Lerociclib, a selective oral CDK4/6 inhibitor, combined with fulvestrant, has shown promising results in patients with hormone receptor-positive (HR+), HER2-negative (HER2-) locally advanced or metastatic breast cancer who have progressed on prior endocrine therapy (ET). The phase 3 LEONARDA-1 trial (NCT05054751) demonstrated superior progression-free survival (PFS) and a manageable safety profile compared to placebo plus fulvestrant.
Improved Progression-Free Survival
The LEONARDA-1 trial met its primary endpoint, demonstrating a median PFS of 11.07 months in the lerociclib plus fulvestrant arm compared to 5.49 months in the placebo plus fulvestrant arm (HR: 0.451; 95% CI: 0.311–0.656; P = 0.000016). A blinded independent committee review (BICR) assessment confirmed these findings (HR: 0.353; 95% CI: 0.228–0.547; P = 0.000002).
"Lerociclib, 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," wrote Binghe Xu, MD, director of the National Clinical Research Center for New Anticancer Drugs, in the study publication.
Broad Efficacy Across Subgroups
The PFS improvement with lerociclib was observed across all patient subgroups, including those with primary ET resistance (HR: 0.374; 95% CI: 0.182–0.769), liver metastasis (HR: 0.487; 95% CI: 0.297–0.796), ≥4 metastatic sites (HR: 0.326; 95% CI: 0.160–0.665), those who received one prior line of chemotherapy for recurrent or metastatic disease (HR: 0.286; 95% CI: 0.138–0.593), and pre- or perimenopausal women or men (HR: 0.471; 95% CI: 0.258–0.860).
Safety and Tolerability
The most common treatment-emergent adverse events (AEs) of any grade were neutropenia, leukopenia, and anemia. Grade 3 or higher AEs were reported in 57.7% of patients in the lerociclib arm and 15.2% in the placebo arm. The incidence of grade 3 or 4 neutropenia with lerociclib was 46.7%, with a low incidence of grade 4 (5.1%), and no febrile neutropenia was reported. Neutropenia was effectively managed through dose interruption/reduction and/or the use of granulocyte colony-stimulating factor (G-CSF), with no cases of treatment discontinuation due to neutropenia. Only one patient (0.7%) discontinued lerociclib treatment due to an AE.
Gastrointestinal toxicity, including diarrhea, nausea, and vomiting, was observed in less than 20% of patients treated with lerociclib, and no grade 3 or 4 diarrhea was reported.
Study Design and Patient Population
The LEONARDA-1 trial randomized 275 patients 1:1 to receive either 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 on day 15 of cycle 1. The primary endpoint was investigator-assessed PFS.
Across both cohorts, all patients had previous ET resistance, with 25.5% displaying primary resistance. Most patients had received prior chemotherapy in the relapsed/metastatic phase (92.4%), 29.1% received frontline chemotherapy, and 43.3% were pre- or perimenopausal.
Implications for Treatment
These findings support the application of lerociclib plus fulvestrant as a treatment option for patients with HR+/HER2- advanced breast cancer whose disease has progressed on prior ET. The combination offers a significant improvement in PFS with a manageable safety profile, addressing a critical unmet need in this patient population.
