Gedatolisib and Fulvestrant Show Promise in Advanced Breast Cancer

Data from the phase 3 VIKTORIA-1 trial has revealed that the combination of gedatolisib, a PI3K/AKT/mTOR (PAM) inhibitor, and fulvestrant significantly improves progression-free survival (PFS) in patients suffering from hormone receptor (HR)–positive, HER2-negative, PIK3CA wild-type advanced breast cancer. This advancement is particularly noteworthy for those who have experienced disease progression after treatment with a CDK4/6 inhibitor and an aromatase inhibitor.

Results from the VIKTORIA-1 trial were presented at the 2025 ESMO Congress, marking a significant milestone in cancer treatment. The study indicated that patients receiving the combination therapy showed clinically meaningful improvements not only in PFS but also in median duration of response (DOR) and objective response rates (ORRs) compared to those treated with fulvestrant alone.

Sara A. Hurvitz, MD, FACP, senior vice president and director of the Clinical Research Division at Fred Hutch, highlighted the trial’s importance, stating, “VIKTORIA-1 is the first study to demonstrate a statistically significant and clinically meaningful improvement in progression-free survival with PAM inhibition in patients with PIK3CA wild-type disease, all of whom received prior CDK4/6 inhibitor.”

Significant Findings from the Trial

The trial involved three treatment arms: a triplet regimen of gedatolisib, fulvestrant, and palbociclib; a doublet regimen of gedatolisib and fulvestrant; and a control group receiving fulvestrant alone. The triplet therapy reduced the risk of disease progression by 76% compared to fulvestrant alone, achieving a median PFS of 9.3 months (95% CI, 7.2-16.6) versus 2.0 months (95% CI, 1.8-2.3) for the control group. The hazard ratio was 0.24 (95% CI, 0.17-0.35; P < 0.0001). Patients in the triplet arm also exhibited a disease control rate (DCR) of 85.5% and a median DOR of 17.5 months (95% CI, 8.8-NE). In contrast, the doublet arm yielded an ORR of 28.3% and a median DOR of 12.0 months (95% CI, 8.1-NE). The monotherapy arm had a markedly lower ORR of 1.0% with no complete responses recorded.

The safety profile of gedatolisib was generally acceptable, with no new safety signals reported. Discontinuations due to treatment-related adverse effects (TRAEs) occurred in three patients from the triplet arm and four from the doublet arm. Notably, two deaths were reported in the triplet therapy group. Common treatment-related adverse events included stomatitis, rash, diarrhea, and hyperglycemia.

Implications for Future Treatment

The PAM pathway is critical in driving breast cancer growth and has been linked to resistance against endocrine and CDK4/6 inhibitors. Current therapies predominantly target activated PI3K pathways, leaving a significant unmet need for patients with PIK3CA wild-type disease. Dr. Hurvitz noted that therapeutic attempts to block the PAM pathway have historically been limited by toxicity.

The VIKTORIA-1 trial aimed to explore the efficacy of gedatolisib as a multitarget PAM inhibitor in patients who had previously shown resistance to standard treatments. The trial design included 392 patients randomized to one of three treatment regimens. It ensured that pre- and postmenopausal patients with measurable disease were eligible, provided they had progressed after prior therapies.

Demographic and baseline characteristics were well-balanced across treatment arms, reinforcing the robustness of the trial’s findings. Igor Gorbatchevsky, MD, chief medical officer of Celcuity, expressed optimism regarding the results, stating, “We are very excited that treatment with gedatolisib combined with fulvestrant with or without palbociclib was well-tolerated by the VIKTORIA-1 patients.”

According to recent press releases, a rolling new drug application (NDA) has been submitted in conjunction with the FDA’s Real-Time Oncology Review Program. This application is based on the outcomes from the PIK3CA wild-type cohort of the VIKTORIA-1 trial. The NDA is anticipated to be completed by the end of 2025, with topline data expected in the first half of 2026. Meanwhile, the phase 3 VIKTORIA-2 trial is currently ongoing, designed to assess gedatolisib in frontline settings.

The findings from the VIKTORIA-1 trial present a potentially transformative option for patients battling HR-positive, HER2-negative, PIK3CA wild-type advanced breast cancer, paving the way for future advancements in treatment strategies.