sNDA Submitted to FDA for Gedatolisib in PIK3CA-Mutant, HR+/HER2-Negative Advanced Breast Cancer

A supplemental new drug application (sNDA) has been submitted to the FDA seeking the approval of gedatolisib (Revtorpyk) in combination with fulvestrant (Faslodex), with or without palbociclib (Ibrance), for the treatment of adult patients with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer harboring a PIK3CA mutation who have progressed on or after at least 1 line of endocrine therapy in the metastatic setting.¹

This sNDA seeks to broaden gedatolisib’s current indication beyond hormone receptor–positive, HER2-negative advanced breast cancer without a PIK3CA mutation following progression on or after at least 1 line of endocrine therapy in the metastatic setting, for which it received FDA approval in combination with fulvestrant, with or without palbociclib, in July 2026.²

“[If the gedatolisib indication becomes PIK3CA] mutation agnostic, you could give it to [patients] regardless of their mutation status and expect a benefit,” Adam M. Brufsky, MD, PhD, said in an interview with OncLive^®. “It’s going to be interesting to see where this goes. Where we position it is still going to be in the second- and third-line settings. What we give after is going to be interesting. It is something a lot of us are excited about. The only hesitation, the mucositis, I think we’re all going to be able to deal with. I’m not worried about that. I’m not worried about the hyperglycemia. I’m not worried about rash. Those happen, but at much lower frequencies than [with] other drugs.”

Brufsky is a professor of medicine and the associate division chief for the Division of Hematology/Oncology in the Department of Medicine at the University of Pittsburgh School of Medicine; as well as medical director of the Magee-Women’s Cancer Program, associate director for clinical investigations, and codirector of the Comprehensive Breast Cancer Center at the University of Pittsburgh Medical Center Hillman Cancer Center, in Pennsylvania.

The sDNA filing was supported by data from the cohort of patients with PIK3CA-mutant disease (Study 2) in the phase 3 VIKTORIA-1 trial (NCT05501886), in which gedatolisib-based regimens generated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs alpelisib (Piqray) plus fulvestrant.¹ At a data cutoff of March 9, 2026, and a median follow-up of 12.8 months (IQR, 7.5-19.9), gedatolisib plus palbociclib and fulvestrant (the gedatolisib triplet; n = 155) elicited a median PFS of 11.1 months (95% CI, 9.0-16.7) vs 5.6 months (95% CI, 5.2-7.4) with alpelisib plus fulvestrant (n = 155) by blinded independent central review (BICR; HR, 0.50; 95% CI, 0.37-0.68; P < .0001).³ Gedatolisib plus fulvestrant (the gedatolisib doublet; n = 52) produced a median PFS of 11.3 months (95% CI, 9.1-22.1; HR vs control, 0.51; 95% CI, 0.33-0.79; P = .0013).

“This submission allows us to potentially make [gedatolisib] available to all patients with hormone receptor–positive/HER2-negative locally advanced or metastatic breast cancer, regardless of PIK3CA mutation status,” Igor Gorbatchevsky, MD, chief medical officer of Celcuity, stated in a news release.¹

How is the VIKTORIA-1 trial designed?

VIKTORIA-1 is an open-label, randomized trial evaluating gedatolisib plus fulvestrant, with or without palbociclib, in adults with hormone receptor–/HER2-negative advanced breast cancer whose disease progressed on or after treatment with a CDK4/6 inhibitor in combination with an aromatase inhibitor.³ The trial enrolled patients and evaluated them in 2 studies according to PIK3CA mutation status. Study 2 comprised patients with PIK3CA-mutant disease (n = 362), who were randomly assigned 3:1:3 to receive the gedatolisib triplet, the gedatolisib doublet, or alpelisib plus fulvestrant. Randomization was stratified by the presence of lung or liver metastases, time to progression on the immediate prior therapy, and geographic region. Gedatolisib was given at 180 mg intravenously once weekly on a 3-weeks-on, 1-week-off schedule; palbociclib was administered at 125 mg daily on a 21-days-on, 7-days-off schedule; fulvestrant was given at 500 mg on days 1 and 15 of cycle 1 and every 4 weeks thereafter; and alpelisib was administered at 300 mg orally once daily for 4 weeks.

The primary end point was PFS by BICR for the gedatolisib triplet vs alpelisib plus fulvestrant, with OS, PFS for the gedatolisib doublet, objective response rate (ORR), duration of response (DOR), safety, and quality of life among the secondary end points. The ORR by BICR was 48.9% with the gedatolisib triplet and 35.7% with the doublet vs 26.0% with alpelisib plus fulvestrant; the median DORs were 15.7 months (95% CI, 9.2-20.6), 24.2 months (95% CI, 7.4-not evaluable [NE]), and 7.5 months (95% CI, 5.5-15.8), respectively. OS data were immature at the interim analysis, at which no statistically significant difference was observed between the gedatolisib triplet and alpelisib plus fulvestrant (median, not reached [95% CI, 21.5 months-NE] vs 31.1 months [95% CI, 20.0-NE]; HR, 0.76; 95% CI, 0.50-1.14; P = .0908).

How did gedatolisib perform in the PIK3CA wild-type cohort of VIKTORIA-1?

In the PIK3CA wild-type cohort (Study 1) of VIKTORIA-1, data from which supported gedatolisib’s July 2026 FDA approval, the gedatolisib triplet and doublet significantly improved PFS vs fulvestrant alone, at respective medians of 9.3 months (95% CI, 7.2-16.6) and 7.4 months (95% CI, 5.5-9.9) vs 2.0 months (95% CI, 1.8-2.3; HR vs gedatolisib triplet, 0.24 [95% CI, 0.17-0.35; P .0001]; HR vs gedatolisib doublet, 0.33 [95% CI, 0.24-0.48; P < .0001]).²

What is the safety profile of gedatolisib?

Adverse effects (AEs) associated with gedatolisib-based treatment in Study 2 were primarily grade 1 or 2 in severity, and the safety profile of the regimens was consistent with those observed in the PIK3CA wild-type cohort.³ Treatment-related AEs (TRAEs) of any grade occurred in 98.0% of patients in the gedatolisib triplet arm, 96.2% of those in the doublet arm, and 96.7% of those given alpelisib plus fulvestrant. TRAEs led to study treatment discontinuation in 2.6%, 3.8%, and 7.1% of patients, respectively. Rates of any-grade hyperglycemia (15.0% for the triplet, 11.5% for the doublet) and diarrhea (15.0% and 9.6%, respectively) were lower in the gedatolisib arms than those reported with alpelisib plus fulvestrant (57.9% and 40.1%, respectively). Stomatitis was among the most common any-grade TRAEs associated with the gedatolisib triplet (61.4%) and doublet (61.5%), and neutropenia (any-grade, 63.4%; grade 3, 47.7%; grade 4, 11.1%) was frequent in the triplet arm. One treatment-related death occurred in the gedatolisib triplet arm, and 2 treatment-related deaths occurred in the alpelisib-plus-fulvestrant arm.

References

1. Celcuity submits sNDA to FDA for Revtorpyk (gedatolisib) for HR+/HER2-, PIK3CA mutant locally advanced or metastatic breast cancer. News release. Celcuity Inc. August 26, 2026. Accessed August 26, 2026. https://ir.celcuity.com/news-releases/news-release-details/celcuity-submits-snda-fda-revtorpyktm-gedatolisib-hrher2-pik3ca
2. 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 August 26, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-gedatolisib-fulvestrant-or-without-palbociclib-hr-positive-her2-negative-locally
3. 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