5 minAt the 2026 ASCO Annual Meeting, the U.S. biotechnology company Celcuity unveiled the latest results from its pivotal Phase 3 registration trial, VIKTORIA-1. Data indicate that the company’s core product, Gedatolisib, achieved breakthrough efficacy in patients with HR-positive, HER2-negative (HR+/HER2-), PIK3CA-mutant advanced breast cancer. Compared to the current standard of care—alpelisib plus fulvestrant—the Gedatolisib-based regimen reduced the risk of disease progression or death by approximately 50% and doubled the median progression-free survival (PFS).
These results represent a significant milestone in PI3K/AKT/mTOR (PAM) pathway-targeted therapy and position Gedatolisib as a potential new standard of care for this patient population.
Unmet Needs in Advanced HR+/HER2- Breast Cancer
HR+/HER2- breast cancer is the most common subtype, accounting for approximately 70% of all breast cancer cases. While the combination of CDK4/6 inhibitors and endocrine therapy has become the first-line standard, most patients eventually develop resistance and experience disease progression. Notably, PIK3CA mutations are among the most common acquired oncogenic drivers, appearing in roughly 40% of these cases.
Although the currently approved PI3Kα inhibitor, alpelisib, improves outcomes, its efficacy is limited by significant toxicities—most notably hyperglycemia and rash—which often compromise long-term treatment adherence. Consequently, optimizing the inhibition of the PI3K/AKT/mTOR signaling pathway has become a top priority in breast cancer research.
VIKTORIA-1: The First "Head-to-Head" Phase 3 Trial of PAM Inhibitors
Gedatolisib is a next-generation PAM pathway inhibitor developed to address these limitations. Unlike existing agents that target single components, Gedatolisib inhibits all four class I PI3K isoforms as well as mTORC1 and mTORC2, providing a comprehensive blockade of the PI3K/AKT/mTOR signaling network. Mechanistically, this multi-target strategy is designed to circumvent the adaptive activation and bypass resistance common in single-target therapies.
VIKTORIA-1 is the world's first Phase 3 trial to directly compare two PAM pathway inhibitors. The study enrolled 701 patients with HR+/HER2- advanced breast cancer, with independent analysis performed based on PIK3CA mutation status. The PIK3CA-mutant cohort included 350 patients who had progressed on or after prior CDK4/6 inhibitor and aromatase inhibitor therapy. Patients were randomized 3:3:1 to receive either a Gedatolisib triplet (plus fulvestrant and palbociclib), the standard alpelisib plus fulvestrant regimen, or a Gedatolisib doublet (plus fulvestrant).
Key Findings: Doubling Progression-Free Survival
The most striking data emerged from the comparison between the Gedatolisib triplet regimen and the alpelisib control arm. Independent central review confirmed that the Gedatolisib triplet reduced the risk of disease progression or death by 50% (Hazard Ratio [HR] = 0.50; 95% CI: 0.37-0.68, P<0.0001). Furthermore, median PFS was doubled, increasing from 5.6 months in the alpelisib arm to 11.1 months in the triplet arm.
For patients who have failed CDK4/6 inhibitor therapy, achieving a PFS exceeding 10 months in the post-progression setting is considered a formidable goal. Celcuity noted that this 11.1-month median PFS is the longest reported to date in any Phase 3 study involving endocrine therapy for second-line HR+/HER2- advanced breast cancer.
Beyond delaying progression, Gedatolisib significantly improved tumor response rates. The objective response rate (ORR) reached 48.9% for the triplet arm, compared to 26.0% for the alpelisib arm. Additionally, the median duration of response (DoR) doubled, from 7.5 months in the control group to 15.7 months in the triplet group. The Gedatolisib doublet also demonstrated impressive results, with a median PFS of 11.3 months (HR=0.51) and a median DoR of 24.2 months.
Safety: Higher Efficacy with Better Tolerability
Perhaps more unexpected than the efficacy data is the superior safety profile of Gedatolisib compared to the current standard of care.
Hyperglycemia has long been a significant concern with alpelisib, frequently leading to dose reductions or treatment discontinuation. In this trial, the incidence of Grade 3 or higher hyperglycemia was 14.5% in the alpelisib arm, compared to only 2.6% in the Gedatolisib triplet arm (and 0% in the doublet arm). Similarly, severe rash occurred in 15.1% of patients in the alpelisib arm, versus 6.5% and 5.8% in the Gedatolisib triplet and doublet groups, respectively.
Consequently, discontinuation due to treatment-related adverse events was notably lower: 2.6% (triplet) and 3.8% (doublet) for Gedatolisib, compared to 7.1% for alpelisib.
While overall survival (OS) data remain immature, investigators observed positive trends. Should future OS analyses confirm these benefits, Gedatolisib will likely become one of the most influential new therapies in the HR+/HER2- advanced breast cancer landscape.
Future Outlook
Celcuity intends to submit a supplemental New Drug Application (sNDA) to the FDA based on the VIKTORIA-1 results. Meanwhile, the company’s NDA for PIK3CA wild-type patients has already been granted Priority Review, with a PDUFA target date of July 17, 2026. Furthermore, two VIKTORIA-2 Phase 3 trials evaluating first-line therapy in both endocrine-resistant and endocrine-sensitive settings are currently underway.
As the industry shifts focus toward extending the benefit of later-line therapies in the post-CDK4/6 era, the success of VIKTORIA-1 provides a compelling case for comprehensive PAM pathway inhibition, potentially establishing a new standard of care for patients worldwide.
