Gedatolisib-Based Regimens for HR-Positive, HER2-Negative, PIK3CA Wild-Type Advanced Breast Cancer

Key Clinical Summary: 

• Design/Population: In the phase 3 VIKTORIA-1 trial, 392 patients with HR-positive, HER2-negative, PIK3CA wild-type advanced breast cancer who progressed on prior CDK4/6 inhibitor and aromatase inhibitor therapy were randomized to receive either gedatolisib plus palbociclib and fulvestrant, gedatolisib plus fulvestrant, or fulvestrant monotherapy.
• Key Outcomes: Gedatolisib-based regimens significantly improved progression-free survival compared with fulvestrant alone, with the greatest benefit observed in the triplet arm. Both regimens substantially reduced the risk of disease progression or death, with higher objective response rates observed versus monotherapy.
• Clinical Relevance: These results support PI3K/mTOR pathway inhibition with gedatolisib as an effective strategy in patients with PIK3CA wild-type disease following CDK4/6 inhibitor progression, offering a potential new treatment option in this setting.

Results from the phase 3 VIKTORIA-1 trial demonstrate that gedatolisib-based combinations significantly improved outcomes compared with fulvestrant alone among previously treated patients with hormone receptor (HR]-positive, HER2-negative, PIK3CA wild-type advanced breast cancer. 

When patients progress on first-line regimens “combination therapy with an endocrine agent and a [CDK]4/6 inhibitor is recommended… [however] the majority of patients eventually develop resistant disease, and the optimal sequencing of subsequent therapies remains undefined,” stated Sara Hurvitz, MD, Fred Hutchinson Cancer Center, Seattle, Washington, and coauthors. “Gedatolisib potently targets all 4 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.”

In this open-label study, 392 patients were randomized 1:1:1 to receive either gedatolisib (180 mg; once weekly for 3 weeks on days 1, 8, and 15, followed by 1 week off) plus palbociclib (125 mg; once daily for 3 weeks followed by 1 week off) and fulvestrant (500 mg intramuscularly as 2 x 5 mL injections; every 2 weeks on days 1 and 15, followed by once every 4 weeks thereafter), gedatolisib plus fulvestrant, or fulvestrant monotherapy, administered in 28-day cycles. Patients assigned to the fulvestrant arm were permitted to cross over to either the doublet or triplet arms upon radiographically confirmed disease progression. 

The primary end point was progression-free survival (PFS), assessed by blinded independent central review, comparing each gedatolisib-containing arm versus fulvestrant monotherapy. Key secondary end points included objective response rate (ORR), duration of response, and safety. At a median follow-up of 10.1 months, median PFS was 9.3 months in the triplet arm, 7.4 months in the doublet arm, and 2 months in the fulvestrant monotherapy arm. This corresponded to a significant reduction in the risk of progression or death with both the triplet (hazard ratio [HR], 0.24; 95% confidence interval [CI], 0.17 to 0.35; P < .001) and the doublet (HR, 0.33; 95% CI, 0.24 to 0.48; P < .001) regimens.

Median treatment duration was 6.2 months in the triplet arm, 5.7 months in the doublet arm, and 1.8 months in the fulvestrant monotherapy arm with 25.4%, 26.9%, and 4.9% of patients still on study treatment. The ORR was 31.5% in the triplet arm, 28.3% in the doublet arm, and 1% in the fulvestrant monotherapy arm. Median duration of response was 17.5 months in the triplet arm and 12 months in the doublet arm. Median duration of response could not be calculated in the fulvestrant monotherapy arm due to only 1 response.

The most frequently reported grade ≥ 3 treatment-related adverse events in the triplet and doublet arms included neutropenia, stomatitis, rash, hyperglycemia, and diarrhea. Adverse events led to treatment discontinuation in 2.3% of patients in the triplet arm and 3.1% in the doublet arm.

“The addition of gedatolisib to fulvestrant, with or without palbociclib, significantly reduced the risk of disease progression or death in patients with [HR-positive]/HER2-[negative], PIK3CA [wild-type] advanced breast cancer,” concluded Dr Hurvitz et al. 

“Gedatolisib-based combinations expand the population that may benefit from PI3K/AKT/mTOR inhibitors to those without defined mutations in the pathways,” added Journal of Clinical Oncology senior deputy editor Kathy Miller, MD, Indiana University Health, Indianapolis, Indiana. “Future studies should compare these regimens to other second-line options to define the optimal agents and sequence.” 

Source: 

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