FDA Approves Gedatolisib Plus Fulvestrant ± Palbociclib for Hormone Receptor–Positive, HER2-Negative, Locally Advanced/Metastatic Breast Cancer

The FDA has approved gedatolisib (Revtorpyk) plus fulvestrant (Faslodex), with or without palbociclib (Ibrance), for the treatment of adult patients with hormone receptor–positive, HER2-negative advanced breast cancer without a PIK3CA mutation following progression on or after treatment with 1 or more lines of endocrine therapy in the metastatic setting.¹

The decision was supported by data from the PIK3CA wild-type cohort of the phase 3 VIKTORIA-1 trial (NCT05501886; Study 1), which were presented at the 2025 ESMO Congress.^1,2 Patients who received gedatolisib plus fulvestrant (Faslodex) and palbociclib (Ibrance; n = 131) had a median progression-free survival (PFS) of 9.3 months (95% CI, 7.2-16.6) compared with 2.0 months (95% CI, 1.8-2.3) in those treated with fulvestrant alone (n = 131; adjusted HR, 0.24; 95% CI, 0.17-0.35; P < .0001). Patients who received gedatolisib plus fulvestrant without palbociclib (n = 130) achieved a median PFS of 7.4 months (95% CI, 5.5-9.9), conferring a benefit compared with fulvestrant monotherapy (HR, 0.33; 95% CI, 0.24-0.48; P < .0001).

The new drug application seeking the approval of gedatolisib in this indication was submitted under the FDA’s Real-Time Oncology Review program, which is designed to facilitate shorter regulatory review periods.³

What is the mechanism of action of gedatolisib?

Gedatolisib is a multitarget PI3K/AKT/mTOR inhibitor designed to target all 4 class I PI3K isoforms, as well as mTORC1 and mTORC2, to comprehensively block the PI3K/AKT/mTOR pathway. Its mechanism of action differs from those of currently approved single-target PI3K/AKT/mTOR pathway inhibitors. Inhibiting only a single PI3K/AKT/mTOR component often allows for cross-activation of the uninhibited components, limiting suppression of the pathway.

Comprehensive inhibition with gedatolisib enables full suppression of the PI3K/AKT/mTOR pathway by minimizing adaptive cross-activation. Nonclinical studies and early clinical trials have shown that unlike single-target inhibitors, gedatolisib has comparable potency and cytotoxicity in both PIK3CA-mutant and PIK3CA wild-type breast tumor cells.

How was the VIKTORIA-1 trial designed?

VIKTORIA-1 enrolled pre- and postmenopausal women, as well as men, with hormone receptor–positive, HER2-negative advanced breast cancer who had progressed during or following treatment with a CDK4/6 inhibitor in combination with a nonsteroidal aromatase inhibitor.² Patients could have received a maximum of 2 prior lines of endocrine therapy for advanced disease. In total, 392 patients with PIK3CA wild-type breast cancer were randomly assigned 1:1:1 to receive fulvestrant at 500 mg on days 1 and 15 of cycle 1, then every 4 weeks thereafter (arm C); fulvestrant in combination with gedatolisib at 180 mg once weekly for 3 weeks on and 1 week off (arm B); or fulvestrant in combination with gedatolisib and palbociclib at 125 mg daily for 21 days on and 7 days off (arm A).

The co-primary end points were PFS between arms A and C and between arms B and C.^1,2 Secondary end points were OS, overall response rate (ORR), safety, and quality of life.

What additional efficacy data supported the FDA approval of gedatolisib for PIK3CA wild-type breast cancer?

At the time of the PFS analysis, the OS data were not mature.¹ However, at a data cutoff of May 30, 2025, the median OS in arm A was 23.7 months (95% CI, 21.4-not evaluable [NE]) compared with 18.5 months (95% CI, 15.8-NE) in arm C (adjusted HR, 0.69; 95% CI, 0.43-1.12; P = .1328).² In arm B, the median OS was not reached (95% CI, NE-NE), showing a benefit vs arm C (adjusted HR, 0.74; 95% CI, 0.46-1.19; P = .2122).

In arms A, B, and C, the respective ORRs were 32% (95% CI, 23%-40%), 28% (95% CI, 20%-38%), and 1% (95% CI, 0%-5%).¹ The respective median DORs were 17.5 months (95% CI, 8.8-not estimable [NE]), 12.0 months (95% CI, 8.1-NE), and NE (95% CI, NE-NE).

What notable toxicities have been seen with gedatolisib?

The most frequently reported any-grade adverse effects across arms A, B, and C, respectively, were stomatitis (69.2%; 56.9%; 0%), neutropenia (65.4%; 1.5%; 0.8%), nausea (43.8%; 43.1%; 3.3%), vomiting (27.7%; 23.1%; 0.8%), rash (27.7%; 32.3%; 0%), fatigue (22.3%; 20.8%; 4.1%), diarrhea (16.9%; 12.3%; 0%), and hyperglycemia (9.2%; 11.5%; 0%).²

References

1. 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 July 14, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-gedatolisib-fulvestrant-or-without-palbociclib-hr-positive-her2-negative-locally
2. Hurvitz SA, Layman RM, Curigliano G, et al. Gedatolisib plus fulvestrant, with and without palbociclib, vs fulvestrant in patients with HR+/HER2-/PIK3CA wild-type advanced breast cancer: first results from VIKTORIA-1. Ann Oncol. 2025;36(suppl 2):S1562-S1563. doi:10.1016/j.annonc.2025.09.027
3. 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 July 14, 2026. https://ir.celcuity.com/news-releases/news-release-details/celcuity-announces-fda-acceptance-new-drug-application