Editor's Note: The 2024 American Society of Clinical Oncology (ASCO) Annual Meeting concluded successfully. At this conference, two studies from Professor Xichun Hu’s team at Fudan University Shanghai Cancer Hospital were featured as a rapid oral report and a poster display. The studies are titled "ACE-Breast-02: A pivotal phase II/III trial of ARX788, a novel anti-HER2 antibody-drug conjugate (ADC), versus lapatinib plus capecitabine for HER2+ advanced breast cancer (ABC)" (Abstract 1020) and "LEONARDA-2: Lerociclib plus letrozole versus placebo plus letrozole in HR+/HER2- advanced or metastatic breast cancer" (Abstract 1052). "Oncology Frontier" invited Professor Xichun Hu to introduce the background and latest data of these studies at the conference.Study : LEONARDA-2 (Abstract 1052)
LEONARDA-2 is a randomized, double-blind, placebo-controlled phase III study that enrolled HR+/HER2- advanced or metastatic breast cancer patients who had not received prior systemic treatment for advanced disease. Patients were randomized 1:1 to receive lerociclib (150 mg twice daily) plus letrozole or placebo plus letrozole. The primary endpoint was progression-free survival (PFS) assessed by investigators. Secondary endpoints included PFS assessed by blinded independent central review (BICR), objective response rate (ORR), overall survival (OS), and safety. Interim analysis was planned after approximately 80 PFS events.
As of September 20, 2023, 279 patients were randomized (137 to the lerociclib+letrozole group and 142 to the placebo+letrozole group) with a median follow-up of 12.91 months. Baseline characteristics were similar between the groups.
With a median follow-up of 12.9 months, 83 PFS events were reported. Lerociclib+letrozole significantly improved PFS compared to placebo+letrozole (median PFS: not reached [NR] vs. 16.56 months; HR=0.464; 95% CI: 0.293-0.733; P=0.0004). BICR analysis confirmed these results (median PFS: NR vs. NR; HR=0.457; 95% CI: 0.274-0.761; P=0.0011). Subgroup benefits were consistent, including patients with visceral metastases, extensive metastatic sites, and prior (neo)adjuvant endocrine therapy. For patients with measurable disease at baseline, the ORR for lerociclib+letrozole was higher (62.3%) than for the placebo group (48.5%).
At data cut-off, OS data were immature. Adverse events (AEs) were mainly hematologic, with higher rates of grade 3-4 neutropenia (grade 3: 41.6% vs. 0.7%; grade 4: 5.1% vs. 0%) and leukopenia (grade 3: 27.0% vs. 0%; grade 4: 1.5% vs. 0%) in the lerociclib group. All neutropenia and leukopenia events were considered treatment-related. Grade 3 diarrhea was rare, with only one case (0.7%) in the lerociclib group. QTc prolongation was similar between groups (lerociclib group: 4.4%, grade 3: 1.5%; 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 (0.7% in the lerociclib group).
Researcher Commentary: Professor Xichun Hu:
At the 2024 ASCO Annual Meeting, our team presented the study on the CDK4/6 inhibitor lerociclib (Abstract 1052: LEONARDA-2: Lerociclib plus letrozole versus placebo plus letrozole in HR+/HER2- advanced or metastatic breast cancer) as a poster display. Reflecting on the 2023 ASCO meeting, Academician Binghe Xu’s team reported positive results of lerociclib/fulvestrant in second-line treatment of HR+/HER2- advanced breast cancer patients (Abstract 1017: Lerociclib/Fulvestrant May Reduce Risk of Disease Progression in Advanced HR-Positive/HER2-Negative Breast Cancer). LEONARDA-1 was the first phase III randomized controlled trial of lerociclib for HR+/HER2- recurrent or metastatic breast cancer, enrolling patients who had received at least one chemotherapy regimen including taxanes, anthracyclines, or cyclophosphamide; 29.1% had received first-line chemotherapy in the recurrent/metastatic setting. Data presented at the 2023 ASCO showed that lerociclib/fulvestrant significantly improved PFS compared to fulvestrant/placebo (HR 0.45, P<0.001).
At the 2024 ASCO, we reported the efficacy and safety of lerociclib plus letrozole versus placebo plus letrozole (LEONARDA-2 study) in first-line treatment of HR+/HER2- advanced or metastatic breast cancer patients. The results showed that lerociclib plus letrozole demonstrated excellent safety and significantly prolonged PFS in HR+/HER2- advanced or metastatic breast cancer patients, with consistent benefits across all clinical subgroups, indicating that lerociclib is a viable first-line treatment option with a favorable efficacy-risk balance.
Both the LEONARDA-1 and LEONARDA-2 studies highlight the good safety profile of lerociclib combined with endocrine therapy in HR+/HER2- breast cancer patients. This suggests the importance of choosing highly effective treatments early in the patient’s course to ensure both efficacy and safety in advanced breast cancer treatment. Ensuring patient safety and quality of life during treatment encourages more patients to continue using the drug, improving treatment adherence.
I hope lerociclib will be approved in China soon, and I look forward to head-to-head clinical trials of different CDK4/6 inhibitors to determine which is the most effective and safest, aiding clinical decision-making.
