FDA Accepts Gedatolisib for Real-Time Review in HR+/HER2– Advanced Breast Cancer

The US FDA has agreed to review a new drug application (NDA) for gedatolisib, an investigational multitarget pan-PI3K and mTORC1/2 inhibitor, under its Real-Time Oncology Review (RTOR) program.¹

This action follows positive topline data from the phase 3 VIKTORIA-1 trial (NCT05501886), which demonstrated clinically meaningful and statistically significant improvements in progression-free survival (PFS) for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–), PIK3CA wild-type advanced breast cancer whose disease has progressed on or after prior CDK4/6 inhibitor therapy.

“On the heels of announcing positive pivotal data last month, we are pleased that the FDA agreed to review our NDA application for gedatolisib under the RTOR program,” said Brian Sullivan, CEO and co-founder of Celcuity, in a press release. “Gedatolisib previously received both breakthrough therapy and fast track designations based on our promising preliminary clinical data. The FDA’s decision further highlights the urgent need for more efficacious therapies than those currently available for patients with HR+, HER2– advanced breast cancer who have received prior treatment with a CDK4/6 inhibitor. We look forward to working with the FDA to complete the review of our NDA for gedatolisib.”

The pivotal data from the VIKTORIA-1 trial, announced last month, established new benchmarks for this patient population, which has historically had limited treatment options following CDK4/6 inhibitor failure. The company plans to initiate a rolling submission of the NDA in September 2025, with a targeted completion by the fourth quarter of the same year. The RTOR program facilitates a more efficient review process, allowing for earlier evaluation of efficacy and safety data for drugs that have the potential to offer substantial improvements over existing therapies.

In-Depth Analysis of VIKTORIA-1 Trial Efficacy and Safety Data

The VIKTORIA-1 trial was a randomized, open-label phase 3 study evaluating gedatolisib in combination with fulvestrant, with or without palbociclib (Ibrance), against standard-of-care fulvestrant monotherapy in a heavily pretreated patient cohort.² The trial’s primary endpoints were met for both the gedatolisib triplet and doublet regimens in the PIK3CA wild-type population.

The gedatolisib triplet regimen reduced the risk of disease progression or death by 76% (HR, 0.24; 95% CI, 0.17–0.35; P <.0001) compared with fulvestrant monotherapy. This combination resulted in a median PFS of 9.3 months, a significant increase from the 2.0 months observed in the fulvestrant control arm.

Similarly, the gedatolisib doublet regimen, which included gedatolisib and fulvestrant, reduced the risk of disease progression or death by 67% (HR, 0.33; 95% CI, 0.24–0.48; P <.0001) relative to fulvestrant alone. The median PFS for the doublet was 7.4 months, representing a 5.4-month incremental improvement.

Safety and tolerability data from the trial were also favorable. The most common adverse events, such as hyperglycemia and stomatitis, were reported at lower rates than expected, suggesting a manageable safety profile that could enhance patient compliance and treatment duration.

Mechanism of Action and Clinical Significance

Gedatolisib's unique mechanism of action as a pan-PI3K and mTORC1/2 inhibitor offers a comprehensive blockade of the PI3K/AKT/mTOR (PAM) pathway. This pathway is a critical driver of proliferation and survival in many cancers, including HR+/HER2– breast cancer. Existing PI3K inhibitors often target only the PI3Kα isoform, which can lead to a compensatory cross-activation of uninhibited targets and subsequent resistance. By targeting all 4 class I PI3K isoforms, mTORC1, and mTORC2, gedatolisib is designed to circumvent these resistance mechanisms and maintain more robust pathway suppression.

The clinical data from the VIKTORIA-1 trial support this differentiated mechanism. The pronounced efficacy in the PIK3CA wild-type cohort is particularly significant, as this patient group represents approximately 60% of HR+/HER2– advanced breast cancer cases and has not benefited from PI3Kα-specific inhibitors like those approved for PIK3CA-mutant disease. The substantial PFS improvements seen with gedatolisib, even in patients whose tumors are not driven by the PIK3CA mutation, suggest that its comprehensive PAM pathway inhibition is effective at a broader level.

FAQs

What is gedatolisib and what is its purpose?

Gedatolisib is an investigational multitarget pan-PI3K and mTORC1/2 inhibitor. Its purpose is to treat hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–), PIK3CA wild-type advanced breast cancer, particularly in patients whose disease has progressed after prior CDK4/6 inhibitor therapy. It aims to offer a more efficacious treatment option for this patient population.

What significant results did the VIKTORIA-1 trial show for gedatolisib?

The VIKTORIA-1 trial demonstrated clinically meaningful and statistically significant improvements in progression-free survival (PFS) for patients treated with gedatolisib. Specifically, the gedatolisib triplet regimen (with fulvestrant and palbociclib) reduced the risk of disease progression or death by 76% compared with fulvestrant monotherapy, with a median PFS of 9.3 months vs 2.0 months. The gedatolisib doublet regimen (with fulvestrant) reduced this risk by 67%, resulting in a median PFS of 7.4 months.

How does gedatolisib's mechanism of action differ from other PI3K inhibitors?

Gedatolisib is a pan-PI3K and mTORC1/2 inhibitor, meaning it comprehensively blocks the PI3K/AKT/mTOR (PAM) pathway. Unlike existing PI3K inhibitors that often target only the PI3Kα isoform, which can lead to resistance, gedatolisib targets all four class I PI3K isoforms, mTORC1, and mTORC2. This broader inhibition is designed to overcome resistance mechanisms and maintain more robust pathway suppression, making it effective even in PIK3CA wild-type cases.

What is the significance of gedatolisib being reviewed under the FDA's Real-Time Oncology Review (RTOR) program?

The FDA's Real-Time Oncology Review (RTOR) program facilitates a more efficient and expedited review process. This designation for gedatolisib indicates that the FDA recognizes the potential for this drug to offer substantial improvements over existing therapies for HR+/HER2– advanced breast cancer, highlighting an urgent unmet medical need in this patient population. Gedatolisib also previously received breakthrough therapy and fast track designations, further emphasizing its potential impact.

This article was generated with assistance from Google Gemini and NotebookLM. It was edited and reviewed by Targeted Oncology staff. If you have any questions about the use of AI, please contact us.

REFERENCES:

1. Celcuity to Initiate NDA Submission of Gedatolisib in PIK3CA Wild-Type Cohort in HR+/HER2- Advanced Breast Cancer Under FDA’s Real-Time Oncology Review Program. News release. Celcuity Inc. August 27, 2025. Accessed August 28, 2025. https://tinyurl.com/bdes6m8k

2. Celcuity Announces Clinically Meaningful Improvement in Both Progression-Free Survival (“PFS”) Primary Endpoints from PIK3CA Wild-Type Cohort of Phase 3 VIKTORIA-1 Trial. News release. Celcuity Inc. July 28, 2025. Accessed July 29, 2025. https://tinyurl.com/5n7px38n