Gedatolisib-Based Regimens May Advance PIK3CA Wild-Type Metastatic Breast Cancer Care

Findings from the phase 3 VIKTORIA-1 study (NCT05501886) suggest that triplet and doublet gedatolisib (PF-05212384)-based regimens may offer new, effective treatment strategies for patients with hormone receptor–positive, HER2-negative, PIK3CA wild-type metastatic breast cancer, according to Sara A. Hurvitz, MD, FACP.

In an interview with OncLive®, Hurvitz discussed the design of VIKTORIA-1, key efficacy findings, the safety profile of the gedatolisib-based regimens, and how these data may influence the expansion of the metastatic breast cancer treatment paradigm.

“These are exciting findings in PIK3CA wild-type, metastatic estrogen receptor–positive breast cancer,” Hurvitz said during the 2025 ESMO Congress.

Hurvitz noted that the VIKTORIA-1 findings build on previously reported data from a phase 1 trial (NCT02626507), in which gedatolisib plus palbociclib (Ibrance) and fulvestrant (Faslodex) produced an estimated 1-year progression-free survival (PFS) rate of 79% (95% CI, 56%-91%) in patients with PIK3CA wild-type disease (n = 25) vs 71% (95% CI, 26%-92%) in those with PIK3CA-mutated disease (n = 7).1

At the 2025 ESMO Congress, Hurvitz presented findings from VIKTORIA-1, which demonstrated that patients treated with gedatolisib plus palbociclib and fulvestrant (n = 131) experienced 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 patients given fulvestrant alone (n = 131; HR, 0.24; 95% CI, 0.17-0.35; P < .0001).2 Furthermore, the median PFS was 7.4 months (95% CI, 5.5-9.9) for patients treated with gedatolisib plus fulvestrant (n = 130; HR vs fulvestrant alone, 0.33; 95% CI, 0.24-0.48; P < .0001).

Hurvitz is senior vice president, the director of and professor in the Clinical Research Division, the Smith Family Endowed Chair in Women’s Health, and an affiliate investigator in the Translational Science and Therapeutics Division at Fred Hutch Cancer Center in Seattle, Washington. She is also a professor in and head of the Division of Hematology and Oncology in the Department of Medicine at the University of Washington School of Medicine.

OncLive: What is the rationale for blocking the PI3K and mTOR pathways in hormone receptor–positive breast cancer?

Hurvitz: The PI3K pathway is altered in approximately 40% of hormone receptor–positive, HER2-negative breast cancers. For the past 13 years, we've had agents available that target the PI3K pathway. Many of the agents that have been approved target only 1 part of the pathway, because targeting multiple parts of the pathway has been shown to be toxic.

Gedatolisib is an intravenous PI3K and mTOR inhibitor. It inhibits all class IA isoforms of PI3K, as well as mTORC1/2. In a phase 1b study, patients were treated with gedatolisib, fulvestrant, and palbociclib. Benefit was seen in patients regardless of whether their tumors had a PIK3CA mutation.

These exciting data led to the development of the VIKTORIA-1 clinical trial, which had 2 study parts. Study 1 was in patients with PIK3CA wild-type tumors. Study 2, [results from] which will be presented [in 2026], was in patients who had tumors that were PIK3CA mutated. Study 1 evaluated patients who had previously received a CDK4/6 inhibitor with endocrine therapy. Patients were randomly assigned to 1 of 3 treatment arms: fulvestrant plus gedatolisib and palbociclib, fulvestrant plus gedatolisib, or fulvestrant [alone].

What treatment challenges exist for patients with hormone receptor–positive, HER2-negative breast cancer who experience disease progression on or after a CDK4/6 inhibitor–based regimen? How might gedatolisib-based combinations address some of these unmet needs?

After treatment with a CDK4/6 inhibitor, most studies that have investigated single-agent endocrine therapy have demonstrated a [median] PFS of less than 6 months. [Treatment decision-making is] challenging for patients who have experienced disease progression on frontline CDK4/6 inhibitor therapy. Adverse effect profiles are another important consideration.

The VIKTORIA-1 study demonstrated a statistically significant improvement in PFS with the triplet combination of gedatolisib plus fulvestrant and palbociclib, as well as with the doublet combination. Both were statistically significantly better than fulvestrant alone. The data were impressive, even for patients with endocrine-resistant breast cancer, where the triplet seemed particularly impressive.

What were the safety findings from VIKTORIA-1?

Interestingly, when you target the PI3K pathway, on-target toxicities you can see are hyperglycemia and diarrhea. However, in this study, hyperglycemia rates and diarrhea rates were lower than we've seen with other PI3K pathway inhibitors. However, patients had a risk of stomatitis [despite] the use of oral steroid mouthwash, so this would need to be monitored in patients receiving this therapy.

What are the potential clinical implications of the VIKTORIA-1 trial findings?

We'll have to see if the triplet and doublet become FDA-approved and available to us. If they do, we will have a new regimen for patients without PIK3CA mutations in their tumors.

With VIKTORIA-1 and other trials bringing a plethora of research to the post-CDK4/6 inhibitor setting, what will be the importance of personalizing treatment approaches?

[Treatments are becoming increasingly] personalized as we assess and treat hormone receptor–positive disease. We're evaluating the tumors for ESR1 mutations, PIK3CA mutations, PI3K alterations, etc., and using that information to help select the best therapy for a patient. It's interesting that in the VIKTORIA-1 study, patients didn't need to have a PIK3CA mutation to benefit from [the investigational treatment approaches]. It makes you wonder: Do we need to test for that in this setting? We'll have to see what the regulatory authorities think.

References

1. Wesolowski R, Rugo HS, Specht JM, et al. Gedatolisib combined with palbociclib and letrozole in patients with no prior systemic therapy for hormone receptor-positive, HER2-negative advanced breast cancer. Clin Cancer Res. 2025;31(19):4040-4048. doi:10.1158/1078-0432.CCR-25-0992
2. Hurvitz SA, Layman RM, Curigliano G, et al. Gedatolisib Plus Fulvestrant, With & Without Palbociclib, vs Fulvestrant in Patients With HR+/HER2-/PIK3CA Wild-Type Advanced Breast Cancer: First Results from VIKTORIA-1. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA17.