Gedatolisib Plus Fulvestrant ± Palbociclib Is a Potential New SOC in HR+ PIK3CA Wild-Type Advanced Breast Cancer

Gedatolisib plus fulvestrant (Faslodex) with or without palbociclib (Ibrance) continued to showcase significant efficacy vs fulvestrant alone when used as second-line treatment in patients with hormone receptor–positive, HER2-negative, PIK3CA wild-type advanced breast cancer, irrespective of duration of prior treatment, according to updated data from the phase 3 VIKTORIA-1 trial (NCT05501886).¹

Findings from additional analyses, which were shared during the 2025 San Antonio Breast Cancer Symposium, looked at progression-free survival (PFS) by time to progression (TTP) on immediate prior therapy. Those with a TTP longer than 6 months who received the gedatolisib triplet experienced a median PFS of 9.9 months (95% CI, 7.2-19.2) vs just 1.9 months (95% CI, 1.8-2.3) with fulvestrant monotherapy (HR, 0.20; 95% CI, 0.13-0.30; P < .0001); those given the gedatolisib doublet experienced a median PFS of 7.6 months (95% CI, 5.5-10.0; HR, 0.25; 95% CI, 0.17-0.37; P < .0001). Those with a TTP longer than 12 months who received the triplet had a median PFS of 10.7 months (95% CI, 7.2-19.2) vs 1.9 months (95% CI, 1.8-3.5) with the monotherapy (HR, 0.21; 95% CI, 0.15-0.31; P < .0001); treatment with the doublet led to a median PFS of 9.1 months (95% CI, 5.5-13.6; HR, 0.26; 95% CI, 0.18-0.37; P < .0001).

In those who had a TTP of longer than 18 months, the median PFS with the gedatolisib triplet was 12.4 months (95% CI, 7.0-19.3) compared with 1.9 months (95% CI, 1.8-3.5) with fulvestrant alone (HR, 0.17; 95% CI, 0.11-0.28; P < .0001); the median PFS with the gedatolisib doublet was 10.0 months (95% CI, 5.6-not evaluable [NE]; HR, 0.19; 95% CI, 0.12-0.31; P < .0001). Lastly, in those with a TTP of longer than 24 months who received the combination vs the monotherapy, the median PFS was 12.4 months (95% CI, 7.4-NE) vs 2.0 months (95% CI, 1.8-3.7), respectively (HR, 0.26; 95% CI, 0.26-0.28; P < .0001); with the gedatolisib doublet, the median PFS was 13.6 months (95% CI, 7.6-NE; HR, 0.14; 95% CI, 0.08-0.27; P < .0001).

“VIKTORIA-1 is the first study to demonstrate a statistically significant and clinically meaningful improvement in PFS with PAM inhibition in patients with PIK3CA wild-type disease, all of whom received prior CDK4/6 inhibition,” Barbara Pistilli, MD, the head of the Breast Cancer Unit at Gustave Roussy, in Villejuif, France, said in a rapid fire presentation of the data. “These additional analyses confirm the efficacy of gedatolisib irrespective of the duration of prior treatment.”

What was the design of the VIKTORIA-1 trial evaluating gedatolisib in this breast cancer population?

The study enrolled premenopausal and postmenopausal patients with hormone receptor–positive, HER2-negative, advanced breast cancer who progressed on or following CDK4/6 inhibition and a nonsteroidal aromatase inhibitor.² Patients received no more than 2 prior lines of endocrine therapy for advanced disease, were tested for PIK3CA status, and did not have prior exposure to an mTOR inhibitor, a PI3K inhibitor, an AKT inhibitor, or chemotherapy for advanced disease.

Those with PIK3CA wild-type disease were randomly assigned 1:1:1 (n = 392) to 1 of 3 treatment arms: gedatolisib plus palbociclib and fulvestrant (arm A), gedatolisib plus fulvestrant (arm B), and fulvestrant alone (arm C). Gedatolisib was administered at a once weekly dose of 180 mg as part of a 3-weeks-on/3-weeks-off schedule; palbociclib was given at a daily dose of 125 mg for 21 days on and 7 days off; and fulvestrant was administered at 500 mg on days 1 and 15 and then every 4 weeks. Those in arm C were able cross over to arms A or B when they experienced disease progression.

Stratification factors included presence of lung or liver metastases (yes vs no), TTP on immediate prior therapy (≤6 vs >6 months), and region (US/Canada vs rest of the world).

The primary end points of the study were PFS by blinded independent central review for arm A vs arm C and for arm B vs arm C. Key secondary end points comprised overall survival (OS), objective response rate (ORR), safety, and quality of life (QOL).

What data have previously been reported from VIKTORIA-1 with the gedatolisib combinations?

Data from the primary analysis of VIKTORIA-1 presented during the 2025 ESMO Congress indicated that the gedatolisib triplet (n = 131) led to a median PFS of 9.3 months (95% CI, 7.2-16.6) vs 2.0 months (95% CI, 1.8-2.3) with fulvestrant monotherapy (n = 131), translating to a 76% reduction in the risk of disease progression or death (HR, 0.24; 95% CI, 0.17-0.35; P < .0001). The gedatolisib doublet (n = 130) led to a median PFS of 7.4 months (95% CI, 5.5-9.9), which translated to a 67% reduction in the risk of disease progression or death vs single-agent fulvestrant (HR, 0.33; 95% CI, 0.24-0.48; P < .0001).

At the time of the interim analysis, immature OS data showed that the median OS with the triplet was 23.7 months (95% CI, 21.4-NE) vs 18.5 months (95% CI, 15.8-NE) with fulvestrant alone (HR, 0.69; 95% CI, 0.43-1.12; P = .1328); the median OS with the gedatolisib doublet was not reached (NR; 95% CI, NE-NE; HR, 0.74; 95% CI, 0.46-1.19; P = .2122). Additionally, ORRs of the the triplet, doublet, and monotherapy were 31.5%, 28.3%, and 1.0%, respectively; with median duration of response of 17.5 months (95% CI, 8.8-NE), 12.0 months (95% CI, 8.1-NE), and NR (95% CI, NE-NE).

What additional efficacy data were reported from the analyses shared during SABCS?

PFS was also examined by bone metastases status.¹ Findings indicated that in those with bone-only metastases, the gedatolisib triplet led to a median PFS that was NR (95% CI, 7.0-NE) vs 8.2 months (95% CI, 1.7-NE) with fulvestrant (HR, 0.30; 95% CI, 0.04-2.37; P = .2969); the gedatolisib doublet resulted in a median PFS that was also NR (95% CI, 3.5-NE; HR, 0.41; 95% CI, 0.12-1.54; P = .2098).

In those with non–bone only metastases, the gedatolisib triplet resulted in a median PFS of 9.3 months (95% CI, 5.7-16.6) vs 1.9 months (95% CI, 1.8-2.0) with fulvestrant (HR, 0.23; 95% CI, 0.16-0.33; P < .0001); the gedatolisib doublet led to a median PFS of 7.3 months (95% CI, 5.5-9.4; HR, 0.32; 95% CI, 0.23-0.45; P < .0001).

What did additional safety analysis reveal about the gedatolisib regimens?

“Stomatitis was the most frequent adverse [effect] reported in the VIKTORIA-1 trial, and I want to remind you that the study protocol recommended prophylactic use of a steroid containing mouthwash,” Pistilli noted. “The majority of patients experienced grade 1 stomatitis as the first event.”

Treatment-related stomatitis was reported in 69.2% of those given the triplet (n = 130) and in 56.9% of those given the doublet (n = 130), and the median time to onset was 7.5 days (range, 1-259) and 4.0 days (range, 1-524), respectively. Of those in the triplet arm, 57 had a grade 1 event, 24 experienced a grade 2 event, and 9 had a grade 3 event; the median time to first onset ranged from 4.0 days (range, 1-20) to 8.0 days (range, 1-259). In the doublet arm, 48 patients experienced a grade 1, 16 had a grade 2 event, and 10 had a grade 3 event with median time to first onset ranging from 3.5 days (range, 2-87) to 4.5 days (range, 1-524).

“Most stomatitis events occurred within the first 3 weeks of treatment initiation, the majority were grade 1, and very few patients experienced grade 3 stomatitis as this event,” she said.

In the triplet arm, the median time to improvement from grade 3 to lower was 12.0 days (range, 3-103), from grade 2 to lower was 14.0 days (range, 4-229), and from grade 1 to lower was 27.5 days (range, 1-402). In the doublet arm, the median time to improvement from grade 3, grade 2, or grade 1 to lower was 7.5 days (range, 2-112), 9.0 days (range, 3-41), and 17.5 days (range, 1-317), respectively. “Grade 2/3 [effects] generally improved to a lower grade within 1 to 2 weeks,” Pistilli said.

She added that median glucose levels were stable. All-grade hyperglycemia occurred in 9.2% of those who received the triplet, 11.5% of those given the doublet, and no patients who received the monotherapy. Change in median HbA1c from baseline to end of therapy in the respective arms was 0.5 (range, –1.6 to –2.9), 0.6 (range, –0.7 to –8.2), and 0.2 (range, –0.6 to 1.3). “Gedatolisib did not produce clinically relevant hyperglycemia and had no dose reductions or withdrawals due to hyperglycemia,” Pistilli said.

What was learned in terms of PROs?

The median time to definitive deterioration in EQ-5D-5L was “meaningfully delayed” with gedatolisib vs fulvestrant,” she added. In the triplet arm the median time to definitive deterioration was 23.7 months (95% CI, 6.8-NE) vs 4.0 months (95% CI, 2.8-8.2) in the monotherapy arm (HR, 0.39; 95% CI, 0.25-0.67; P = .0003); in the doublet arm, the median time to definitive deterioration was NR (95% CI, 7.1-NE; HR, 0.37; 95% CI, 0.24-0.66; P = .0003).

What is the take-home message of the updated VIKTORIA-1 data?

“Gedatolisib plus fulvestrant, with or without palbociclib, represents a potential new standard of care for patients with hormone receptor–positive, HER2-negative, PIK3CA wild-type advanced breast cancer whose disease progressed on or after treatment with a CDK4/6 inhibitor,” Pistilli concluded.

In November 2025, a new drug application seeking approval of gedatolisib for use in patients with hormone receptor–positive, HER2-negative advanced breast cancer was submitted to the FDA for review.³ The NDA was supported by findings from the PIK3CA wild-type cohort of VIKTORIA-1.

Disclosures: Pistilli disclosed receipt of consulting fees from Astrazeneca (institutional), Seagen (institutional), Gilead (institutional), Novartis (institutional), Lilly (institutional), MSD (institutional), Pierre Fabre (personal), Daiichi Sankyo (institutional/personal), and Olema (institutional). Research funding (institutional) was provided by AstraZeneca, Daiichi Sankyo, Gilead, Seagen, and MSD. Travel support was provided by AstraZeneca, Gilead, MSD, Daiichi Sankyo, Accord, and Pfizer.

References

1. Pistilli B, Layman RM, Curigliano G, et al. Gedatolisib, a multitarget PI3K/AKT/mTOR inhibitor, plus fulvestrant with or without palbociclib for second-line treatment of patients with HR+/HER2-/PIK3CA-WT advanced breast cancer: updated results from the randomized, phase 3 VIKTORIA-1 trial. Presented at: 2025 San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX. Abstract R47-04.
2. Hurvitz SA, Layman RM, Curigliano G, et al. Gedatolisib plus fulvestrant, with and without palbociclib, vs fulvestrant in patients with HR+/HER2-/PIK3CA wild-type advanced breast cancer: first results from VIKTORIA-1. Presented at: 2025 ESMO Annual Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA17.
3. Celcuity announces completion of submission of its new drug application to the US FDA for gedatolisib in HR+/HER2-/PIK3CA wild-type advanced breast cancer. News release. Celcuity, Inc. November 17, 2025. Accessed December 11, 2025. https://ir.celcuity.com/press-releases/