients with endocrine resistance or those who experienced a short time to progression following frontline therapy.

Hurvitz is the Smith Family Endowed chair in Women’s Health and senior vice president and director of the Clinical Research Division at the Fred Hutch Cancer Center.

Transcript:

Gedatolisib is unique in that it targets all isoforms of PI3Kclass I, as well as mTORC1 and mTORC2. That complete inhibition of the PAM pathway is unique and may relate to the real evidence of efficacy that we are seeing. Also, because it is given intravenously rather than orally, a patient is receiving only about 3 doses in a given month, whereas, when taking a PI3K inhibitor orally, it is 16 to 28 doses. That may account for the higher toxicity we are seeing with hyperglycemia and diarrhea with the oral-based regimens.

Whether to use the triplet regimen or the doublet regimen is going to be a question that will probably stimulate much debate. Looking at our subgroup analyses and comparing the benefit of the triplet vs the doublet as an exploratory measure, it does seem that patients who have endocrine-resistant disease [or] who experienced a short time to progression on frontline therapy may be the ones who are going to benefit more from a triplet than a doublet.

Reference

Hurvitz SA, Layman RM, Curigliano G, et al. Gedatolisib plus fulvestrant, with & without palbociclib, vs fulvestrant in patients with HR+/HER2-/PIK3CA wild-type advanced breast cancer: first results from VIKTORIA-1. Presented at: European Society for Medical Oncology (ESMO) Congress 2025; October 17-21, 2025; Berlin, Germany. Abstract LBA17