Gedatolisib and Fulvestrant Enhance Survival in Advanced Breast Cancer

Recent findings from the phase 3 VIKTORIA-1 trial indicate that the combination of the PI3K/AKT/mTOR inhibitor gedatolisib and fulvestrant (Faslodex), with or without palbociclib (Ibrance), significantly improves progression-free survival (PFS) in patients with advanced breast cancer characterized by hormone receptor (HR)-positivity, HER2-negativity, and PIK3CA wild-type status. This study was presented at the March 2025 ESMO Congress and highlights promising advancements for patients who have progressed after previous treatments.

The VIKTORIA-1 trial, registered under NCT05501886, involved patients who experienced progression following treatment with a CDK4/6 inhibitor and an aromatase inhibitor. Results demonstrated a clinically meaningful enhancement in PFS for those receiving gedatolisib alongside fulvestrant. In particular, patients treated with the triplet regimen of gedatolisib, fulvestrant, and palbociclib exhibited a remarkable 76% reduction in the risk of disease progression compared to those on fulvestrant alone. The median PFS for the triplet therapy was recorded at 9.3 months (95% CI, 7.2-16.6), while those on fulvestrant alone had a median PFS of just 2.0 months (95% CI, 1.8-2.3).

Key Findings from VIKTORIA-1 Trial

The trial’s results also revealed significant improvements in the median duration of response (DOR) and overall response rates (ORRs). Patients receiving the triplet therapy achieved a DOR of 17.5 months (95% CI, 8.8-NE), while the ORR reached 50% in this group. Conversely, the doublet regimen of gedatolisib and fulvestrant delivered an ORR of 28.3%, with a median DOR of 12.0 months (95% CI, 8.1-NE). In the monotherapy arm with fulvestrant alone, the ORR was notably low at 1.0%, highlighting the efficacy of the combination treatments.

Dr. Sara A. Hurvitz, senior vice president and director of the Clinical Research Division at Fred Hutch, emphasized the significance of these findings, stating, “VIKTORIA-1 is the first study to demonstrate a statistically significant and clinically meaningful improvement in progression-free survival with PAM inhibition in patients with PIK3CA wild-type disease, all of whom received prior CDK4/6 inhibitor.”

The tolerability of gedatolisib was generally favorable, with no new safety signals reported. Among the participants, three patients in the triplet arm and four in the doublet arm discontinued treatment due to treatment-related adverse effects (TRAEs). Notably, two deaths occurred in the triplet therapy group. Adverse events of interest included stomatitis, rash, diarrhea, and hyperglycemia, occurring at varying rates across the treatment arms.

Investigating the PAM Pathway

The PAM pathway is crucial in driving breast cancer growth and contributing to resistance against endocrine and CDK4/6 inhibitors. Current therapies primarily target patients with activated PI3K pathways, leaving a significant unmet need for those with wild-type disease. Dr. Hurvitz pointed out that therapeutic efforts to block the PAM pathway have previously been hampered by toxicity issues. “Most available therapies target a single component of the pathway and have modest efficacy limited to biomarker-selected patient populations,” she explained.

The objective of the VIKTORIA-1 trial was to assess the effectiveness of gedatolisib in combination with fulvestrant and palbociclib as a second-line therapy for patients who had experienced disease progression. The study’s design involved randomizing 392 patients into three groups, with options for cross-over to other treatment arms upon progression. Eligibility criteria included having measurable disease and a screening result for PIK3CA status.

Dr. Igor Gorbatchevsky, chief medical officer of Celcuity, expressed optimism regarding the trial’s results, stating, “We are very excited that treatment with gedatolisib combined with fulvestrant with or without palbociclib was well-tolerated by the VIKTORIA-1 patients.” He noted that the incremental improvements in median PFS offered potentially transformative outcomes for patients with HR-positive, HER2-negative, PIK3CA wild-type advanced breast cancer.

Looking ahead, a rolling new drug application (NDA) has been submitted to the FDA in conjunction with the agency’s Real-Time Oncology Review Program. The NDA is anticipated to be finalized before the end of 2025, with topline data from the trial expected in the first half of 2026. Additionally, the phase 3 VIKTORIA-2 trial is currently underway to evaluate gedatolisib in the frontline treatment setting, further exploring its potential impact on advanced breast cancer management.