A triplet of drugs extends progression-free survival in advanced breast cancer

Breast cancer treatment has been a showcase of increasing precision—from surgery and chemotherapy, to endocrine therapies and targeted treatments. Breast cancer subtypes can be defined by expression of hormone receptors and HER2, which significantly impact treatment course. For patients with advanced hormone receptor positive, HER2 negative breast cancer, first-line therapy typically combines a hormone-blocking drug with a class of cell cycle blocking agents called CDK4/6 inhibitors. Most patients with advanced disease initially respond well but eventually the treatment stops working.  

When treatment resistance develops typically the length of disease control is much shorter with each subsequent line of therapy. Although multiple next-line options exist, choosing among them is complicated. Tumor genomic testing often guides next steps. But what if there were a more generalized treatment for this group of patients that did not require a genetic alteration?

In preclinical studies, a critical growth signaling pathway known as PI3K/AKT/mTOR, or “PAM” has been linked to resistance to hormone receptor therapy and CDK4/6 inhibitors. In other words, when hormone and CDK4/6 pathways are blocked, PAM takes over, allowing the tumor to push forward in the presence of inhibitors.

A new phase III clinical trial, published in the Journal of Clinical Oncology may offer a promising new option to halt these tumors. The large, multi-institution “VIKTORIA-1” trial was led by Dr. Sara Hurvitz of Fred Hutch in collaboration with the VIKTORIA-1 study group and involved over 100 sites in dozens of countries, including UW/FHCC. Jennifer Specht served as the local principal investigator of VIKTORIA-1 at UW/FHCC. The concept is to block all three aforementioned tumor-promoting pathways—hormone receptors, CDK4/6 and PAM—leaving tumors with limited options to drive their growth.

The study focused on a drug called gedatolisib, which targets the PAM pathway broadly, inhibiting all class I PI3K isoforms and both mTOR complexes, mTORC1 and mTORC2. This drug is promising in that it strikes the balance between broad pathway neutralization and limited toxicity.

The trial enrolled 392 patients whose cancer had progressed after treatment with both a CDK4/6 inhibitor and an aromatase inhibitor (a hormone-targeting therapy). All patients in this particular arm of the trial had tumors without mutations in PIK3CA, the gene encoding one of the drug’s targets, PI3K. Patients were randomly assigned to one of three groups: gedatolisib combined with palbociclib (a CDK4/6 inhibitor) and fulvestrant (a hormone-blocking drug)—the “triplet combination,” gedatolisib combined with fulvestrant alone—“doublet combination,” or fulvestrant alone as the control.

The results were striking. Patients receiving the triplet combination went a median of 9.3 months before their disease progressed, compared to just 2.0 months for those receiving fulvestrant alone, one of the largest improvements ever reported in a second- to third-line regimen in a phase III trial for this patient population. The doublet combination also outperformed fulvestrant, with a median progression-free survival of 7.4 months. Notably, the benefit held up consistently across clinical subgroups, suggesting the effect is robust rather than driven by a particular subset of patients. It’s still too early to determine whether these results translate to gedatolisib increasing patients’ overall survival.

Lead author Dr. Sara Hurvitz expands upon these results: “Both the triplet and doublet gedatolisib regimens were associated with statistically significant improvements in progression-free survival versus standard of care single agent fulvestrant (67-76% relative improvement in progression free survival)— these results could potentially change clinical practice for patients with PIK3CA-wild-type advanced breast cancer.” This is particularly significant because most existing PAM pathway drugs only work in patients who carry the PIK3CA mutation.

The inclusion of 3 different drug groups allowed researchers to tease apart another important nuance of gedatolisib. “It is very interesting that in a population of patients who had all been previously treated with a first-line CDK4/6 inhibitor, the triplet combination (including a CDK4/6i) had a longer progression-free survival than the doublet combination (excluding a CDK4/6i). Of particular note was that patients treated previously with palbociclib, and then retreated with palbociclib as part of the triplet, responded as well as patients who had previously received ribociclib (a different CDK4/6 inhibitor). This could very well indicate that gedatolisib is restoring CDK4/6i sensitivity. This is the first study I am aware of that shows using palbociclib after progression on a CDK4/6i is associated with a longer PFS,” Hurvitz elaborates.

On the safety front, the most common side effect was mouth sores, affecting roughly two-thirds of patients in both gedatolisib groups. However, the majority were mild, most resolved within two weeks, and a preventive mouth rinse regimen introduced during the trial helped reduce their severity. Investigators were also on the lookout for hyperglycemia, since this is a serious and common side effect of PAM pathway inhibitors due to disruption of insulin signaling. Thankfully high blood sugar occurred in less than 13% of patients on gedatolisib.

The results position gedatolisib combination therapy as a compelling candidate for a new standard of care in second-line advanced breast cancer and open the door to testing it even earlier in the treatment sequence. In fact, “the ongoing VIKTORIA-2 study (that Dr. Vidhya Nair is leading at Fred Hutch as site-PI) is evaluating gedatolisib combination therapy in first line advanced breast cancer. We are also interested in exploring other potential indications in breast cancer where gedatolisib combination regimens could be evaluated, for example in HER2 positive metastatic breast cancer,” Dr. Hurvitz shares.

The researchers are eagerly anticipating results from arm 2 of VIKTORIA-1 which will assess the efficacy of gedatolisib-based therapy in patients with PIK3CA tumor mutations.

Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Member Dr. Sara Hurvitz contributed to this research.

The spotlighted research was funded by Celcuity Inc.

Hurvitz SA, Layman RM, Curigliano G, André F, Cristofanilli M, Kim SB, Martínez Rodríguez JL, Nadal JC, Kim GM, Lo L, Remolina-Bonilla YA, Rosselli G, Emile G, Korbenfeld E, Puig JM, Wesolowski R, Martin M, Ring A, Han HS, Giordano A, Mutka SC, Moss K, Su. 2026. 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. doi: 10.1200/JCO-25-02643.