In VIKTORIA-1, Gedatolisib Combos Cut Risk of Progression by Half vs Alpelisib in PIK3CA-Mutant Advanced Breast Cancer

Results from the PIK3CA-mutant cohort of the pivotal phase 3 VIKTORIA-1 trial (NCT05501886) show that a pair of gedatolisib-based regimens reduced the risk of disease progression or death by approximately 50% compared with alpelisib plus fulvestrant, which investigators described as a potential new standard of care in second-line hormone receptor–positive (HR+), HER2-negative (HER2−) advanced breast cancer.¹

The findings were presented June 2, 2026, in a late-breaking abstract oral session at the American Society of Clinical Oncology Annual Meeting by Sara A. Hurvitz, MD, principal investigator and senior vice president and director, Clincial Research Division, Fred Hutchinson Cancer Center, Seattle, Washington.^1,2

The PAM Pathway and Clinical Rationale

The PI3K/AKT/mTOR, or PAM, pathway is a key oncogenic drivery of HR+/HER2- breast cancer, and mutations in PIK3CA are common in this population.³ Currently approved PAM pathway inhibitors, which include alpelisib (a PI3Kα inhibitor), capivasertib (an AKT inhibitor), and everolimus (an mTORC1 inhibitor), target only a single node of the pathway, leaving tumors with potential escape mechanisms through cross-activation of uninhibited targets.⁴

Gedatolisib, being developed by Celcuity, is an investigational, intravenously (IV) administered, multitarget PAM inhibitor that simultaneously blocks all 4 class I PI3K isoforms, mTORC1, and mTORC2, thereby inducing comprehensive pathway suppression.⁵ Preclinical studies demonstrated superior potency and cytotoxicity for gedatolisib compared with alpelisib, capivasertib, and everolimus across both PIK3CA-mutant and wild-type breast cancer cell lines.

VIKTORIA-1 is the first phase 3 trial to directly compare 2 PAM pathway inhibitors head-to-head. The trial enrolled 701 patients regardless of PIK3CA status and evaluated patients in 2 separate cohorts. Results from the PIK3CA wild-type cohort, were previously reported,⁶ showing hazard ratios of 0.24 and 0.33 for the gedatolisib triplet and doublet, respectively, vs fulvestrant alone. The current presentation covers the PIK3CA-mutant cohort, known as Study 2.^1,2

Trial Includes Both Doublet and Triplet of Study Drug

According to the abstract,¹ eligible patients had HR+/HER2− advanced breast cancer with prior CDK4/6 inhibitor plus aromatase inhibitor therapy, no prior chemotherapy for advanced disease, no prior PAM pathway inhibitor use, measurable disease per RECIST criteria v1.1, and glycated hemoglobin A_1C below 6.5%. A total of 362 patients with confirmed PIK3CA mutations were randomly assigned 3:3:1 to the following arms¹:

• Gedatolisib triplet: gedatolisib (180 mg IV weekly, 3 weeks on/1 week off) plus palbociclib (125 mg daily, 21/7 days) plus fulvestrant 500 mg;
• Comparator: alpelisib (300 mg daily) plus fulvestrant;
• Gedatolisib doublet: gedatolisib plus fulvestrant alone.

The study’s primary end point was progression-free survival (PFS) for the gedatolisib triplet vs alpelisib/fulvestrant, assessed by blinded independent central review per RECIST criteria v1.1.^1,2

Efficacy Results Include Strongest Responses in This Population

At the March 9, 2026, data cutoff, with a median follow-up of 11.0 months, the trial met its primary end point. Median PFS for the gedatolisib triplet (n = 155) was 11.1 months vs 5.6 months for alpelisib/fulvestrant (n = 155), representing a 50% reduction in the risk of progression or death (hazard ratio, 0.50; 95% CI, 0.37-0.68; P < .0001). The gedatolisib doublet (n = 52) achieved a median PFS of 11.3 months vs 5.6 months for the comparator arm (hazard ratio, 0.51; 95% CI, 0.33-0.79; P < .0013).^1,2

Response data further distinguished the gedatolisib regimens: the triplet recorded an objective response rate (ORR) of 48.9% with a median duration of response (DOR) of 15.7 months, compared with an ORR of 26.0% and a median DOR of 7.5 months for alpelisib/fulvestrant. The gedatolisib doublet produced an ORR of 35.7% with a notably durable median DOR of 24.2 months.^1,2

According to the investigators, the median PFS of 11.1 months and ORR of 48.9% for the triplet are both the highest ever reported in a phase 3 trial for patients with HR+/HER2− advanced breast cancer receiving endocrine-based therapy in the second-line setting.²

Safety Data Show Low Discontinuation Rates

Investigators reported that the gedatolisib regimens were generally well tolerated. Treatment-related adverse event–driven discontinuation rates were low: 2.6% for the gedatolisib triplet, 3.8% for the gedatolisib doublet, and 7.1% for alpelisib/fulvestrant. A key differentiator was the substantially lower rate of hyperglycemia—a class-effect toxicity associated with PAM inhibitors—with all-grade rates of 15.0% and 11.5% for the triplet and doublet, respectively, compared with 57.9% for alpelisib/fulvestrant (grade 3 rates were 2.6%, 0.0%, and 13.8%). Stomatitis was more common with gedatolisib regimens (all-grade rates were 61.4% for the triplet and 61.5% for the doublet vs 34.2% for alpelisib/fulvestrant), although grade 3 rates were low at 16.3% and 5.8% vs 5.3% for the comparator.

“Therapies that target only PI3Kα or AKT typically offer modest benefit for patients with PIK3CA mutant HR+/HER2– advanced breast cancer whose disease has progressed while on or after treatment with a CDK4/6 inhibitor,” Hurvitz said in a statement from Celcuity. “By comprehensively blocking the PI3K/AKT/mTOR, or PAM, pathway, gedatolisib combined with fulvestrant, with or without palbociclib, showed it can offer these patients 2 times the likelihood of survival without disease progression or death relative to a single-target inhibitor of the PAM pathway.²

“With these results,” she continued, “the gedatolisib regimens, if approved, represent a new potential standard of care for patients with HR+, HER2-negative, PIK3CA mutant advanced breast cancer whose disease progressed on or after treatment with a CDK4/6 inhibitor.”²

“It is rare in oncology for a targeted therapy to offer both improved efficacy and better safety results relative to another drug in its class,” Brian Sullivan, CEO and cofounder of Celcuity, said in a statement. “This second positive phase 3 data readout further underscores the broad potential of multitarget PAM inhibition and increases our excitement about our 2 phase 3 trials in the first-line setting for HR+/HER2– advanced breast cancer.”²

In the statement, Sullivan said the company, which funded the trial, was “on track” to submit a supplemental new drug application with the FDA in the third quarter of 2026. Celcuity has previously received priority review for gedatolisib in the wild-type population, with a deadline for action of July 17, 2026.²

References

1. Hurvitz SA, Curigliano G, Andre F, 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. 2026;44(suppl 17):LBA1008. doi:10.1200/JCO.2026.44.17_suppl.LBA1008
2. Celcuity’s gedatolisib combination regimens doubled the likelihood of survival without disease progression or death compared to alpelisib plus fulvestrant in the PIK3CA mutant cohort of the pivotal phase 3 VIKTORIA-1 trial in patients with HR+/HER2- advanced breast cancer. News release. Celcuity. June 2, 2026. Accessed June 11, 2026. https://bit.ly/4ehTwrA
3. Nunnery SE, Mayer IA. Targeting the PI3K/AKT/mTOR pathway in hormone-positive breast cancer. Drugs. 2020;80(16):1685-1697. doi:10.1007/s40265-020-01394-w
4. Browne IM, Okines AFC. Resistance to targeted inhibitors of the PI3K/AKT/mTOR pathway in advanced oestrogen-receptor-positive breast cancer. Cancers (Basel). 2024;16(12):2259. doi:10.3390/cancers16122259
5. Gedatolisib is a potential first-in-class PI3K/AKT/mTOR (PAM) inhibitor. Celcuity. Accessed June 11, 2026. https://www.celcuity.com/gedatolisib/
6. Hurvitz SA, Layman RM, Curigliano G; VIKTORIA-1 Study Group. 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. 2026;44(12):1108-1119. doi:10.1200/JCO-25-02643