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 and palbociclib (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).

“For patients with HR-positive/HER2-negative locally advanced or metastatic breast cancer, there is an urgent need for new treatment options that can meaningfully increase the likelihood of survival without disease progression or death,” Sara Hurvitz, MD, senior vice president of the Clinical Research Division at the Fred Hutchinson Cancer Center, the Smith Family Endowed Chair in Women’s Health and professor and head of the Division of Hematology and Oncology at the University of Washington School of Medicine in Seattle, and co-principal investigator for the VIKTORIA-1 trial, said in a statement to OncLive. “With the approval of REVTORPYK, oncologists now have an effective new treatment option for these patients.”

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