Dr McCann on the Potential Clinical Utility of Gedatolisib in Advanced Breast Cancer

“VIKTORIA-1 is an important trial because gedatolisib is a PI3K and mTOR inhibitor. It hits both of those in the same pathway. mTOR inhibition is also an effective way to target the PI3K pathway, [regardless of] whether a patient has a PI3K or AKT mutation. This is an incredibly promising drug.”

Kelly E. McCann, MD, PhD, an assistant clinical professor of medicine at the UCLA School of Medicine and a hematologist oncologist at UCLA Health, discussed the clinical implications of findings from the phase 3 VIKTORIA-1 trial (NCT05501886) investigating gedatolisib (PF-05212384)–based combinations in patients with hormone receptor–positive, HER2-negative advanced breast cancer following progression on a CDK4/6 inhibitor and a nonsteroidal aromatase inhibitor.

Gedatolisib is a highly potent multitarget inhibitor of the PI3K/AKT/mTOR (PAM) pathway, McCann began. It targets all class I PI3K isoforms, as well as mTORC1 and mTORC2. McCann noted that the VIKTORIA-1 trial is an important reminder that mTOR inhibition is an effective strategy for targeting the PI3K pathway and is potentially effective regardless of whether the patient harbors a PI3K or AKT mutation.

The study included a cohort of patients whose disease was PIK3CA wild-type. Patients were randomly assigned into 3 distinct treatment arms to receive fulvestrant (Faslodex) alone, fulvestrant plus gedatolisib, or fulvestrant combined with gedatolisib and palbociclib (Ibrance).

A key distinction of gedatolisib compared with currently available PI3K inhibitors is its route of administration: it is an intravenous (IV) therapy given once weekly, McCann contextualized. Although weekly IV administration could be perceived as time-consuming, the benefit is that the drug is well tolerated, she added. In the trial, patients generally received 3 doses of gedatolisib during the course of 1 cycle.

The gedatolisib-based regimens were notable for resulting in a lower incidence of expected adverse effects associated with drugs targeting the PAM pathway, such as hyperglycemia and stomatitis, according to McCann. The incidence of stomatitis was reported at 69.2% with the triplet and 56.9% with the doublet; the rates of grade 3 stomatitis were 19.2% and 12.3%, respectively, with no grade 4 events reported. Hyperglycemia rates were also relatively low: 9.2% for the triplet arm and 11.5% for the doublet arm.

Furthermore, the study was inclusive, allowing diabetic patients to enroll, McCann reported. The rates of treatment discontinuation due to treatment-related AEs were low, recorded at 2.3% in the triplet arm and 3.1% in the doublet arm.