Resistance to first-line (1L) endocrine therapy (ET) and cyclin-dependent kinase (CDK)4/6 inhibitors in hormone receptor (HR)-positive/HER2-negative advanced breast cancer (ABC) is common, with dysregulation of the PI3K/AKT/mTOR (PAM) pathway being a likely mechanism of resistance. Gedatolisib, a pan-PAM pathway inhibitor, has the potential to restore therapeutic sensitivity and enhance efficacy compared with selective inhibitors of PI3Kα, AKT, or mTORC1 alone. This article summarizes the phase 3 VIKTORIA-1 (NCT055001886) trial evaluating gedatolisib-based therapies in patients with HR-positive/HER2-negative/PIK3CA wild-type (WT) ABC.
The VIKTORIA-1 trial was a randomized, open-label, phase 3 study enrolling patients with HR-positive/HER2-negative ABC who experienced progression on or after CDK4/6 inhibitors and aromatase inhibitor (AI) treatment. PIK3CA mutational status was assessed, and 392 patients with PIK3CA WT disease were randomized to receive 1 of the following regimens in 28-day cycles: gedatolisib/palbociclib/fulvestrant (triplet; n=131), gedatolisib/fulvestrant (doublet; n=130), or fulvestrant monotherapy (n=131). Treatment doses were as follows: gedatolisib 180 mg intravenously weekly for 3 weeks of each cycle, palbociclib 125 mg orally once daily for 21 days, and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1, then every 28 days. Co-primary endpoints were progression-free survival (PFS), assessed by blinded independent central review, comparing the triplet versus fulvestrant and the doublet versus fulvestrant. Secondary endpoints included overall response rates (ORR), overall survival (OS), and safety. Statistical analyses were performed using a stratified log-rank test.
At the data cutoff (May 30, 2025), the median follow-up was 10.1 months (interquartile range, 6.6-15.1). The study met both primary endpoints. Median PFS was significantly improved with the triplet compared with fulvestrant monotherapy (9.3 vs 2.0 months; adjusted hazard ratio, 0.24; 95% confidence interval [CI], 0.17-0.35; P<.0001) and with the doublet compared with fulvestrant (7.4 vs 2.0 months; adjusted hazard ratio, 0.33; 95% CI, 0.24-0.48; P<.0001). PFS benefits were consistent across all prespecified subgroups. ORR was higher with the triplet (32%, including 1 complete response) and the doublet (28.3%) compared with fulvestrant (1%). Interim OS analysis showed a trend favoring the gedatolisib combinations, with adjusted hazard ratios of 0.69 (95% CI, 0.43-1.12; P=.1328) for the triplet and 0.74 (95% CI, 0.46-1.19; P=.2122) for the doublet. At the data cutoff, 99 patients (25.3%) across the arms died. There were 30 (22.9%) deaths in the gedatolisib triplet arm, 32 (24.6%) deaths in the gedatolisib doublet arm, and 37 (28.2%) deaths in the fulvestrant arm.
The safety profiles of the gedatolisib-containing regimens were consistent with the known profiles of the individual agents. Rates of treatment-related adverse events (TRAEs) leading to discontinuation were low (2.3% for the triplet and 3.1% for the doublet). Hyperglycemia was the most common treatment-emergent adverse event of interest, occurring in 9.2% and 11.5% of patients in the triplet and doublet arms, respectively. Grade 3 neutropenia was the most common TRAE in the triplet arm (52.3%) and stomatitis was the most common TRAE in the doublet arm (12.3%).
The VIKTORIA-1 trial demonstrated that the addition of gedatolisib to fulvestrant, with or without palbociclib, significantly improved PFS compared with fulvestrant monotherapy in patients with HR-positive/HER2-negative/PIK3CA WT ABC who progressed following CDK4/6 inhibitors and AI treatment. Gedatolisib-based combination therapy was associated with a manageable safety profile and a low rate of treatment discontinuation due to TRAEs. These findings support gedatolisib combinations as a potential new standard of care for second-line treatment in this patient population.
Source: Hurvitz SA, Layman RM, Curigliano G, et al. Gedatolisib (geda) + fulvestrant ± palbociclib (palbo) vs fulvestrant in patients (pts) with HR+/HER2-/PIK3CA wild-type (WT) advanced breast cancer (ABC): first results from VIKTORIA-1. Presented at: ESMO Congress 2025. October 18, 2025; Berlin, Germany. Abstract LBA17.