Ipatasertib Plus Fulvestrant Demonstrates Significant PFS Benefit in ER+/HER2– Metastatic Breast Cancer

Ipatasertib Plus Fulvestrant in ER+/HER2–

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Ipatasertib in combination with fulvestrant (Faslodex) significantly prolonged progression-free survival (PFS) compared with placebo plus fulvestrant in patients with estrogen receptor (ER)–positive, HER2-negative metastatic breast cancer following disease progression on frontline CDK4/6 inhibitor and aromatase inhibitor (AI) treatment, according to data from the phase 3 FINER trial (NCT04650581) presented during the 2025 ASCO Annual Meeting.

Findings from the final PFS analysis demonstrated that patients who received the combination in the intention-to-treat population (ITT; n = 125) achieved a median PFS of 5.32 months (95% CI, 3.58-5.62) compared with 1.94 months (95% CI, 1.84-3.22) in the placebo arm (n = 125; HR, 0.61; 95% CI, 0.46-0.81; 2-sided P = .0007). The median PFS per blinded independent central review (BICR) in the ITT population was 9.07 months (95% CI, 5.45-12.91) in the investigational arm vs 3.71 months (95% CI, 2.00-7.89) in the control arm (HR, 0.65; 95% CI, 0.46-0.93; 2-sided P = .0177).

“The ipatasertib and fulvestrant combination is generally tolerable and improved PFS in both the ITT and the AKT-altered cohort; both [findings] were statistically significant and clinically meaningful,” Stephen K.L. Chia, MD, FRCPC, said during the presentation.

Chia is a full professor of medicine and the head of the Division of Medical Oncology, Department of Medicine, at the University of British Columbia, BC Cancer Vancouver Cancer Center in Canada. He is also the head of the Department of Clinical Research and a distinguished scientist at BC Cancer and BC Cancer Research Institute, as well as the chair of the British Columbia Breast Tumor Group.

Exploring the Study Design

FINER enrolled patients with stage IV ER-positive, HER2-negative breast cancer who received prior treatment with a CDK4/6 inhibitor and an AI. Patients were required to have an ECOG performance status of 0 or 1 and measurable or evaluable disease.

Patients were randomly assigned 1:1 to receive ipatasertib or placebo, both in combination with fulvestrant. Ipatasertib was administered at a dose of 400 mg on days 1 through 21. Patients in both arms received 500 mg of intramuscular fulvestrant on days 1, 14, and 28, then every 28 days.

The primary end point was PFS per RECIST 1.1 criteria in the ITT population. Key secondary end points included PFS by BICR in the ITT population, PFS in the AKT pathway altered cohort, overall survival (OS), safety, quality of life, health economics, and correlative analyses.

The baseline characteristics were generally well balanced between the ipatasertib and placebo arms; the median ages were 60 years (range, 29-89) and 59 years (range, 33-83), respectively. Most patients in both arms were female (98.4% vs 99.2%), White (78.4% vs 85.6%), had an ECOG performance status of 0 (56% vs 60.8%), had lung and/or liver involvement (66.4% vs 66.4%), and had wild-type or unknown PIK3CA/PTEN/AKT status (54.4% vs 56.8%).

Secondary End Points Data and Safety Results

At a median follow-up of 15.2 months, additional findings from FINER showed that the median OS in the ITT population was 23.13 months (95% CI, 18.6-31.08) in the combination arm compared with 24.87 months (95% CI, 19.91-not reached) in the placebo arm (HR, 1.07; 95% CI, 0.68-1.69; 2-sided P = .75). Chia noted that the OS data were at 50% maturity for the final analysis.

The median PFS by BICR among patients with an AKT pathway alteration was 12.88 months (95% CI, 5.45-no upper bound) in the combination arm (n = 57) vs 3.68 months (95% CI, 1.91-12.68) in the placebo arm (n = 54; HR, 0.50; 95% CI, 0.29-0.87; 2-sided P = .011). The median PFS values per RECIST 1.1 criteria in these arms were 5.45 months (95% CI, 3.55-11.01) and 1.91 months (95% CI, 1.77-3.48), respectively (HR, 0.47; 95% CI, 0.31-0.72; 2-sided P = .0005).

Findings from an exploratory analysis showed that the median PFS in the ESR1 wild-type cohort (n = 128) was 5.55 months (95% CI, 3.71-12.88) in the combination arm vs 2.00 months (95% CI, 1.84-3.68) in the placebo arm (HR, 0.54; 95% CI, 0.36-0.83). The median PFS values were 3.71 months (95% CI, 2.04-5.45) and 1.87 months (95% CI, 1.77-4.24), respectively, in the ESR1-mutated cohort (n = 122; HR, 0.61; 95% CI, 0.41-0.91).

In terms of safety, the most common any-grade adverse effects (AEs) possibly attributed to ipatasertib that were reported in over 10% of patients in the investigational arm (n = 124) included diarrhea (87.1%), nausea (58.9%), hyperglycemia (43.6%), and fatigue (40.3%). The most common grade 3 AEs possibly related to ipatasertib included diarrhea (16.1%), fatigue (3.2%), vomiting (1.6%), and maculopapular rash (1.6%).

In the control arm (n = 124), the most common any-grade AEs included hyperglycemia (33.1%), fatigue (25.0%), nausea (25.0%), and diarrhea (25.0%). Grade 3 nausea (0.8%) and vomiting also occurred (0.8%).

Patients in both the ipatasertib and placebo arms discontinued therapy due to AEs related to protocol treatment (6.5% vs 0.8%, respectively), disease progression (67.7% vs 78.2%), symptomatic progression (4.0% vs 4.8%), and intercurrent illness (0.8% vs 1.6%). Four patients in the placebo arm discontinued treatment due to patient refusal not related to an AE.

“This combination provides a potential treatment option immediately post CDK4/6 and AI [disease] progression in [patients with] ER-positive, HER2-negative metastatic breast cancer,” Chia said in conclusion.

Disclosures: Chia received honoraria from AstraZeneca, Daiichi Sankyo, Gilead Sciences, Lilly, Novartis, and Pfizer. He also received research funding from AstraZeneca, Novartis, and Pfizer.

Reference

Chia SKL, Redfern A, Ayoub JP, et al. A double-blind placebo controlled randomized phase III trial of fulvestrant and ipatasertib as treatment for advanced HER2-negative and estrogen receptor positive (ER+) breast cancer following progression on first line CDK 4/6 inhibitor and aromatase inhibitor: the CCTG/BCT MA.40/FINER study (NCT04650581). J Clin Oncol. 2025;43(suppl 17):LBA1005. doi:10.1200/JCO.2025.43.17_suppl.LBA1005