FDA Reviews Gedatolisib Expansion into PIK3CA-Mutated Breast Cancer
- The FDA has accepted an sNDA for gedatolisib (Revtorpyk) plus fulvestrant, with or without palbociclib, in patients with PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer, with a PDUFA target action date of June 25, 2027.
- In the PIK3CA-mutated cohort of VIKTORIA-1, the gedatolisib triplet nearly doubled median PFS vs alpelisib plus fulvestrant (11.1 vs 5.6 months; adjusted HR, 0.50; P < .0001), while the doublet showed a similar median PFS of 11.3 months.
- If approved, gedatolisib would be available as second-line therapy regardless of PIK3CA mutation status, building on its July 2026 approval for patients without a detectable PIK3CA mutation.
“The FDA’s acceptance of this sNDA takes us one step closer to bringing [gedatolisib] to more patients,” Brian Sullivan, chief executive officer and cofounder of Celcuity, stated in a news release.¹ Sullivan added that, if approved, the agent would be available as second-line therapy regardless of tumor PIK3CA mutation status.
What is the current FDA-approved indication for gedatolisib?
Gedatolisib is an intravenous inhibitor of the class I PI3K isoforms (α, β, δ, and γ) and of mTORC1 and mTORC2, thereby blocking downstream signaling through effectors, such as AKT. The FDA approved gedatolisib on July 14, 2026, for use with fulvestrant, with or without palbociclib, in adult patients with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer with no detectable PIK3CA mutation and progression during or after at least 1 line of endocrine therapy in the metastatic setting.³
That approval was based on data from VIKTORIA-1 Study 1, in which 392 patients were randomly assigned 1:1:1 to receive the gedatolisib triplet, the gedatolisib doublet, or fulvestrant alone. The median PFS by blinded independent central review BICR was 9.3 months (95% CI, 7.2-16.6) with the triplet vs 2.0 months (95% CI, 1.8-2.3) with fulvestrant (HR, 0.24; 95% CI, 0.17-0.35; P < .0001) and 7.4 months (95% CI, 5.5-9.9) with the doublet (HR vs fulvestrant alone, 0.33; 95% CI, 0.24-0.48; P < .0001). The FDA label includes warnings for stomatitis, dermatologic adverse effects, hyperglycemia, and embryo-fetal toxicity.
How was VIKTORIA-1 Study 2 designed?
Eligible patients were pre- or postmenopausal women or men whose disease had progressed during or after a CDK4/6 inhibitor plus a nonsteroidal aromatase inhibitor, who had received no more than 2 prior lines of endocrine therapy for advanced disease and no prior chemotherapy in that setting, and who had measurable disease per RECIST 1.1 criteria.²
Patients (n = 362) were randomly assigned 3:3:1 to receive the gedatolisib triplet (gedatolisib at 180 mg intravenously once weekly for 3 weeks on and 1 week off, palbociclib at 125 mg daily for 21 days on and 7 days off, and fulvestrant at 500 mg on cycle 1 days 1 and 15 and then every 4 weeks after that), alpelisib at 300 mg daily plus fulvestrant, or the gedatolisib doublet. The primary end point was BICR-assessed PFS for the triplet vs alpelisib plus fulvestrant. Key secondary end points were overall survival for the triplet and the doublet vs alpelisib plus fulvestrant, PFS for the doublet, response, safety, and quality of life. At the March 9, 2026, data cutoff, the median follow-up was 12.8 months (interquartile range, 7.5-19.9).
What efficacy data supported the sNDA submission for gedatolisib for PIK3CA-mutated advanced breast cancer?
The objective response rate was 48.9% with the triplet, 35.7% with the doublet, and 26.0% with alpelisib plus fulvestrant in the response-evaluable population, with median durations of response of 15.7 months (95% CI, 9.2-20.6), 24.2 months (95% CI, 7.4–not evaluable), and 7.5 months (95% CI, 5.5-15.8), respectively.
At the interim overall survival (OS) analysis, a total of 110 patients (30.4%) in the trial had died, and the OS data were at 45.8% maturity for the final analysis of the triplet and alpelisib arms. The median OS was not reached (95% CI, 21.5 months-not evaluable [NE]) with the triplet vs 31.1 months (95% CI, 20.0-NE) with alpelisib plus fulvestrant (HR, 0.76; 95% CI, 0.50-1.14; P = .0908), and 22.8 months (95% CI, 17.6-NE) with the doublet (HR, 0.93; 95% CI, 0.55-1.6; P = .4026).
What is the safety profile of gedatolisib?
Treatment-related adverse effects (AEs) of any grade occurred in 98.0% of patients receiving the gedatolisib triplet, 96.2% of patients receiving the gedatolisib doublet, and 96.7% of patients receiving alpelisib plus fulvestrant. Treatment discontinuation due to treatment-related AEs occurred in 2.6%, 3.8%, and 7.1% of patients, respectively, and deaths due to treatment-related serious AEs occurred in 1 patient, 0 patients, and 2 patients, respectively.
Stomatitis occurred in 61.4% of patients (grade 3, 16.3%) with the gedatolisib triplet, 61.5% of those (grade 3, 5.8%) with the gedatolisib doublet, and 34.2% of those (grade 3, 5.3%) with alpelisib plus fulvestrant. Hyperglycemia occurred in 15.0%, 11.5%, and 57.9% of patients in these respective arms. Neutropenia occurred in 63.4% of patients with the gedatolisib triplet, including grade 3 events in 47.7% and grade 4 events in 11.1% of patients.
Gedatolisib is also under evaluation in the phase 3 VIKTORIA-2 trial (NCT06757634) in the first-line setting for patients with hormone receptor–positive, HER2-negative advanced breast cancer.¹
References
- Celcuity announces FDA acceptance of sNDA for Revtorpyk (gedatolisib) for HR+/HER2-, PIK3CA mutant locally advanced or metastatic breast cancer. News release. Celcuity. November 9, 2026. Accessed November 9, 2026. https://ir.celcuity.com/news-releases/news-release-details/celcuity-announces-fda-acceptance-snda-revtorpyktm-gedatolisib
- Hurvitz SA, Curigliano G, Andre F, et al. A randomized, open-label, phase 3 study of gedatolisib + fulvestrant ± palbociclib vs standard of care in HR+/HER2-/PIK3CA-mutant advanced breast cancer (VIKTORIA-1 Study 2). J Clin Oncol. 2026;44(suppl 17):LBA1008. doi:10.1200/JCO.2026.44.17_suppl.LBA1008
- FDA approves gedatolisib with fulvestrant, with or without palbociclib, for HR-positive, HER2-negative locally advanced or metastatic breast cancer. FDA. July 14, 2026. Accessed November 9, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-gedatolisib-fulvestrant-or-without-palbociclib-hr-positive-her2-negative-locally
