FDA Approves Gedatolisib for HR+/HER2−, PIK3CA Wild-Type Advanced Breast Cancer

The FDA has approved gedatolisib (Revtorpyk) in combination with fulvestrant (Faslodex) and palbociclib (Ibrance), or in combination with fulvestrant alone, for the treatment of adults with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2−), PIK3CA wild-type locally advanced or metastatic breast cancer following progression on or after a CDK4/6 inhibitor and an aromatase inhibitor.¹ The approval marks the first regulatory authorization of a multi-target PI3K/AKT/mTOR (PAM) pathway inhibitor for patients with PIK3CA wild-type disease, a population representing approximately 60% of patients with HR+/HER2− advanced breast cancer who lack the mutation targeted by currently approved PI3K isoform-specific inhibitors.

The approval is supported by data from the PIK3CA wild-type cohort of the phase 3 VIKTORIA-1 trial (NCT05501886), a randomized, open-label study that met both co-primary end points of progression-free survival (PFS) improvement with the gedatolisib-based triplet and doublet regimens vs fulvestrant monotherapy.²

Supporting Trial: VIKTORIA-1

VIKTORIA-1 enrolled adults with HR+/HER2− advanced breast cancer whose disease had progressed on or after treatment with a CDK4/6 inhibitor combined with a nonsteroidal aromatase inhibitor. In the PIK3CA wild-type cohort (n = 392), patients were randomly assigned 1:1:1 to receive gedatolisib 180 mg intravenously weekly for 3 weeks per cycle plus palbociclib 125 mg orally on days 1 through 21 plus fulvestrant 500 mg intramuscularly (triplet; arm A); gedatolisib plus fulvestrant (doublet; arm B); or fulvestrant monotherapy (arm C). The co-primary end points were PFS in arm A vs arm C and PFS in arm B vs arm C, assessed by blinded independent central review (BICR).

At the data cutoff of May 30, 2025, with a median follow-up of 10.1 months, both primary end points were met. Patients receiving the gedatolisib triplet achieved a median PFS of 9.3 months (95% CI, 7.2-16.6) compared with 2.0 months (95% CI, 1.8-2.3) for those receiving fulvestrant monotherapy, corresponding to a 76% reduction in the risk of disease progression or death (HR, 0.24; 95% CI, 0.17–0.35; P <.0001). Patients in the gedatolisib doublet arm achieved a median PFS of 7.4 months (95% CI, 5.5-9.9), representing a 67% reduction in risk compared with fulvestrant alone (HR, 0.33; 95% CI, 0.24-0.48; P <.0001). PFS benefits were consistent across all prespecified subgroups.

Secondary end point results further supported clinical activity. The objective response rate (ORR) was 32% with the triplet (including 1 complete response) and 28.3% with the doublet, compared with 1% for fulvestrant monotherapy. The median duration of response (DOR) was 17.5 months with the triplet and 12.0 months with the doublet. An interim overall survival (OS) analysis showed a trend favoring both gedatolisib-containing arms, though results did not reach statistical significance at the time of the interim analysis (triplet: HR, 0.69; 95% CI, 0.43-1.12; P =.1328; doublet: HR, 0.74; 95% CI, 0.46-1.19; P =.2122); OS follow-up is ongoing.

Mechanism of Action

Gedatolisib is a multi-target inhibitor of all four class I PI3K isoforms (PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ), mTORC1, and mTORC2, enabling comprehensive blockade of the PAM pathway. This mechanistic profile distinguishes gedatolisib from currently approved single-target PAM inhibitors such as the PI3Kα-selective inhibitor alpelisib (Piqray) and the AKT inhibitor capivasertib (Truqap). Inhibition of only a single component of the PAM pathway permits compensatory cross-activation of uninhibited nodes, limiting the durability of pathway suppression. Gedatolisib's multi-target approach is intended to minimize this adaptive resistance. Importantly, preclinical data demonstrate equivalent potency in both PIK3CA-mutant and PIK3CA wild-type breast tumor cells, supporting its potential utility in the broader HR+/HER2− population regardless of PIK3CA mutational status.

Safety Profile

The safety data from VIKTORIA-1 indicated that both gedatolisib-based regimens were generally well tolerated. Rates of treatment discontinuation due to treatment-related adverse events (TRAEs) were low, at 2.3% for the triplet and 3.1% for the doublet.

The most frequently reported TRAE was stomatitis, occurring in more than half of patients across both gedatolisib-containing arms. The majority of initial stomatitis events were grade 1, and the introduction of a prophylactic swish-and-spit regimen in VIKTORIA-1 reduced the incidence and severity compared with earlier-phase studies of gedatolisib; most events resolved within 2 weeks with proactive management. Grade 3 stomatitis occurred in 19.2% of patients in the triplet arm and 12.3% in the doublet arm.

Grade 3 neutropenia was the most common TRAE in the triplet arm (52.3%), consistent with the known hematologic toxicity of palbociclib; it occurred in 0.8% of patients in the doublet arm. Hyperglycemia of any grade, a recognized class effect of PAM pathway inhibition, was reported in 9.2% and 11.5% of patients in the triplet and doublet arms, respectively, at lower rates than those observed with isoform-specific PI3K inhibitors such as alpelisib. Grade 3 hyperglycemia occurred in 2.3% of patients in both gedatolisib-containing arms. Additional grade 3 TRAEs included rash (4.6% triplet; 5.4% doublet) and diarrhea (1.5% triplet; 0.8% doublet). Grade 4 TRAEs in the triplet arm included neutropenia (10.0%) and leukopenia (0.8%); grade 4 pneumonitis was reported in 0.8% of patients in the doublet arm.

Regulatory Background

Gedatolisib previously received both breakthrough therapy and fast track designations from the FDA based on earlier clinical data.^3,4 The new drug application was submitted in November 2025 under the agency's Real-Time Oncology Review (RTOR) program, which is designed to facilitate more efficient review of therapies demonstrating the potential to address substantial unmet medical need.⁵ Full results from the VIKTORIA-1 PIK3CA wild-type cohort were published in the Journal of Clinical Oncology in March 2026.²

Clinical Context

Patients with HR+/HER2− advanced breast cancer who have progressed on CDK4/6 inhibitor–based therapy represent a clinically challenging population with limited second-line treatment options. Approximately 60% of these patients have PIK3CA wild-type disease and are therefore ineligible for currently approved PI3Kα-specific inhibitors. Prior to this approval, available second-line regimens—including everolimus-based combinations and capivasertib plus fulvestrant—provided only modest PFS improvements in this molecular subgroup. The VIKTORIA-1 data represent the first phase 3 demonstration of statistically significant and clinically meaningful PFS improvement with PAM pathway inhibition in PIK3CA wild-type HR+/HER2− advanced breast cancer.

Clinicians should be aware of the need for baseline and ongoing monitoring for stomatitis, hyperglycemia, and cytopenias in patients initiating gedatolisib-based therapy. Prophylactic oral care protocols for stomatitis management and baseline glycemic assessment are expected to be incorporated into prescribing guidance.

In an interview with Targeted Oncology, Sara Hurvitz, MD, discusses how gedatolisib is changing the landscape of breast cancer treatment.

REFERENCES

1. FDA approves gedatolisib with fulvestrant, with or without palbociclib, for HR-positive, HER2-negative locally advanced or metastatic breast cancer. News release. US FDA. July 14, 2026. Accessed July 14, 2026. https://tinyurl.com/3bc988ps

2. Hurvitz SA, Layman RM, Curigliano G, et al. VIKTORIA-1 trial of gedatolisib plus fulvestrant with or without palbociclib in hormone receptor–positive/HER2−/PIK3CA wild-type advanced breast cancer. J Clin Oncol. Published online March 9, 2026. doi:10.1200/JCO-25-02643

3. Celcuity Inc. Celcuity announces completion of submission of its new drug application to the US FDA for gedatolisib in HR+/HER2−/PIK3CA wild-type advanced breast cancer. News release. November 17, 2025. https://tinyurl.com/ymcc4fwc

4. Celcuity Inc. Celcuity announces FDA acceptance of new drug application for gedatolisib in HR+/HER2−/PIK3CA wild-type advanced breast cancer. News release. January 20, 2026. https://tinyurl.com/kazve4xh

5. Gedatolisib plus fulvestrant with or without palbociclib vs standard-of-care for the treatment of patients with advanced or metastatic HR+/HER2− breast cancer (VIKTORIA-1). ClinicalTrials.gov. NCT05501886. Updated June 24, 2025. https://clinicaltrials.gov/study/NCT05501886

6. Pistilli B, Layman RM, Curigliano G, et al. Gedatolisib, a multitarget PI3K/AKT/mTOR inhibitor, plus fulvestrant with or without palbociclib for second-line treatment of patients with HR+/HER2−/PIK3CA-WT advanced breast cancer: updated results from the randomized, phase 3 VIKTORIA-1 trial. Abstract presented at: 2025 San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX. Abstract R47-04.