Gedatolisib Combinations Improve PFS in Advanced Breast Cancer

The phase 3 VIKTORIA-1 trial (NCT05501886) demonstrated that adding the multitarget inhibitor gedatolisib to fulvestrant (Faslodex), both with and without palbociclib (Ibrance), significantly improved progression-free survival (PFS) for patients with hormone receptor (HR)–positive, HER2-negative, PIK3CA wild-type (WT) advanced breast cancer, according to results published in The Journal of Clinical Oncology.

The global, randomized study showed that these gedatolisib-based regimens provided a clinically meaningful benefit after patients had disease progression on previous treatment with a CDK4/6 inhibitor and an aromatase inhibitor (AI).

Main Data from VIKTORIA-1

At a median follow-up of 10.1 months, treatment with the gedatolisib triplet (gedatolisib, palbociclib, and fulvestrant) resulted in a median PFS of 9.3 months (95% CI, 7.2-16.6) compared with 2.0 months (95% CI, 1.8-2.3) in the fulvestrant monotherapy group (HR, 0.24; 95% CI, 0.17-0.35; P <.001).

For patients receiving the gedatolisib doublet (gedatolisib and fulvestrant), the median PFS was 7.4 months (95% CI, 5.5-9.9) compared with 2.0 months (95% CI, 1.8-2.3) for those receiving fulvestrant alone (HR, 0.33; 95% CI, 0.24-0.48; P <.001). Subgroup analyses indicated that the treatment effect was generally consistent across prespecified groups, including those based on age, menopause status, and the presence of visceral metastases.

The confirmed objective response rate (ORR) was 31.5% in the triplet group—including 1 complete response—28.3% in the doublet group, and 1.0% in the fulvestrant group. The median duration of response was 17.5 months for the triplet and 12.0 months for the doublet. With only 1 responder in the monotherapy group, the median duration of response could not be calculated.

“VIKTORIA-1 met its primary end point, showing that the addition of gedatolisib to fulvestrant, with or without palbociclib, achieved clinically meaningful improvements in PFS relative to fulvestrant in patients with [HR-positive/HER2-negative] PIK3CA-WT advanced breast cancer that progressed on or after a CDK4/6 [inhibitor] and a nonsteroidal aromatase inhibitor [NSAI],” Sara A. Hurvitz, MD, MPH, senior vice president, director, and professor of the Clinical Research Division and Smith Family Endowed Chair in Women’s Health at Fred Hutch, and coauthors wrote in the paper. “To our knowledge, the magnitude of difference between the gedatolisib triplet and fulvestrant is the largest reported in a contemporary phase 3 trial in this patient population, underlying the importance of combination treatment in this setting and, importantly, validating the PAM pathway as a molecular driver even in PIK3CA-WT disease.”

Trial Details

VIKTORIA-1 enrolled 392 patients between December 5, 2022, and January 23, 2025, across 147 sites in 23 countries. Eligible adults were 18 years or older with HR-positive/HER2-negative metastatic or locally advanced breast cancer that was PIK3CA wild-type. Patients must have experienced disease progression during or after treatment with a combined CDK4/6 inhibitor and an NSAI.

Patients were randomly assigned in a 1:1:1 ratio to receive 1 of 3 regimens in 28-day cycles:

• Gedatolisib triplet: Gedatolisib at 180 mg intravenously (IV) weekly for 3 weeks followed by 1 week off; palbociclib at 125 mg orally once daily for 3 weeks followed by 1 week off; and fulvestrant at 500 mg intramuscularly (IM).
• Gedatolisib doublet: Gedatolisib at 180 mg IV weekly for 3 weeks followed by 1 week off, and fulvestrant at 500 mg IM.
• Fulvestrant monotherapy: Fulvestrant at 500 mg IM.

Fulvestrant was administered on days 1 and 15 of cycle 1, and then once every 4 weeks starting with cycle 2. Patients in the fulvestrant monotherapy group were permitted to cross over to a gedatolisib-based regimen upon radiographically confirmed disease progression.

Main End Points

The primary objective of the study was to compare PFS, as assessed by blinded independent central review (BICR) per RECIST v1.1, for the gedatolisib triplet vs fulvestrant and the gedatolisib doublet vs fulvestrant.

Secondary end points included overall survival (OS), ORR, duration of response, safety, quality of life, and pharmacokinetics. OS analysis was conducted hierarchically; at the time of the primary analysis, the stratified HR for death was 0.69.

Safety

The safety profiles of the gedatolisib-based regimens were generally consistent with the known effects of the individual agents. Treatment-related adverse events (TRAEs) of grade 3 or higher were reported in the gedatolisib-triplet and gedatolisib-doublet groups.

Common grade 3 or higher TRAEs in the triplet and doublet groups included:

• Neutropenia: 62.3% (triplet) vs 0.8% (doublet)
• Stomatitis: 19.2% (triplet) vs 12.3% (doublet)
• Rash: 4.6% (triplet) vs 5.4% (doublet)
• Hyperglycemia: 2.3% (triplet) vs 2.3% (doublet)
• Diarrhea: 1.5% (triplet) vs 0.8% (doublet)

Discontinuation of study treatment due to TRAEs occurred in 2.3% of patients in the triplet group and 3.1% of patients in the doublet group. To manage potential AEs, a prophylactic steroid-containing "swish-and-spit" regimen was mandated for all patients in the gedatolisib groups.

Reference

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