SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 321,910 new cases of female breast cancer will be diagnosed in 2026, and about 42,140 women will die of the disease, largely due to metastatic recurrence.
Therapeutic Challenges Following CDK4/6 Inhibitor Progression
Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. The most common subtype of metastatic breast cancer is Hormone Receptor-positive (HR-positive), HER2-negative breast cancer (65% of all metastatic breast tumors). The treatment landscape for this group of patients has evolved substantially with the incorporation of CDK4/6 inhibitors in combination with endocrine therapy. However, disease progression following a CDK4/6 inhibitor and Aromatase Inhibitor remains a common clinical challenge, and the optimal approach after progression continues to evolve.
Targeting the PI3K/AKT/mTOR signaling pathway has become an established strategy in this setting, particularly for tumors harboring PIK3CA mutations. Several approved therapies, including PI3K, AKT, and mTOR inhibitors, have demonstrated clinical benefit, but each acts at a single point within the pathway. This approach may permit compensatory signaling through alternative pathway components, potentially contributing to treatment resistance. In addition, class-associated toxicities such as hyperglycemia and diarrhea can affect treatment delivery and patient experience.
Gedatolisib was developed as a comprehensive inhibitor of the PI3K/AKT/mTOR pathway. Unlike currently available agents that target individual nodes within the pathway, Gedatolisib inhibits all four class I PI3K isoforms while also targeting both mTORC1 and mTORC2. Because its activity is not dependent on a specific PIK3CA mutation, the agent has been investigated in both PIK3CA-mutated and PIK3CA wild-type disease.
VIKTORIA-1 Trial Design
The Phase 3 VIKTORIA-1 trial was designed to evaluate Gedatolisib-based regimens in patients with HR-positive, HER2-negative advanced breast cancer whose disease had progressed during or after treatment with a CDK4/6 inhibitor and an Aromatase Inhibitor. The study enrolled patients with measurable disease who had not received chemotherapy for advanced disease and had no prior exposure to PI3K, AKT, or mTOR inhibitors. Patients with PIK3CA-mutated disease were randomized in a 3:3:1 ratio to receive one of three treatment regimens:
- Gedatolisib, Palbociclib, and Fulvestrant
- Alpelisib and Fulvestrant
- Gedatolisib and Fulvestrant
Gedatolisib was administered at 180 mg IV weekly for three consecutive weeks followed by one week off treatment. Palbociclib was administered according to the standard 125 mg orally, 21-days-on, 7-days-off schedule, while Fulvestrant was administered 500 mg IM every 2 weeks in cycle 1 then every 4 weeks. Alpelisib was administered orally at 300 mg daily.
The Primary endpoint was Progression-Free Survival (PFS) comparing the Gedatolisib triplet regimen with Alpelisib plus Fulvestrant. Secondary endpoints included PFS for the Gedatolisib doublet versus Alpelisib plus Fulvestrant, Overall Survival (OS), Objective Response Rate (ORR), Duration of Response (DOR), Clinical Benefit Rate (CBR), Quality of Life (QOL) measures, pharmacokinetics, and Safety.
Progression-Free Survival Results in PIK3CA-Mutated Disease
The Primary analysis included 362 patients with PIK3CA-mutated disease and a median Progression-Free Survival follow-up of 11 months.
The trial met its Primary endpoint. Patients treated with the Gedatolisib, Palbociclib, and Fulvestrant combination experienced a median PFS of 11.1 months compared with 5.6 months for those receiving Alpelisib plus Fulvestrant. This translated into a 50% reduction in the risk of disease progression or death (Hazard Ratio [HR], 0.50; 95% confidence interval [CI], 0.37–0.68; P<0.0001).
A PFS benefit was also observed with the Gedatolisib and Fulvestrant doublet. Median PFS was 11.3 months compared with 5.6 months for Alpelisib plus Fulvestrant (HR, 0.51; 95% CI, 0.33–0.79; P=0.0013).
The magnitude of benefit observed with both Gedatolisib-containing regimens resulted in an absolute improvement in median PFS of approximately 5.5-5.7 months relative to the comparator arm.
Response Outcomes
Additional efficacy analyses demonstrated higher ORR with Gedatolisib-based therapy.
Objective Response Rates were:
- 48.9% with Gedatolisib, Palbociclib, and Fulvestrant
- 35.7% with Gedatolisib and Fulvestrant
- 26.0% with Alpelisib and Fulvestrant
Responses also appeared more durable in the Gedatolisib-containing treatment groups. Median Duration of Response was:
- 15.7 months with the Gedatolisib triplet
- 24.2 months with the Gedatolisib doublet
- 7.5 months with Alpelisib plus Fulvestrant
Overall Survival data remain immature and continue to be evaluated.
Findings Across PIK3CA Mutation Subgroups
The results from the PIK3CA-mutated cohort build on findings previously reported from the PIK3CA wild-type cohort of VIKTORIA-1.
In the wild-type population, both Gedatolisib plus Fulvestrant and Gedatolisib plus Palbociclib and Fulvestrant demonstrated significant improvements in PFS compared with Fulvestrant alone. These earlier findings suggested that comprehensive pathway inhibition may provide benefit regardless of PIK3CA mutation status.
The consistency of efficacy observed across both molecular subgroups supports further evaluation of Gedatolisib as a treatment option beyond the traditionally defined PIK3CA-mutated population.
Safety Profile
Safety analyses showed distinct differences in adverse event patterns between Gedatolisib-containing regimens and Alpelisib plus Fulvestrant.
Hyperglycemia, a commonly observed toxicity associated with PI3K inhibition, occurred less frequently in patients receiving Gedatolisib-based therapy: 15.0% with the Gedatolisib triplet, 11.5% with the Gedatolisib doublet and 57.9% with Alpelisib plus Fulvestrant. Grade 3 hyperglycemia occurred in 2.6% of patients receiving the Gedatolisib triplet, 0% receiving the Gedatolisib doublet and 13.8% receiving Alpelisib plus Fulvestrant.
Similarly, diarrhea was reported less frequently with Gedatolisib-containing regimens than with Alpelisib plus Fulvestrant.
Treatment discontinuation due to treatment-related adverse events was also less common in the Gedatolisib arms: 2.6% with the Gedatolisib triplet, 3.8% with the Gedatolisib doublet and 7.1% with Alpelisib plus Fulvestrant. In contrast, stomatitis was observed more frequently with Gedatolisib-based therapy. Grade 3 stomatitis occurred in 16.3%, 5.8%, and 5.3% of patients, respectively.
Implications for Treatment Sequencing
The VIKTORIA-1 findings contribute to ongoing discussions regarding optimal sequencing of targeted therapies after progression on first-line CDK4/6 inhibitor-based treatment.
The trial provides randomized Phase 3 evidence supporting comprehensive inhibition of the PI3K/AKT/mTOR pathway compared with approaches directed at a single pathway component. Whether Gedatolisib should be introduced immediately after progression on a CDK4/6 inhibitor or reserved for later lines of therapy following exposure to other targeted agents remains an area for further investigation. The availability of multiple pathway-directed therapies raises additional questions regarding resistance mechanisms, treatment sequencing, and patient selection that are not fully addressed by the current analysis.
Practical Considerations
A distinguishing feature of Gedatolisib is its route of administration. Unlike currently available oral PI3K, AKT, and mTOR inhibitors, Gedatolisib requires IV on a weekly schedule for three weeks of each four-week cycle. This treatment schedule introduces logistical considerations related to infusion visits, patient convenience, and healthcare resource utilization. These factors may influence treatment selection in clinical practice, particularly when multiple active therapeutic options are available.
As treatment decisions increasingly incorporate both efficacy and patient preference, the balance between clinical benefit, toxicity profile, and treatment burden will likely play a role in determining how Gedatolisib-based regimens are incorporated into routine care.
Conclusion
The Phase 3 VIKTORIA-1 trial demonstrated significant improvements in PFS with both Gedatolisib-containing regimens compared with Alpelisib plus Fulvestrant in patients with PIK3CA-mutated HR-positive, HER2-negative advanced breast cancer previously treated with a CDK4/6 inhibitor and Aromatase Inhibitor. Improvements were also observed in Objective Response Rates and Duration of Response.
The findings complement previously reported results in PIK3CA wild-type disease and support further evaluation of comprehensive PI3K/AKT/mTOR pathway inhibition across molecular subgroups. Ongoing follow-up will determine the impact on Overall Survival and help clarify the role of Gedatolisib within the evolving treatment sequence for HR-positive, HER2-negative advanced breast cancer.
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). Hurvitz SA, Curigliano G, Andre F, et al. J Clin Oncol 44, 2026 (suppl 17; abstr LBA1008)
