Efficacy and safety of SPH4336 plus endocrine therapy in HR-positive/HER2-negative metastatic breast cancer with brain metastases: A multicenter, single-arm, phase II study.

1076 Background: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors plus endocrine therapy are standard first-line treatment for HR-positive/HER2-negative (HR + /HER2 - ) metastatic breast cancer (MBC). However, patients with brain metastases have poor prognosis and limited treatment options due to inadequate blood-brain barrier penetration of most agents and limited evidence for intracranial efficacy. SPH4336, a novel oral CDK4/6 inhibitor, exhibits potent CDK4/6 inhibition in preclinical models with favorable blood-brain barrier penetration. It has shown acceptable safety profiles and preliminary antitumor activities in advanced solid tumors, including HR + /HER2 - MBC. This study assessed the efficacy and safety of SPH4336 plus endocrine therapy in HR + /HER2 - MBC with brain metastases. Methods: This open-label, single-arm, phase II study enrolled patients aged 18-75 years with histologically confirmed HR + /HER2 - and radiologically confirmed brain metastases at 25 centers in China. Prior CDK4/6 inhibitor exposure before brain metastases was limited to <2 agents. Patients received SPH4336 (400 mg orally once daily) plus physician's choice of endocrine therapy (letrozole, fulvestrant, or exemestane) in 28-day cycles until disease progression or unacceptable toxicity. Primary endpoint was intracranial objective response rate (ORR) per RANO-BM criteria. Results: Between September 19, 2023, and August 22, 2025, 30 patients were enrolled. Two patients (6.7%) had a history of palliative radiotherapy for brain metastases. As of December 10, 2025, the median follow-up was 11.7 months (range: 1.6-26.7). Per RANO-BM criteria in 29 evaluable subjects, the intracranial ORR, disease control rate (DCR), and clinical benefit rate were 37.9% (95% CI: 20.7-57.7), 72.4% (95% CI: 52.8-87.3), and 44.8% (95% CI: 26.4-64.3), respectively. Based on RECIST 1.1, the extracranial ORR and DCR were 33.3% (95% CI:17.3-52.8) and 66.7% (95% CI: 47.2-82.7), respectively. The overall ORR was 33.3% (95% CI: 17.3-52.8), and the overall DCR was 60.0% (95% CI: 40.6-77.3). The median intracranial, extracranial, and overall progression-free survival were 8.4 months (95% CI: 1.9-not reached [NR]), 11.0 months (95% CI: 1.9-NR), and 8.1 months (95% CI: 1.9-11.0), respectively. Grade ≥3 treatment-related adverse events occurred in 70.0% of patients, most commonly γ-glutamyltransferase elevation (43.3%), aspartate aminotransferase elevation (20.0%), and neutrophil count decrease (20.0%). No treatment-related death occurred. Conclusions: SPH4336 plus endocrine therapy demonstrated clinically meaningful intracranial antitumor activity with a manageable safety profile in HR + /HER2 - MBC with brain metastases. These findings warrant further investigation in randomized studies for this patient population with high unmet medical need. Clinical trial information: NCT05872347 .