Gedatolisib Plus Faslodex Shows Efficacy in Advanced HR+ Breast Cancer

Gedatolisib plus Faslodex (fulvestrant) with or without Ibrance (palbociclib) continued to show efficacy compared to Faslodex 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.

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 six months who received the gedatolisib triplet experienced a median PFS of 9.9 months versus just 1.9 months with Faslodex monotherapy; those given the gedatolisib doublet experienced a median PFS of 7.6 months. Those with a TTP longer than 12 months who received the triplet had a median PFS of 10.7 months versus 1.9 months with the monotherapy; treatment with the doublet led to a median PFS of 9.1 months.

In those who had a TTP of longer than 18 months, the median PFS with the gedatolisib triplet was 12.4 months compared with 1.9 months with Faslodex alone; the median PFS with the gedatolisib doublet was 10 months. Lastly, in those with a TTP of longer than 24 months who received the combination versus the monotherapy, the median PFS was 12.4 months, respectively; with the gedatolisib doublet, the median PFS was 13.6 months.

“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,” Dr. Barbara Pistilli, 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. Patients received no more than two 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 (392 patients) to one of three treatment arms: gedatolisib plus Ibrance and Faslodex (arm A), gedatolisib plus Faslodex (arm B), and Faslodex alone (arm C). Gedatolisib was administered at a once weekly dose of 180 mg as part of a three-weeks-on/three-weeks-off schedule; Ibrance was given at a daily dose of 125 mg for 21 days on and 7 days off; and Faslodex was administered at 500 mg on days 1 and 15 and then every four 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 versus no), TTP on immediate prior therapy (≤6 versus >6 months), and region (US/Canada versus rest of the world).

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

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 (130 patients) and in 56.9% of those given the doublet (130 patients), and the median time to onset was 7.5 days and 4 days, 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 days to 8 days. 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 to 4.5 days.

“Most stomatitis events occurred within the first three 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 days, from grade 2 to lower was 14 days, and from grade 1 to lower was 27.5 days. In the doublet arm, the median time to improvement from grade 3, grade 2, or grade 1 to lower was 7.5 days, 9 days and 17.5 days, respectively. “Grade 2/3 [effects] generally improved to a lower grade within one to two 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, 0.6 and 0.2. “Gedatolisib did not produce clinically relevant hyperglycemia and had no dose reductions or withdrawals due to hyperglycemia,” Pistilli said.

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

“Gedatolisib plus Faslodex, with or without Ibrance, 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. The NDA was supported by findings from the PIK3CAwild-type cohort of VIKTORIA-1.

References

1. “Gedatolisib, a multitarget PI3K/AKT/mTOR inhibitor, plus Faslodex with or without Ibrance for second-line treatment of patients with HR+/HER2-/PIK3CA-WT advanced breast cancer: updated results from the randomized, phase 3 VIKTORIA-1 trial” by Dr. Pistilli, et al., San Antonio Breast Cancer Symposium.
2. “Gedatolisib plus Faslodex, with and without Ibrance, versus Faslodex in patients with HR+/HER2-/PIK3CA wild-type advanced breast cancer: first results from VIKTORIA-1” by Dr. Hurvitz, et al., ESMO Annual Congress.
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” by Celcuity, Inc., news release.

For more news on cancer updates, research and education, don’t forget to subscribe to CURE®’s newsletters here