Gedatolisib Combinations Improve PFS in PIK3CA Wild-Type Advanced Breast Cancer

Two gedatolisib-based combination regimens demonstrated statistically significant and clinically meaningful improvements in progression-free survival (PFS) compared with fulvestrant (Faslodex) monotherapy in patients with hormone receptor–positive (HR+), HER2–negative (HER2−), PIK3CA wild-type (WT) advanced breast cancer whose disease had progressed following CDK4/6 inhibitor and aromatase inhibitor (AI) therapy, according to results from the phase 3 VIKTORIA-1 trial (NCT05501886) published March 9, 2026, in the Journal of Clinical Oncology.^1,2

In the PIK3CA WT cohort, the triplet of gedatolisib plus palbociclib (Ibrance) and fulvestrant achieved a median PFS of 9.3 months vs 2.0 months with fulvestrant alone (HR, 0.24; 95% CI, 0.17-0.35; P < .0001), representing a 76% reduction in the risk of disease progression or death. The doublet of gedatolisib plus fulvestrant yielded a median PFS of 7.4 months (HR, 0.33; 95% CI, 0.24-0.48; P < .0001), a 67% risk reduction vs fulvestrant.¹

“VIKTORIA-1 is the first phase 3 study to show a significant improvement in median [PFS] with inhibition of the PI3K/AKT/mTOR pathway in patients with PIK3CA [WT] HR+/HER2– advanced breast cancer who previously received a CDK4/6 inhibitor,” said Sara A. Hurvitz, MD, FACP, in a news release.¹ Hurvitz is the lead study author and senior vice president, Clinical Research Division, Fred Hutchinson Cancer Center; Smith Family Endowed Chair in Women’s Health; professor and head, Division of Hematology and Oncology, Department of Medicine, at the University of Washington in Seattle.

Background and Clinical Context

HR+/HER2− breast cancer is the most prevalent breast cancer subtype, accounting for approximately 70% of all diagnoses.³ Globally, more than 2 million breast cancer cases were diagnosed in 2022, and approximately 30% of patients diagnosed with or who progress to metastatic disease are expected to survive 5 years following diagnosis. Three interconnected oncogenic signaling pathways—estrogen, cyclin D1–CDK4/6, and PI3K/AKT/mTOR (PAM)—drive HR+/HER2− breast cancer, and resistance to CDK4/6 inhibitors and endocrine therapies remains a major clinical challenge.

Currently approved PAM pathway inhibitors for breast cancer target a single pathway node—PI3Kα (alpelisib [Piqray], inavolisib [Itovebi]), AKT (capivasertib [Truqap]), or mTORC1 (everolimus [Afinitor])—leaving adaptive resistance mechanisms largely intact through cross-activation of uninhibited targets. Gedatolisib, an investigational pan-PI3K/mTORC1/2 inhibitor, was designed to address this limitation by simultaneously targeting all 4 class I PI3K isoforms along with both mTOR complexes, thereby comprehensively blocking PAM pathway activity.

A key pharmacologic feature of gedatolisib is its demonstrated equivalent potency in both PIK3CA-mutant and PIK3CA WT breast tumor cells in preclinical models, distinguishing it mechanistically from single-target PAM inhibitors that have shown more limited activity in PIK3CA WT disease. This characteristic informed the VIKTORIA-1 trial design, which enrolled patients regardless of PIK3CA mutational status while enabling separate efficacy analyses by PIK3CA subgroup.

Trial Design

VIKTORIA-1 is a phase 3, open-label, randomized clinical trial that enrolled adults with HR+/HER2− advanced breast cancer whose disease had progressed on or after a CDK4/6 inhibitor combined with a nonsteroidal AI. In the PIK3CA WT cohort of 392 patients, participants were randomly assigned 1:1:1 to gedatolisib 180 mg intravenously weekly for 3 weeks per cycle plus palbociclib 125 mg orally on days 1 through 21 plus fulvestrant 500 mg intramuscularly; gedatolisib plus fulvestrant; or fulvestrant monotherapy. The primary end point was PFS by blinded independent central review, assessed separately for each gedatolisib regimen vs fulvestrant.¹

Efficacy Outcomes

Both primary end points were met. For the gedatolisib triplet, the PFS benefit translated to a median incremental improvement of 7.3 months over fulvestrant. The objective response rate (ORR) was 31.5% in the triplet arm compared with 1% in the fulvestrant arm, and the median duration of response (DOR) was 17.5 months. For the gedatolisib doublet, the median PFS improvement over fulvestrant was 5.4 months, with an ORR of 28.3% and a median DOR of 12.0 months. The median DOR in the fulvestrant arm was not estimable because only 1 patient had an objective response.¹

Safety Profile

Both gedatolisib-containing regimens were generally well tolerated, with treatment-related adverse events (TRAEs) predominantly of low grade. The most common grade 3 TRAEs for the gedatolisib triplet, gedatolisib doublet, and fulvestrant groups, respectively, were neutropenia (52.3%, 0%, and 0.8%), stomatitis (19.2%, 12.3%, and 0%), rash (4.6%, 5.4%, and 0%), and hyperglycemia (2.3%, 2.3%, and 0%).¹

Grade 4 TRAEs were uncommon. In the triplet arm, primary grade 4 TRAEs included neutropenia (10.0%) and leukopenia (0.8%). In the doublet arm, grade 4 events included neutropenia (0.8%) and pneumonitis (0.8%). Rates of treatment discontinuation due to TRAEs were low: 2.3% in the triplet group, 3.1% in the doublet group, and 0% in the fulvestrant group.¹

Regulatory Status and Next Steps

The FDA has granted priority review of the new drug application for gedatolisib and assigned a Prescription Drug User Fee Act goal date of July 17, 2026.⁴ A separate cohort of VIKTORIA-1 enrolling patients with PIK3CA-mutated disease is also fully enrolled; efficacy and safety data from that cohort are forthcoming and are expected to further define the role of gedatolisib-based therapy in the broader HR+/HER2− population.²

The phase 3 VIKTORIA-2 trial (NCT06757634) is currently evaluating gedatolisib in combination with palbociclib and fulvestrant as first-line treatment for patients with endocrine-resistant HR+/HER2− ABC.

REFERENCES

1. Hurvitz SA, Layman RM, Curigliano G, et al. VIKTORIA-1 trial of gedatolisib plus fulvestrant with or without palbociclib in hormone receptor–positive/HER2−/PIK3CA wild-type advanced breast cancer. J Clin Oncol. Published online March 9, 2026. doi:10.1200/JCO-25-02643

2. Celcuity announces publication of results from PIK3CA wild-type cohort of phase 3 VIKTORIA-1 study of gedatolisib regimens in HR+/HER2- advanced breast cancer in Journal of Clinical Oncology. News release. Celcuity. March 9, 2026. Accessed March 10, 2026. https://tinyurl.com/342ds293

3. Cancer stat facts: female breast cancer subtypes. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Accessed March 2026. https://seer.cancer.gov/statfacts/html/breast-subtypes.html

4. Celcuity announces FDA acceptance of new drug application for gedatolisib in HR+/HER2-/PIK3CA wild-type advanced breast cancer. News release. Celcuity Inc. January 20, 2026. Accessed March 10, 2026. https://tinyurl.com/mxzywcxd