VIKTORIA-2 Trial Evolves to Evaluate Gedatolisib in Endocrine-Sensitive and -Resistant Breast Cancer

Significant protocol amendments have been made to the ongoing phase 3 VIKTORIA-2 clinical trial (NCT06757634). The study, which evaluates the PI3K and mTOR inhibitor gedatolisib in the first-line setting for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced or metastatic breast cancer, will now expand to include endocrine-sensitive patients. This development follows a type B meeting with the FDA and reflects a broader effort to integrate gedatolisib into the frontline treatment paradigm.¹

Expanded Study Design and Patient Populations

The revised VIKTORIA-2 protocol partitions the trial into 2 distinct studies based on endocrine sensitivity status. Study 1 will enroll approximately 440 patients with endocrine-resistant disease, defined as disease progression within 12 months of completing adjuvant endocrine therapy or while receiving endocrine therapy for metastatic disease. In this cohort, patients will be randomized to receive the triplet regimen of gedatolisib plus palbociclib (Ibrance) and fulvestrant (Faslodex), or a control arm of ribociclib (Kisqali) combined with fulvestrant.

Study 2 focuses on approximately 740 endocrine-sensitive patients who will receive either the triplet of gedatolisib, palbociclib, and letrozole (Femara), or the standard-of-care doublet of ribociclib and letrozole. Notably, the efficacy analyses for both studies will evaluate the full intent-to-treat (ITT) population, encompassing both PIK3CA wild-type (WT) and mutant-type tumors. This differs from the previous VIKTORIA-1 trial (NCT05501886), which utilized a more stratified approach based on mutation status.

Rationale for Early PI3K/mTOR Inhibition

The PI3K/AKT/mTOR (PAM) pathway is frequently dysregulated in HR+/HER2– breast cancer and serves as a primary mechanism of resistance to both endocrine therapy and CDK4/6 inhibitors. Unlike isoform-specific inhibitors, gedatolisib is a potent, dual inhibitor that targets all 4 class I PI3K isoforms (α, β, γ, δ) as well as mTORC1 and mTORC2.

Preclinical and early-phase clinical data suggest that simultaneous blockade of these nodes may prevent the compensatory activation that often limits the efficacy of single-node inhibitors.

Clinical End Points and Safety Profile

The primary end point for both study 1 and study 2 is progression-free survival (PFS) as determined by blinded independent central review per RECIST 1.1 criteria. Secondary end points include overall survival, objective response rate, and duration of response.

The safety profile of gedatolisib has been characterized in previous trials, with common treatment-related adverse events including stomatitis, rash, diarrhea, and hyperglycemia.² The triplet regimen in the PIK3CA-wild-type cohort of VIKTORIA-1 showed manageable toxicity, with grade 3+ stomatitis occurring in approximately 19% of patients. To improve long-term administration and patient convenience, Celcuity, the sponsor, is also developing a subcutaneous formulation of gedatolisib, for which patent applications have recently been filed.¹

Therapeutic Implications

The decision to utilize ribociclib as the comparator in VIKTORIA-2 is a rigorous benchmark, given ribociclib’s established overall survival benefits in the frontline HR+/HER2– setting. By positioning gedatolisib as a first-line intervention, investigators aim to delay the onset of endocrine resistance and maximize the duration of clinical benefit before moving to subsequent lines of cytotoxic chemotherapy.

If successful, VIKTORIA-2 could redefine the standard of care for treatment-naive patients, providing a more comprehensive blockade of oncogenic signaling than current doublet therapies. Topline results from the second-line VIKTORIA-1 trial are expected in 2026, which may provide further validation for this dual-inhibition strategy.

Recent Gedatolisib News

Earlier this month, data from the phase 3 VIKTORIA-1 trial (NCT05501886) evaluating gedatolisib in combination with fulvestrant and palbociclib met its primary end point, demonstrating a statistically significant and clinically meaningful improvement in PFS in patients with PIK3CA-mutant breast cancer compared with alpelisib (Piqray) and fulvestrant.³

The VIKTORIA-1 trial previously reached its primary end point in the cohort of patients with PIK3CA-WT tumors. As published in the Journal of Clinical Oncology in March 2026, the combination of gedatolisib and fulvestrant resulted in a 55% reduction in the risk of disease progression or death compared with fulvestrant monotherapy (HR, 0.45; P <.0001).⁴

The new drug application (NDA) of gedatolisib in patients with PIK3CA-WT disease received priority review in January 2026. The FDA has set a Prescription Drug User Fee Act (PDUFA) target action date of July 17, 2026.⁵ Celcuity intends to submit a supplemental NDA based on these findings in the PIK3CA-mutant cohort.⁶

REFERENCES

1. Celcuity’s Phase 3 VIKTORIA-2 Trial of Gedatolisib as a First-Line Treatment for HR+/HER2- Advanced Breast Cancer Expanding to Include Endocrine-Sensitive Patients. News release. Celcuity Inc. May 14, 2026. Accessed May 14, 2026. https://tinyurl.com/4bvm979c

2. Hurvitz SA, Layman RM, Curigliano G, et al. Gedatolisib Plus Fulvestrant, With & Without Palbociclib, vs Fulvestrant in Patients With HR+/HER2-/PIK3CA Wild-Type Advanced Breast Cancer: First Results from VIKTORIA-1. Presented at: 2025 ESMO Annual Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA17.

3. Celcuity's Phase 3 VIKTORIA-1 Trial Achieves Primary Endpoint With Clinically Meaningful Improvement in Progression-Free Survival in PIK3CA Mutant Cohort. News release. Celcuity Inc. May 1, 2026. Accessed May 14, 2026. https://tinyurl.com/2tfx66pb

4. Hurvitz A, Layman RM, Curigliano G, et al. VIKTORIA-1 Trial of Gedatolisib Plus Fulvestrant With or Without Palbociclib in Hormone Receptor-Positive/HER2‚àí/PIK3CA Wild-Type Advanced Breast Cancer. J Clin Oncol. 44, 1108-1119(2026). DOI:10.1200/JCO-25-02643

5. 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 May 14, 2026. https://tinyurl.com/mxzywcxd

6. Celcuity's Phase 3 VIKTORIA-1 Trial Achieves Primary Endpoint With Clinically Meaningful Improvement in Progression-Free Survival in PIK3CA Mutant Cohort. News release. Celcuity Inc. May 1, 2026. Accessed May 14,