Background: While the combination of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) has established efficacy as first-line treatment for HR+/HER2- advanced breast cancer (ABC), resistance remains a critical clinical challenge. Dalpiciclib, a novel Chinese-developed CDK4/6i, has shown promising results in first-line therapy, yet data on its efficacy following progression on prior CDK4/6i is limited. Methods: This retrospective, multicenter study enrolled 58 patients with HR+/HER2− ABC who experienced disease progression after prior CDK4/6i therapy and received dalpiciclib combined with ET between July 2022 and October 2024. The primary endpoint was progression-free survival (PFS); secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. Subgroup analyses were performed based on baseline clinical characteristics and prior treatment histories. Results: The median PFS was 6.3 months (95% CI: 5.2– 11.0). The ORR and DCR were 8.6% and 32.8%, respectively. Patients with liver metastases exhibited significantly shorter PFS compared to those without (4.2 vs 8.0 months, p =0.027; HR=2.19, 95% CI: 1.08– 4.43). Sequential use of dalpiciclib following progression on prior CDK4/6i progression was associated with longer PFS (8.0 vs 5.2 months, p =0.013; HR=0.42, 95% CI: 0.21– 0.86). Patients with secondary endocrine resistance also experienced significantly longer PFS than those with primary resistance (7.2 vs 4.0 months, p =0.002; HR=3.28, 95% CI: 1.52– 7.08). The most common grade ≥ 3 adverse events were neutropenia (22.4%) and leukopenia (17.2%). No patients discontinued treatment due to adverse events. Conclusion: Dalpiciclib combined with endocrine therapy demonstrates clinical efficacy and a manageable safety profile as a cross-line treatment for HR+/HER2- ABC patients who progressed on prior CDK4/6i. Subgroups including those without liver metastases, with secondary endocrine resistance, and receiving sequential CDK4/6i therapy appear to derive greater benefit. These findings support dalpiciclib as a viable cross-line therapeutic option, warranting further prospective validation. Keywords: dalpiciclib, CDK4/6 inhibitor, HR+/HER2- breast cancer, endocrine resistance, cross-line therapy
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