A new phase II clinical trial has demonstrated promising results for the combination of dalpiciclib, a novel CDK4/6 inhibitor, with letrozole in treating postmenopausal women with hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer.
The single-arm, open-label study (NCT05512780) enrolled 35 postmenopausal women with stage II-III HR+/HER2- breast cancer across nine hospitals. Patients received four cycles of treatment consisting of dalpiciclib (125 mg daily for 3 weeks, followed by 1 week off) plus continuous letrozole (2.5 mg daily).
Clinical Efficacy and Response Rates
Among 29 evaluable patients who completed the full treatment course, 16 achieved partial response, resulting in an objective response rate (ORR) of 55.2%. Notably, no patients experienced disease progression during the treatment period. Of the 27 patients who underwent definitive surgery, one patient achieved pathologic complete response (pCR).
The treatment demonstrated significant antiproliferative effects, with mean Ki-67 expression decreasing markedly from 17.5% at baseline to 1.8% after two weeks of therapy. Complete cell cycle arrest (CCCA), defined as Ki-67 ≤2.7%, was observed in 75% of patients after two weeks of treatment.
Safety Profile
The safety analysis revealed manageable toxicity profiles consistent with other CDK4/6 inhibitors. The most common treatment-emergent adverse events included decreased neutrophil count (74.3%), decreased white blood cell count (68.6%), and anemia (34.3%). Grade 3 or 4 neutropenia occurred in 45.7% of patients, with a median duration of 3 days. Importantly, no cases of febrile neutropenia were reported.
Biomarker Analysis and Predictive Model
Through comprehensive gene expression analysis, researchers identified three novel biomarkers - TFRC, SCUBE2, and MMP11A - as potential predictors of treatment response. A predictive model incorporating these biomarkers along with clinical factors achieved an area under the curve (AUC) of 0.928, suggesting strong potential for patient selection.
Clinical Context and Implications
The findings align with previous studies of CDK4/6 inhibitors in combination with aromatase inhibitors, such as the neoMONARCH and PALLET trials. The results support the growing evidence that CDK4/6 inhibitors combined with endocrine therapy may offer an effective treatment option for HR+/HER2- breast cancer patients, particularly in the neoadjuvant setting.
Dr. Li Wei, the study's principal investigator, noted, "These results demonstrate that dalpiciclib plus letrozole could be a promising neoadjuvant treatment option for postmenopausal women with HR+/HER2- breast cancer, offering significant antiproliferative effects with manageable toxicity."
Future Directions
While the results are encouraging, the researchers acknowledge the study's limitations, including its single-arm design and relatively small sample size. A larger follow-up study, DARLING-2, is currently underway to investigate the efficacy and safety of a 6-cycle regimen in endocrine-sensitive breast cancer patients.
