Efficacy and safety of BEBT-209, a primary CDK4 inhibitor, in combination with gemcitabine and carboplatin for metastatic triple-negative breast cancer.

e15144 Background: Metastatic triple-negative breast cancer (mTNBC) represents a significant unmet medical need due to the limited availability of effective targeted therapies and the associated poor patient outcomes. Patients with early relapse ( < 12 months after adjuvant therapy) or failure of first-line chemotherapy exhibit particularly aggressive disease, with a median progression-free survival (mPFS) as short as 3.1 months. Antibody-drug conjugates (ADCs), such as sacituzumab govitecan (SG), demonstrate limited efficacy, achieving a 31% objective response rate (ORR) and mPFS of 4.8 months in the ASCENT trial. BEBT-209, a novel and primary CDK4 inhibitor with six-fold greater potency for CDK4 over CDK6, has shown potential to enhance chemosensitivity and reduce chemoresistance. This therapeutic profile positions BEBT-209 as a promising candidate to address the critical unmet needs in mTNBC by improving efficacy while maintaining a manageable safety profile. Methods: This Phase II study evaluated BEBT-209 in combination with gemcitabine and carboplatin (GC) in patients with mTNBC. The cohorts included patients with early relapse within 12 months of adjuvant therapy and those who had received 1-2 prior lines of systemic therapy in the metastatic setting. BEBT-209 was administered at 150 mg on Day 1 and Day 8, or 150 mg twice on Day 1 and 150 mg on Day 8. Carboplatin [Dose (mg) = AUC × 2 × (creatinine clearance + 25)] and gemcitabine (1000 mg/m²) were administered on Day 2 and Day 9. Efficacy was assessed according to RECIST v1.1 criteria. Key endpoints included ORR, PFS, and safety. Results: A total of 36 patients were treated in the study. Among patients with early relapse (n = 13), the ORR was 38.5% (95% CI: 13.9–68.4), with a mPFS of 7.1 months (95% CI: 4.1–9.6). For patients who had received 1–2 prior lines of metastatic therapy (n = 23), the ORR was 43.5% (95% CI: 19.7–61.5), with a mPFS of 6.7 months (95% CI: 4.4–9.6). These results compare favorably to historical data for SG (31% ORR, 4.8-month mPFS) and conventional chemotherapy (4% ORR, 1.7-month mPFS). The most frequently observed grade 3–4 hematological toxicities during treatment were leukopenia (68%), neutropenia (68%), thrombocytopenia (34%), and anemia (18%). BEBT-209 was well-tolerated, with most adverse events being hematological and aligning with the expected toxicity profile of the GC regimen. Conclusions: BEBT-209 in combination with GC demonstrates promising efficacy and a favorable safety profile in mTNBC patients with early relapse or prior systemic therapy. The observed improvements in ORR and PFS compared to current standards of care highlight the potential of BEBT-209 as a breakthrough therapy for this aggressive disease. A global Phase III trial is planned to further validate these findings. Clinical trial information: NCT06685796 .