Gedatolisib-Based Therapy Improves Progression-Free Survival in PIK3CA Wild-Type Advanced Breast Cance

Clinical Summary:

• Design/Population: The phase 3 VIKTORIA-1 trial randomized 392 patients with HR-positive, HER2-negative, PIK3CA wild-type advanced breast cancer that progressed on or after prior CDK4/6 and aromatase inhibitor therapy to receive gedatolisib plus fulvestrant and palbociclib, gedatolisib plus fulvestrant, or fulvestrant alone.
• Key Outcomes: Both gedatolisib-based regimens significantly improved progression-free survival compared with fulvestrant alone, with the longest median progression-free survival observed with the palbociclib-containing triplet. Treatment discontinuations due to adverse events were low, and gedatolisib demonstrated lower rates of hyperglycemia and diarrhea than historically observed with other PI3K pathway inhibitors.
• Clinical Relevance: These findings supported the FDA approval of gedatolisib plus fulvestrant, with or without palbociclib, and introduce a new PI3K/AKT/mTOR pathway-targeted treatment option for patients with PIK3CA wild-type advanced breast cancer following CDK4/6 inhibitor therapy.

Sara Hurvitz, MD, Fred Hutchinson Cancer Center, Seattle, Washington, discusses results from the phase 3 VIKTORIA-1 trial evaluating gedatolisib-based therapy in patients with HR-positive, HER2-negative, PIK3CA wild-type advanced breast cancer who experienced disease progression on or after treatment with an aromatase inhibitor and a CDK4/6 inhibitor. 

Dr Hurvitz reviews the significant progression-free survival improvements achieved with gedatolisib plus fulvestrant, with or without palbociclib, compared with fulvestrant alone and explains how gedatolisib's inhibition of the PI3K/AKT/mTOR pathway provides a targeted strategy for patients without PIK3CA mutations. Dr Hurvitz also discusses the distinct safety profile of intravenous gedatolisib, practical considerations for toxicity prevention and management, and how the subsequent FDA approval expands treatment options for the common PIK3CA wild-type population after CDK4/6 inhibitor progression.

Transcript:

Hi there, I am Sarah Hurvitz, medical oncologist at the University of Washington Fred Hutch Cancer Center, and I'm presenting the results of the VIKTORIA-1 trial. 

VIKTORIA-1 was a study evaluating a novel agent, gedatolisib, for the treatment of HR-positive, HER2-negative, PIK3CA wild-type advanced breast cancer.

Gedatolisib is a novel agent that targets all 4 PIK3CA class 1 isoforms, as well as mTORC1 and mTORC2, thereby fully blocking the PI3K/AKT/mTOR pathway. This drug has shown promise in early phase clinical trials in combination with CDK4/6 inhibitor and endocrine therapy. 

This is an area of unmet need. Patients with HR-positive metastatic breast cancer do not have curable disease. In spite of the benefits we see with CDK4/6 inhibitors in the frontline setting, the majority of patients will experience disease progression after developing resistance to endocrine therapy. 

The most common type of HR-positive, HER2-negative breast cancer is PIK3CA wild-type, meaning lacking a mutation in the PI3K itself, the gene that encodes PI3K. 

In this clinical trial, which was a phase 3, randomized study, patients were randomly assigned to receive gedatolisib in combination with fulvestrant, gedatolisib in combination with fulvestrant and palbociclib, or single-agent fulvestrant, which was the standard of care at the time the study was designed in patients who had experienced disease progression on or after a CDK4/6 inhibitor. 

Patients had to have PIK3CA wild-type disease that was HR-positive and had to have received a prior CDK4/6 inhibitor and an aromatase inhibitor. In this study, we were evaluating progression-free survival with the two gedatolisib regimens compared to single-agent fulvestrant. It's important to note that in the fulvestrant single-agent arm, patients who experienced disease progression were allowed to go on and cross over to one of the gedatolisib arms, and that would be provided to them. Three hundred and ninety two patients were randomly assigned 1:1:1 to one of the 3 treatment arms.

The median progression-free survival for the gedatolisib triplet that included palbociclib was 9.3 months, 2 months in the fulvestrant arm, and 7.4 months in the gedatolisib doublet arm without palbociclib. The gedatolisib-based arms were statistically significantly better in terms of progression-free survival compared to the fulvestrant alone arm. 

Interestingly, although the use of gedatolisib does target the PI3K pathway, its IV-formulation likely is what has led to a differing side effect profile from that seen with other PI3K pathway inhibitors. Namely, patients treated with gedatolisib had lower rates of hyperglycemia and diarrhea than was seen in patients treated with drugs like alpelisib or capivasertib or inavolisib in other clinical trials.

One side effect that we do see with gedatolisib-based therapy is dermatitis, and for that reason, patients do need to be treated with a prophylactic steroid mouthwash and need to be educated on proper oral care and foods to avoid when starting this therapy. Study treatment discontinuation because of treatment-related adverse events were quite low on the order of 2% to 3% in the gedatolisib arms. 

In summary, the use of gedatolisib in patients whose disease had progressed on or after an aromatase inhibitor and CDK4/6 inhibitor improved progression-free survival compared to single-agent fulvestrant. 

This led to the FDA approval of gedatolisib in combination with fulvestrant with or without palbociclib. It's expected to be ready and available to us in the clinical setting this fall.

I think this could be a game changer for patients. At this point, the only PI3K pathway inhibitor that we have available for patients with PI3K non-activated tumors is everolimus. The other inhibitors all require a mutation in one or another part of the PI3K pathway. This does lead to an improved outcome for patients with PIK3CA wild-type disease. As I said, the most common type of HR-positive, HER2-negative metastatic breast cancer. 

Source:

US Food and Drug Administration. FDA approves gedatolisib with fulvestrant, with or without palbociclib, for HR-positive, HER2-negative locally advanced or metastatic breast cancer. Accessed on: July 14, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-gedatolisib-fulvestrant-or-without-palbociclib-hr-positive-her2-negative-locally

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