Gedatolisib Doublet, Triplet Regimens Improve PFS in Patients With PIK3CA Wild-Type HR+/HER2– Breast Cancer

Gedatolisib (PF-05212384; Celcuity, Inc) yielded clinically meaningful improvements progression-free survival (PFS) as a doublet therapy with fulvestrant (Faslodex; AstraZeneca) and as a triplet therapy with palbociclib (Ibrance; Pfizer Inc) and fulvestrant in patients with hormone receptor-positive (HR+)/HER2-negative (HER2–), PIK3CA wild-type locally advanced or metastatic breast cancer. These topline results are from the phase 3 VIKTORIA-1 clinical trial (NCT05501886).¹

Breast cancer cells | Image Credit: © sknab - stock.adobe.com

The HR+/HER2– breast cancer subtype is one of the most common subtypes, accounting for approximately 70% of all cases. It is marked by aggressive, challenging disease with a high-risk of recurrence.²

“Patients with [HR+/HER2–] PIK3CA wild-type advanced breast cancer whose disease has progressed while on, or after, treatment with a CDK4/6 inhibitor typically derive limited benefit from subsequent endocrine-based therapy,” explained Sara Hurvitz, MD, Senior Vice President, Clinical Research Division, Fred Hutchinson Cancer Center, Professor and Head, Division of Hematology and Oncology, University of Washington, Department of Medicine, and co-principal investigator for the trial, in a press release. “The topline data for both gedatolisib regimens from VIKTORIA-1 are potentially practice-changing. To my knowledge, we have not seen phase 3 results in patients with [HR+/HER2–] advanced breast cancer before where there was a quadrupling of the likelihood of survival without disease progression relative to the study control.”³

Gedatolisib is an investigational, multi-target PAM inhibitor that potently targets all 4 class I PI3K isoforms, mTORC1, and mTORC2 to induce inhibition of the PAM pathway. Its ability to target multiple components makes gedatolisib’s mechanism of action unique from existing approved single-target PAM inhibitors. When only one PAM component is blocked, the unregulated targets cross-activate, providing tumors with a means of escape. Gedatolisib's complete blockage of the PAM pathway guarantees complete suppression of PAM activity by removing the adaptive resistance cross-activation that single-target inhibitors cause.³

Gedatolisib’s efficacy and safety were demonstrated in the phase 3, open-label, randomized VIKTORIA-1 trial evaluating gedatolisib plus fulvestrant with or without palbociclib for the treatment of patients with locally advanced or metastatic HR+/HER2- breast cancer following progression on or after CDK4/6 and aromatase inhibitor therapy. The primary end point is PFS, with secondary outcomes including overall survival, overall response rate, and duration of response.^1,3

Patients receiving the triplet therapy (gedatolisib plus palbociclib and fulvestrant) were treated with gedatolisib at a dosage of 180 mg weekly for 3 weeks (days 1, 8, 15) followed by 1 week off, palbociclib at a dosage of 125 mg given orally daily for 3 weeks (21 days), followed by 1 week off, and fulvestrant at a dosage of 500 mg IM (2 × 5 mL injections) given every 2 weeks during cycle 1 (days 1 and 15), then every 4 weeks beginning with cycle 2 day 1. Patients on the doublet therapy received gedatolisib and fulvestrant at the same doses as the group on the triple regimen but without palbociclib.¹

The gedatolisib triplet significantly improved PFS, reducing the risk of disease progression or death by 76% compared with fulvestrant alone (HR 0.24; 95% CI, 0.17–0.35; P < .0001). Median PFS was 9.3 months with the triplet regimen versus 2.0 months with fulvestrant, representing a 7.3-month improvement.³

The gedatolisib doublet also showed a statistically significant and clinically meaningful improvement in PFS, lowering the risk of disease progression or death by 67% compared with fulvestrant (HR 0.33; 95% CI, 0.24–0.48; P < .0001). Median PFS was 7.4 months with the doublet versus 2.0 months with fulvestrant, reflecting a 5.4-month gain.³

“The topline data from VIKTORIA-1 demonstrate the potential for gedatolisib to become a transformative new medicine for the treatment of patients with [HR+/HER2–] PIK3CA wild-type advanced breast cancer whose disease progressed on or after treatment with CDK4/6 inhibitors,” Igor Gorbatchevsky, MD, Chief Medical Officer of Celcuity, said in a press release. “The 7.3 and 5.4-months incremental improvement in median PFS relative to fulvestrant for the gedatolisib regimens are potentially paradigm shifting results. We are also very excited that treatment with gedatolisib combined with fulvestrant with or without palbociclib was well-tolerated by the VIKTORIA-1 patients and that only a few patients discontinued treatment due to an adverse event.”²

REFERENCES

1. Gedatolisib plus fulvestrant with or without palbociclib vs standard-of-care for the treatment of patients with advanced or metastatic HR+/​HER2- breast cancer (VIKTORIA-1) (VIKTORIA-1). Updated June24, 2025. Accessed July 29, 2025. https://clinicaltrials.gov/study/NCT05501886#study-plan

2. Cancer stat facts: Female breast cancer subtypes. National Cancer Institute. Updated July 29, 2025. https://seer.cancer.gov/statfacts/html/breast-subtypes.html

3. Celcuity announces clinically meaningful improvement in both progression-free survival (“PFS”) primary endpoints from PIK3CA wild-type cohort of phase 3 VIKTORIA-1 trial. Globe Newswire. July 28, 2025. Accessed July 29, 2025. https://www.globenewswire.com/news-release/2025/07/28/3122331/0/en/Celcuity-Announces-Clinically-Meaningful-Improvement-in-Both-Progression-Free-Survival-PFS-Primary-Endpoints-from-PIK3CA-Wild-Type-Cohort-of-Phase-3-VIKTORIA-1-Trial.html