Gedatolisib Combinations Double PFS in PIK3CA-Mutant Breast Cancer

Multi-target inhibition of the PI3K/AKT/mTOR (PAM) pathway significantly improves clinical outcomes compared with single-target standard therapy for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2–) advanced breast cancer harboring PIK3CA mutations, according to data from the phase 3 VIKTORIA-1 study (NCT05501886).¹

The findings, presented by Sara A. Hurvitz, MD, at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, demonstrated a near-doubling of median progression-free survival (mPFS) when evaluating the novel agent gedatolisib in combination with fulvestrant (Faslodex), with or without the CDK4/6 inhibitor palbociclib (Ibrance). In addition to enhanced efficacy, the gedatolisib-based regimens demonstrated a superior safety and tolerability profile compared with the current single-target standard of care, alpelisib (Piqray) plus fulvestrant, marked by lower rates of severe hyperglycemia and diarrhea.

Primary Efficacy Outcomes

The randomized, open-label, international trial evaluated 362 pre- and postmenopausal patients with PIK3CA-mutated advanced breast cancer whose disease had progressed on or after a CDK4/6 inhibitor plus a non-steroidal aromatase inhibitor. The trial met its primary end point by demonstrating a profound reduction in the risk of disease progression or death.

The gedatolisib triplet arm (gedatolisib plus palbociclib and fulvestrant; n = 155) achieved a median PFS of 11.1 months, compared with 5.6 months in the control arm of alpelisib plus fulvestrant (n = 155). This translated to a statistically significant 50% reduction in the risk of progression or death (HR, 0.50; 95% CI, 0.37-0.68; P <.0001).

Concurrently, the secondary end point evaluating the gedatolisib doublet (gedatolisib plus fulvestrant; n = 52) demonstrated a nearly identical clinical benefit, yielding a median PFS of 11.3 months compared with the 5.6 months observed with alpelisib plus fulvestrant (HR, 0.51; 95% CI, 0.33-0.79; P =.0013). Prespecified subgroup analyses confirmed that this survival benefit was highly consistent across key patient demographics, including age, menopausal status, geographic distribution, and the presence of aggressive visceral or liver metastases.

Secondary Response Metrics and Survival

The comprehensive multi-target inhibition of the PAM pathway also translated into superior tumor response metrics. Blinded independent central review (BICR) confirmed that the gedatolisib triplet nearly doubled the objective response rate (ORR) relative to the control arm, achieving 48.9% vs 26.0%, respectively. The gedatolisib doublet elicited an ORR of 35.7%.

The median duration of response (DOR) was notably prolonged in the investigational arms, reaching 15.7 months with the triplet and 24.2 months with the doublet, compared with 7.5 months for the alpelisib group. At the preplanned interim analysis (data cut-off March 9, 2026), overall survival (OS) data remained immature at 45.8% maturity. Median OS was not reached in the triplet arm (HR, 0.76 vs control) and was 22.8 months in the doublet arm (HR, 0.93 vs control), while the control arm demonstrated a median OS of 31.1 months.

Safety and Tolerability Profiles

Gedatolisib, a highly potent intravenous pan-PI3K and mTORC1/2 inhibitor, bypassed several class-effect toxicities commonly associated with selective single-node pathway inhibitors. Discontinuation rates secondary to treatment-related adverse events were substantially lower in the investigational arms (2.6% for the triplet and 3.8% for the doublet) than in the alpelisib arm (7.1%).

Notably, the incidence of any-grade hyperglycemia was drastically reduced with gedatolisib, occurring in 15% of the triplet cohort and 11.5% of the doublet cohort, compared with 57.9% in the alpelisib arm. Diarrhea followed a similar trend, reported in 15% of triplet and 9.6% of doublet patients, compared with 40.1% of those receiving alpelisib. Stomatitis represented the most frequent adverse event associated with gedatolisib, occurring in approximately 61% of patients across both investigational arms. Any-grade neutropenia occurred predominantly in the triplet cohort (63.4% total; 47.7% grade 3), driven by the concomitant administration of palbociclib.

Clinical Implications

The underlying biologic rationale for these findings rests on the pivotal role of the PAM pathway as a primary engine of endocrine and CDK4/6 inhibitor resistance in HR+/HER2– advanced breast cancer. While alpha-specific PI3K inhibitors like alpelisib block a single node, feedback loops and parallel pathway activation frequently blunt their efficacy and induce severe, off-target metabolic toxicities.

By comprehensively targeting pan-PI3K along with both mTORC1 and mTORC2 complexes, gedatolisib achieves more absolute vertical pathway suppression. The data from VIKTORIA-1 Study 2 validate this multi-target mechanism in the biomarker-selected PIK3CA-mutant population. Clinically, the combination of gedatolisib plus fulvestrant, with or without palbociclib, offers a highly effective and significantly more tolerable therapeutic option, positioning it to shift the post-CDK4/6 inhibitor standard of care for this difficult-to-treat patient population.

Data published in the Journal of Clinical Oncology in March 2026 showed that gedatolisib also yielded clinically meaningful and statistically significant improvements in PFS vs fulvestrant monotherapy in patients with PIK3CA wild-type disease.²

"The VIKTORIA-1 trial validates the PAM pathway as a molecular driver in [HR+/HER2–] advanced breast cancer, regardless of PIK3CA mutation status," concluded Hurvitz.

REFERENCES

1. Hurvitz SA et al. A randomized, open-label, phase 3 study of gedatolisib + fulvestrant ± palbociclib vs standard of care in HR+/HER2−/PIK3CA-mutant (MT) advanced breast cancer (VIKTORIA-1 Study 2). J Clin Oncol. 44, 2026 (suppl 17; abstr LBA1008). doi: 10.1200/JCO.2026.44.17_suppl.LBA1008

2. 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