Gedatolisib Shows Impressive PFS in HR+/HER2– Breast Cancer

Positive topline results from the PIK3CA wild-type cohort of the phase 3 VIKTORIA-1 clinical trial (NCT05501886) evaluating gedatolisib, an investigational multitarget PI3K/AKT/mTOR (PAM) inhibitor, in combination with fulvestrant (Faslodex) with or without palbociclib (Ibrance) in hormone receptor-positive (HR+), HER2-negative (–) locally advanced or metastatic breast cancer demonstrated clinically meaningful and statistically significant improvements in progression-free survival (PFS) for both gedatolisib-containing regimens, setting new benchmarks for this challenging patient population.¹

The gedatolisib triplet regimen reduced the risk of disease progression or death by 76% compared with fulvestrant monotherapy (HR, 0.24; 95% CI, 0.17–0.35; P <.0001). The median PFS as assessed by blinded independent central review (BICR) was 9.3 months with the gedatolisib triplet, a substantial incremental improvement of 7.3 months over the 2.0 months observed with fulvestrant alone.

Similarly, the gedatolisib doublet regimen showed a 67% reduction in the risk of progression or death vs fulvestrant (HR, 0.33; 95% CI, 0.24–0.48; P <.0001), achieving a median PFS of 7.4 months compared with 2.0 months for the control arm, an incremental gain of 5.4 months.

"To my knowledge, we have not seen phase 3 results in patients with HR-positive, HER2-negative advanced breast cancer before where there was a quadrupling of the likelihood of survival without disease progression relative to the study control," said Sara Hurvitz, MD, senior vice president of the Clinical Research Division at the Fred Hutchinson Cancer Center and co-principal investigator for the trial, in a press release.

This breakthrough is particularly notable for patients with HR+/HER2–, PIK3CA wild-type advanced breast cancer who have progressed on or after CDK4/6 inhibitor and aromatase inhibitor therapy. This cohort typically experiences limited benefit from subsequent endocrine-based treatments, representing a significant unmet medical need. Gedatolisib stands out as the first inhibitor targeting the PI3K/AKT/mTOR (PAM) pathway to demonstrate positive phase 3 results specifically in this PIK3CA wild-type population after CDK4/6 inhibitor progression.

Beyond efficacy, the safety and tolerability profile of both gedatolisib regimens proved to be favorable. Treatment discontinuation rates due to treatment-related adverse events for both the triplet and doublet combinations were notably lower than those observed in arm D of Celcuity’s phase 1b trial in advanced breast cancer patients,² and also lower than those reported in any phase 3 trials for currently approved drug combinations in HR+/HER2– advanced breast cancer. Furthermore, the gedatolisib regimens were better tolerated compared to the phase 1b study, with lower incidences of hyperglycemia and stomatitis—common challenges associated with other PAM pathway inhibitors. This improved tolerability could enhance patient adherence and overall management in clinical practice.¹

Gedatolisib is an investigational, multitarget PAM inhibitor designed to potently target all 4 class I PI3K isoforms, as well as mTORC1 and mTORC2, providing a comprehensive blockade of the PAM pathway. This differentiated mechanism of action aims to overcome adaptive resistance mechanisms that can arise with single-target inhibitors of the PAM pathway. Preclinical studies and early clinical data have suggested that gedatolisib possesses equal potency and comparable cytotoxicity in both PIK3CA-mutant and -wild-type breast tumor cells. The success in the PIK3CA wild-type cohort of VIKTORIA-1 validates this broad-spectrum inhibition.

Celcuity expects to present the full data from this cohort at an upcoming medical conference later this year. Following these promising results, Celcuity plans to submit a New Drug Application (NDA) for gedatolisib to the US FDA in the fourth quarter of 2025. Topline data for the VIKTORIA-1 PIK3CA mutation cohort is anticipated by the end of 2025, which will provide further insights into the broad applicability of this novel agent across HR+/HER2– advanced breast cancer.

REFERENCES:

1. Celcuity Announces Clinically Meaningful Improvement in Both Progression-Free Survival (“PFS”) Primary Endpoints from PIK3CA Wild-Type Cohort of Phase 3 VIKTORIA-1 Trial. News release. Celcuity Inc. July 28, 2025. Accessed July 29, 2025. https://tinyurl.com/5n7px38n

2. Layman RM, Han HS, Rugo HS, et al. Gedatolisib in combination with palbociclib and endocrine therapy in women with hormone receptor-positive, HER2-negative advanced breast cancer: results from the dose expansion groups of an open-label, phase 1b study. Lancet Oncol. 2024 Apr;25(4):474-487. doi: 10.1016/S1470-2045(24)00034-2.