Background: Hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) represents a significant clinical challenge with evolving treatment strategies. Cyclin-dependent Kinase 4/6 inhibitors (CDK4/6i) and taxanes are commonly used to treat HR+ HER2- mBC. This study investigates the impact of first- and second-line therapy selections on real-world progression-free survival (rwPFS) and real-world overall survival (rwOS) in patients with HR+ HER2- mBC.

Methods: The study cohort included 13,064 patients with HR+ HER2- mBC from the de-identified Tempus real-world multimodal database who received either first- (1L) or second-line (2L) CDK4/6i, taxane, or other therapy. Kaplan-Meier survival analysis and multivariate Cox regression accounting for main epidemiological confounding variables (age at diagnosis, presence of visceral metastases, and recurrent vs. de novo treatment status) were used to assess rwPFS and rwOS. Progression events included death, noted progression event or initiation of a new line of therapy. DNA sequencing data from the Tempus xT assay were analyzed to evaluate mutation landscapes and genetic alterations associated with different treatment sequences.

Results: Patients with HR+ HER2- mBC (N = 13,046) who received 1L CDK4/6i + endocrine therapy (ET) had significantly improved rwPFS and rwOS relative to those receiving a taxane. We observed a trend towards faster progression in patients who received taxane as a 2L treatment after 1L CDK4/6i as opposed to other treatments (HR=1.33, P=0.052). Of patients who received 1L CDK4/6i, 2L rwPFS was longest in patients who were re-challenged with CDK4/6i (predominantly Palbociclib+Letrozole to Palbociclib+Fulvestrant). Patients who received 2L CDK4/6i following 1L taxane had longer 2L rwPFS than those who received a non-CDK4/6i 2L treatment (median PFS=5.9 months 2L CDK4/6i vs 3.6mo non-CDK4/6i). Across all patients who received 2L CDK4/6i, there was a trend toward better 2L rwPFS for those with 1L taxane compared to those who received 1L CDK4/6i (median PFS 5.9 mo vs median PFS=5.1mo). This result of best 2L response in patients receiving CDK4/6i following taxane in 1L remains consistent when fitting a multivariate model including treatment order, age at diagnosis, presence of visceral metastases, treatment recurrence, and prevalent mutations (BRCA, RB1, FGFR2, AKT1, ESR1, PIK3 (HR=0.80, p=0.109).

Conclusion: This study demonstrates that the sequence of taxane and CDK4/6i treatments might impact survival outcomes in patients with HR+ HER2- mBC. While CDK4/6i+ET outperforms taxane in 1L, the findings suggest that taxane may cause sensitization to CDK4/6i, conferring better survival outcomes in a subset of patients where 1L taxane is advised, or a potential advantage to chemo before CDK4/6i re-challenge. These results need validation in additional datasets and underscore the importance of treatment sequencing in optimizing clinical outcomes for patients with HR+ mBC.

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