LEONARDA-2: Lerociclib plus letrozole versus placebo plus letrozole in HR+/HER2- advanced or metastatic breast cancer.

1052 Background: Following promising outcomes in hormone receptor (HR)-positive, HER2-negative endocrine-resistant advanced breast cancer (BC) with lerociclib plus fulvestrant, this study assesses the efficacy and safety of lerociclib and letrozole in HR+/HER2- advanced or metastatic BC. Methods: This randomized, double-blind, placebo-controlled phase III study involved HR+/HER2- advanced or metastatic BC patients without prior systemic therapy for advanced disease. Participants were allocated 1:1 to either lerociclib (150mg twice daily) with letrozole or placebo with letrozole. The primary endpoint was progression-free survival (PFS) as assessed by investigators. Secondary endpoints included PFS (assessed by Blinded Independent Central Review (BICR)), response rates, overall survival (OS), and safety. The interim analysis was planned approximately 80 PFS events. Results: By September 20, 2023, 279 patients were randomized (137 to lerociclib + letrozole, 142 to placebo + letrozole), with a median follow-up of 12.91 months. Baseline characteristics were comparable across groups. At the data cutoff, 83 PFS events were reported. The lerociclib significantly improved PFS versus placebo (median: not reached (NR) versus 16.56 months; hazard ratio: 0.464; 95% CI: 0.293-0.733; p=0.0004). BICR analysis confirmed these results (median: NR versus NR; hazard ratio: 0.457; 95% CI: 0.274-0.761; p=0.0011). Subgroup benefits were consistent, including in patients with visceral metastases, extensive metastatic sites and previous (neo)adjuvant endocrine therapy, etc. For patients with measurable disease, lerociclib plus letrozole showed a higher objective response rate (62.3%) compared to placebo group (48.5%). OS data were immature at the cutoff. Adverse events were primarily hematological toxicity, with higher incidences of grade 3/4 neutropenia (grade 3: 41.6% vs. 0.7%; grade 4: 5.1% vs. 0%) and leucopenia (grade 3: 27.0% vs. 0%; grade 4: 1.5% vs. 0%) in the lerociclib group. All of neutropenia and leukopenia were considered to be treatment related. Grade 3 diarrhea was infrequent, only 1 case (0.7%) was reported in lerociclib group. QTc prolongation was reported comparable between lerociclib group (4.4%, Grade 3:1.5%) and placebo group (3.5%, Grade 3:0.7%). No venous thromboembolism was reported. Serious AEs were slightly higher in the lerociclib group (13.1% vs. 7.7%). Treatment discontinuation due to AEs was rare (1 patient [0.7%]) with lerociclib. Conclusions: Lerociclib with letrozole had an excellent safety profile and significantly prolonged PFS in HR+/HER2- advanced or metastatic BC patients. This benefit was consistent across all clinically relevant subgroups, suggesting lerociclib as a viable first-line therapeutic option with a favorable benefit-risk balance. Clinical trial information: CTR20212139; NCT05851014.