Lerociclib/Fulvestrant Improves PFS, Tolerability in HR+/HER– Breast Cancer

The PFS benefit with lerociclib plus fulvestrant was observed across all patient subgroups for those with HR–positive/HER2–negative advanced breast cancer.

Selective oral CDK4/6 inhibitor lerociclib (GB491) plus fulvestrant (Faslodex) elicited a greater progression-free survival (PFS) benefit and tolerability compared with placebo plus fulvestrant in patients with hormone receptor (HR)–positive/HER2–negative locally advanced or metastatic breast cancer who have progressed on prior endocrine therapy (ET), according to findings from the phase 3 LEONARDA-1 trial (NCT05054751) published in Nature Communications.¹

Efficacy findings from the trial revealed that the pre-specified primary end point was met, with the investigational regimen associated with a median PFS of 11.07 months vs 5.49 months in the placebo arm (HR, 0.451; 95% CI, 0.311-0.656; P = .000016). Blinded-independent committee review (BICR) assessment confirmed this finding (HR, 0.353; 95% CI, 0.228-0.547; P = .000002).

PFS improvement with lerociclib was observed across all patient subgroups. This included notable benefits observed with having received 1 prior line of chemotherapy for recurrent or metastatic disease (HR, 0.286; 95% CI, 0.138-0.593), 4 or more metastatic sites (HR, 0.326; 95% CI, 0.160-0.665), primary ET resistance (HR, 0.374; 95% CI, 0.182-0.769), being pre- or perimenopausal (HR, 0.471; 95% CI, 0.258-0.860), and having liver metastasis (HR, 0.487; 95% CI, 0.297-0.796).

“[L]erociclib, given at a dosage of 150 mg twice daily on a continuous schedule and in combination with fulvestrant, significantly improved PFS with a tolerable safety profile compared with placebo plus fulvestrant,” Binghe Xu, MD, director of the National Clinical Research Center for New Anticancer Drugs, tenured professor, and former director in the Department of Medical Oncology at the Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College, wrote in the publication with study coinvestigators.¹ “These findings support the application of lerociclib plus fulvestrant as a treatment option for patients with [HR-positive/HER2-negative advanced breast cancer] whose disease had progressed on prior ET.”

A total of 275 patients were randomly assigned 1:1 to receive lerociclib plus fulvestrant (n = 137) or placebo plus fulvestrant (n = 138). Patients in the lerociclib arm received 150 mg of lerociclib twice daily with food plus 500 mg of intramuscular fulvestrant on day 1 of each 28-day cycle, with an additional fulvestrant dose received on day 15 of cycle 1. Patients in the placebo arm received placebo at an equivalent dosage with the same fulvestrant regimen.

Patients in the investigational and placebo arms were predominantly younger than 65 (87.6% vs 86.2%), had an ECOG performance status of 0 or 1, and had a visceral metastasis (64.2% vs 62.3%).Additionally, across both cohorts, all patients had previous ET resistance, with 25.5% displaying primary resistance. Most patients received prior relapsed/metastatic phase chemotherapy (92.4%), 29.1% received frontline chemotherapy, and 43.3% were pre- or perimenopausal.

The trial’s primary end point was investigator-assessed PFS.² The trial’s secondary end points included BICR-assessed PFS, overall survival (OS), objective response rate (ORR), duration of response (DOR), disease control rate (DCR), safety and tolerability, and pharmacokinetics (PK).

Additional efficacy results revealed that the ORR was 23.4% (95% CI, 16.27%-30.44%) with the investigational regimen vs 8.7% (95% CI, 3.99%-13.40%) with placebo, with 2.2% and 0% of patients achieving complete responses in the respective arms. Although OS data were immature, 6.6% and 9.4% of patients in the respective arms had died as of data cutoff (HR, 0.630; 95% CI, 0.267-1.484).

Any-grade adverse events (AEs) occurred in 98.5% of the lerociclib arm and 80.4% of the placebo arm. Additionally, grade 3 or higher or serious AEs occurred in 57.7% and 5.8% vs 15.2% and 8.0%, respectively. AEs leading to treatment discontinuation or death occurred in 1 patient each in the lerociclib arm and did not occur in the placebo arm.

References

1. Xu B, Zhang Q, Luo Y, et al. Lerociclib plus fulvestrant in patients with HR+/HER2− locally advanced or metastatic breast cancer who have progressed on prior endocrine therapy: LEONARDA-1 a phase III randomized trial. Nat Commun. 2025;16(1):716. doi:10.1038/s41467-025-56096-2
2. GB491 combined with fulvestrant for HR+ HER2- locally advanced or metastatic breast cancer. ClinicalTrials.gov. Updated October 10, 2024. Accessed January 21, 2025. https://tinyurl.com/4td33bjv