Despite the widespread use of CDK4/6 inhibitors in hormone receptor–positive, HER2-negative advanced breast cancer, most patients eventually develop resistance, and optimal post-CDK4/6 treatment sequencing remains unclear. Activation of the PI3K/AKT/mTOR (PAM) pathway is a key mechanism of resistance, providing a strong biologic rationale for targeting this pathway to restore endocrine sensitivity and potentially overcome CDK4/6 inhibitor resistance.
VIKTORIA-1: Study Design
VIKTORIA-1 is a global, open-label, phase III randomized trial designed to evaluate whether comprehensive inhibition of the PI3K/AKT/mTOR pathway can improve outcomes in a clinically challenging population: patients with hormone receptor–positive, HER2-negative advanced breast cancer who have progressed on prior CDK4/6 inhibitor–based therapy. The study specifically focused on the PIK3CA wild-type subgroup, where effective targeted options remain limited. Patients were randomized to receive either a triplet combination of gedatolisib, fulvestrant, and palbociclib, a doublet of gedatolisib plus fulvestrant, or fulvestrant alone, enabling assessment of both the impact of PAM pathway inhibition and the potential benefit of continuing CDK4/6 blockade beyond progression.
Mechanism & Drug Rationale
Gedatolisib is a potent, intravenous multitarget inhibitor that blocks all class I PI3K isoforms as well as both mTOR complexes (mTORC1 and mTORC2), enabling comprehensive inhibition of the PAM pathway. Preclinical and early clinical data have demonstrated activity in both PIK3CA-mutant and wild-type disease, supporting its evaluation in combination with endocrine therapy, with or without CDK4/6 inhibition.
Efficacy Results
VIKTORIA-1 met its primary endpoint, demonstrating a substantial improvement in progression-free survival with both gedatolisib-based regimens compared with fulvestrant alone. The triplet combination achieved a median PFS of 9.3 months, versus 2.0 months in the control arm (HR 0.24), while the doublet reached 7.4 months (HR 0.33). This magnitude of benefit is particularly notable in a population previously treated with CDK4/6 inhibitors, where endocrine-based therapies typically offer limited disease control. Importantly, the treatment effect was consistent across clinically relevant subgroups, reinforcing the central role of the PAM pathway in resistance biology.
Response and Clinical Signal
In VIKTORIA-1, the improvement in PFS was supported by meaningful response rates. Objective responses were observed in 31.5% of patients receiving the triplet and 28.3% with the doublet, compared with only 1.0% in the fulvestrant arm. Responses were also durable, with a median duration of response of 17.5 months and 12.0 months for the triplet and doublet, respectively. These findings suggest that gedatolisib-based therapy not only delays progression but can induce sustained tumor control in a subset of patients. Overall survival data are immature, with a numerical trend favoring gedatolisib-containing arms (HR 0.69 for the triplet and 0.74 for the doublet), although statistical significance has not been reached.
Safety Profile
Gedatolisib-based regimens were associated with a manageable safety profile. The most common adverse event was stomatitis, reported in over half of patients, with grade ≥3 events in approximately 12–19%. Prophylactic measures appeared to reduce severity compared with earlier studies. Neutropenia was primarily observed in the triplet arm, consistent with the addition of palbociclib, while hyperglycemia, a known class effect of PAM pathway inhibition, occurred at relatively low rates. Treatment discontinuation due to adverse events was low (2.3% and 3.1% in the triplet and doublet arms, respectively), supporting the feasibility of these combinations in clinical practice.
Investigator Perspective
Sara A. Hurvitz, MD, an investigator of the VIKTORIA-1 study, commented:
“VIKTORIA-1 evaluated the multitarget PAM pathway inhibitor gedatolisib in combination with fulvestrant, with or without palbociclib, in patients with advanced breast cancer previously treated with a CDK4/6 inhibitor and endocrine therapy. Study 1, conducted in patients without a PIK3CA mutation, demonstrated both regimens had statistically significant and clinically meaningful improvements in PFS versus standard of care (HR = 0.24 for the triplet and 0.33 for the doublet), results that could potentially change clinical practice for patients with PIK3CA wild-type advanced breast cancer.”
Sara A. Hurvitz, MD, FACP — First author, VIKTORIA-1; Professor of Medicine, Fred Hutchinson Cancer Center, UW Medicine
Dr. Hurvitz noted that the study results are consistent with the hypothesis that PAM pathway inhibition may restore sensitivity to CDK4/6 inhibitors:
It is very interesting that — in a population of patients who had all been previously treated with a CDK4/6 inhibitor — the triplet combination (including a CDK4/6i) had a longer PFS than the doublet combination (excluding a CDK4/6i). Of particular note was that patients treated previously with palbociclib, and then retreated with palbociclib as part of the triplet, responded as well as patients who had previously received ribociclib. This could very well indicate that PAM pathway inhibition is restoring CDK4/6i sensitivity. This is the first study I am aware of that shows using palbociclib after progression on a CDK4/6i is associated with a longer PFS. There are studies evaluating whether other CDK4/6i can be safely combined with gedatolisib.
Dr. Hurvitz also addressed the potential positioning of gedatolisib-based regimens in the treatment sequence after CDK4/6 inhibitor progression:
If gedatolisib is approved based on the results of study 1 of VIKTORIA-1, the initial indication would most likely be in patients with PIK3CA wild-type disease, which is the majority of ER+ breast cancer. Capivasertib is indicated for PIK3CA mutated breast cancer. The data supporting gedatolisib-based therapy are quite strong for wild-type disease after progression on a CDK4/6i-based therapy — stronger than the data supporting everolimus in this setting, since the BOLERO-2 study was done in patients who had not received a prior CDK4/6i. In addition, if results from the PIK3CA MT cohort from the VIKTORIA-1 study are positive, gedatolisib could become the first PAM inhibitor approved to treat ABC regardless of a patient’s PIK3CA mutation status.
Results from the PIK3CA-mutant cohort of VIKTORIA-1 are forthcoming and will further define the role of gedatolisib-based therapy in a broader population. In parallel, the phase III VIKTORIA-2 trial is evaluating this strategy in the first-line setting.
Written by Marine Rushanyan, MD