LEONARDA-1: Phase III randomized study of lerociclib plus fulvestrant in patients with HR+, HER2- locally advanced or metastatic breast cancer that has progressed on prior endocrine therapy.

1017 Background: Lerociclib (GB491), a novel oral CDK4/6 inhibitor with continuously daily dosing, which has demonstrated anti-tumor response and a differentiated safety & tolerability profile in previous clinical trials. The LEONARDA-1 study assessed the efficacy of lerociclib and fulvestrant in endocrine-resistant advanced BC. Methods: This is a randomized, double-blind, placebo-controlled phase III study assessing lerociclib in combination with fulvestrant in pre/peri-menopausal or postmenopausal, HR+, HER2- locally advanced or metastatic BC patients (pts) who had relapsed or progressed on prior endocrine therapy (ET). Eligible patients were allowed one prior line of chemotherapy for metastatic disease. Pre-/peri-menopausal pts also received goserelin. Pts were randomized 1:1 to receive lerociclib (150mg po bid, d1-28, q4w) or placebo (P) plus fulvestrant (F). The primary endpoint was investigator-assessed progression-free survival (PFS) based on RECIST v1.1. Secondary endpoints included PFS (assessed by BICR), overall survival (OS), response assessment, safety and tolerability, pharmacokinetic (PK) profile. Results: By December 2 nd 2022 as data cut-off date, 275 pts were randomized, 137 to receive lerociclib + F and 138 to P + F. Median follow-up time was 7.36 months (range, 0.03-11.93+) for lerociclib + F vs 7.33 months (range, 0.03-11.27) for P + F. Baseline characteristics were well balanced (The median age was 54 years and 53.5 years, 41.6%% and 44.9% were Pre/peri-menopausal, 64.2% and 62.3% had visceral disease, 24.8% and 26.1% were primary resistant to prior ET, 28.5% and 29.0% received one line of chemotherapy for metastatic disease, respectively). At the time of cut-off date, 125 PFS events were observed with a median PFS of 11.07 months for lerociclib + F and 5.49 months for P + F (HR: 0.458; 95% CI: 0.317, 0.661, P< 0.001 by log-rank test). In patients with measurable disease (n=240, 87.3%), the ORR was significantly higher in lerociclib + F 26.9% (2.5% complete response [CR]) vs 9.9% (0% CR) for P + F. Consistent benefit from lerociclib was seen in pre/peri-menopausal and postmenopausal subjects. The most common adverse events (AEs) for lerociclib + F versus P + F were neutropenia (90.5% vs. 4.3%), leucopenia (86.9% vs. 6.5%), anemia (34.3% vs. 10.1%), thrombocytopenia (19.7% vs. 3.6%), and diarrhea (19.7% vs. 3.6%). Grade 3 or 4 neutropenia was reported in 46.7% pts on lerociclib + F (G3: 41.6%, G4: 5.1%) vs 0% pts on P + F. There was no case of ≥Grade3 diarrhea reported. The discontinuation rate due to AEs was 0.7% on lerociclib + F and 0% on P + F. Serious AEs were reported for 5.8% and 8.0%, respectively. Conclusions: Lerociclib at 150mg twice daily plus fulvestrant significantly improved PFS and ORR and demonstrated a favorable tolerable safety profile in pts with HR+ / HER2- endocrine-resistant advanced BC. Clinical trial information: NCT05054751 .