The US Food & Drug Administration has approved gedatolisib (Revtorpyk, Celcuity) plus fulvestrant, with or without palbociclib, for patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer without a PIK3CA mutation detected after progression on or after treatment with at least one line of endocrine therapy in the metastatic setting.
Medscape reports that gedatolisib is a multitarget inhibitor of the PI3K/AKT/mTOR (PAM) pathway, a key oncogenic driver of HR-positive, HER2-negative breast cancer that contributes to treatment resistance.
While previously approved medications target single components of the pathway, gedatolisib blocks PI3K and mTOR together, leading to more comprehensive suppression, which may in turn help restore sensitivity to endocrine therapy and anti-CDK4/6 inhibition.
Approval was based on the VIKTORIA-1 trial, which randomly assigned 392 patients evenly to either gedatolisib, palbociclib, and fulvestrant (gedatolisib triplet); gedatolisib plus fulvestrant (gedatolisib doublet); or fulvestrant alone.
Median progression-free survival, the major efficacy outcome, was 9.3 months in the gedatolisib-triplet group, 7.4 months in the gedatolisib-doublet arm, and 2 months with fulvestrant monotherapy. Overall survival data were not yet mature.
In a paper published in the Journal of Clinical Oncology in March, the investigators acknowledged that fulvestrant monotherapy is no longer standard of care in the second line after anti-CDK4/6 and aromatase inhibitor failure, and that it was chosen as a comparator to meet regulatory requirements.
Still, they said the median progression-free survival in the triplet arm is “among the longest reported for a chemotherapy-free second- to third-line regimen in a phase III trial”.
Grade 3 or higher treatment-related adverse events in the triplet and doublet groups included neutropenia (62.3%, 0.8%), stomatitis (19.2%, 12.3%), rash (4.6%, 5.4%), hyperglycemia (2.3%, 2.3%), and diarrhea (1.5%, 0.8%). Overall, 2.3% of triplet and 3.1% of doublet patients stopped treatment due to adverse events. There were two treatment-related deaths in the triplet arm, one from pneumonia and the other from liver failure.
In June, Celcuity reported similarly favourable survival outcomes among 350 patients in VIKTORIA-1 who had PIK3CA mutations. Median progression-free survival was over 11 months with both the gedatolisib triplet and doublet vs 5.6 months with alpelisib plus fulvestrant, which was the comparator in the cohort with PIK3CA mutations.
The company said it planned to submit a supplemental application to the FDA for approval in patients with PIK3CA mutations.
The recommended dosage for gedatolisib is 180 mg as an intravenous infusion once weekly on days 1, 8, and 15 of every 28-day cycle, in combination with fulvestrant, with or without palbociclib, until disease progression or unacceptable toxicity.
Study details
VIKTORIA-1 Trial of Gedatolisib Plus Fulvestrant With or Without Palbociclib in Hormone Receptor–Positive/HER2−/PIK3CA Wild-Type Advanced Breast Cancer
Sara Hurvitz, Rachel Layman, Giuseppe Curigliano et al.
Published in Journal of Clinical Oncology on 9 March 2026
Abstract
Purpose
Gedatolisib potently targets all four class I PI3K isoforms and mTORC1 and mTORC2 to comprehensively block the PI3K/AKT/mTOR pathway and has shown compelling activity in early clinical trials with palbociclib and fulvestrant.
Methods
This phase III randomised trial evaluated the efficacy of gedatolisib-based therapy, comparing gedatolisib, palbociclib, and fulvestrant (gedatolisib triplet) and gedatolisib plus fulvestrant (gedatolisib doublet) with fulvestrant monotherapy in patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative (HER2−), PIK3CA wild-type (WT) advanced breast cancer. Eligible patients had disease progression during or after CDK4/6 inhibitor and aromatase inhibitor treatment. Comparison of progression-free survival as assessed by blinded independent central review for gedatolisib triplet versus fulvestrant and gedatolisib doublet versus fulvestrant was the primary objective.
Results
A total of 392 patients were randomly assigned 1:1:1. The median study follow-up was 10.1 months. The median progression-free survival was 9.3 months in the gedatolisib-triplet group, 2.0 months in the fulvestrant group (hazard ratio [HR] for progression or death, 0.24 [95% CI, 0.17 to 0.35]; P < .001), and 7.4 months in the gedatolisib-doublet group (HR, 0.33 [95% CI, 0.24 to 0.48]; P < .001 v fulvestrant). Grade ≥3 treatment-related adverse events (TRAEs) reported in the gedatolisib-triplet and gedatolisib-doublet groups, respectively, included neutropenia (62.3%, 0.8%), stomatitis (19.2%, 12.3%), rash (4.6%, 5.4%), hyperglycemia (2.3%, 2.3%), and diarrhea (1.5%, 0.8%). Study treatment discontinuation because of TRAEs was reported in 2.3% (triplet) and 3.1% (doublet) of patients.
Conclusion
The addition of gedatolisib to fulvestrant, with or without palbociclib, significantly reduced the risk of disease progression or death in patients with hormone receptor–positive/HER2−, PIK3CA WT advanced breast cancer.
Medscape article – Gedatolisib Combo Approved for Advanced Breast Cancer (Open access)
See more from MedicalBrief archives:
Fasting diet may boost hormone drugs in breast cancer therapy
New drug with hormone therapy significantly extends breast cancer survival
Combination of experimental and other drug slows breast cancer progression