Second-line Endocrine Therapy of Hormone Receptor-Positive/HER2-negative Advanced Breast Cancer: A Systematic Review and Network Meta-analysis

by Selleckchem | Aug 12 2023

Background: The optimal second-line therapy for hormone receptor-positive (HR+)/ human epidermal growth factor receptor 2 negative (HER2-) advanced or metastatic breast cancer is yet to be established. Therefore, we conducted a network meta-analysis (NMA) of marketed drugs to compare their efficacy.

Methods: We searched the literature in PubMed, Embase, Web of Science databases, and the main international conferences in the past 5 years to find phase III clinical trials on drugs available in the market. Network meta-analysis of progression-free survival (PFS), overall survival (OS), and the objective response rate (ORR) was performed using R software. The efficiency of treatment options was compared using hazard ratios and 95% credibility intervals.

Results: Overall, 12 studies with 6120 patients were included in the analysis. In an indirect comparison of the five regimens, cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) plus 500 mg fulvestrant (Ful500) gave the best PFS results; palbociclib ranked first with a surface under the cumulative ranking (SUCRA) of 94.99%, followed by mammalian target of rapamycin inhibitor (mTORi) plus everolimus (SUCRA=73.07%), phosphoinositide 3-kinase inhibitor (PI3Ki) plus Ful500 (SUCRA=66.73%), Ful500 alone (SUCRA=44.55%), and histone deacetylase inhibitor (HDACi) plus exemestane (SUCRA=43.49%). However, no significant difference was found in the PFS rates of CDK4/6i, mTORi, and PI3Ki. For OS, CDK4/6i plus Ful500 ranked first; the SUCRA of ribociclib, abemaciclib, and palbociclib were 86.20%, 83.98%, and 78.52%, respectively. Alpelisib plus Ful500 (SUCRA=66.91%) ranked second but was not statistically different from CDK4/6i. The mTORi plus everolimus group had the best ORR (SUCRA=88.73%). In terms of safety, 81.56% of patients in the tucidinostat plus exemestane regimen developed neutropenia, suggesting strong hematological toxicity; 13.40% of patients developed grade 3-4 diarrhea after using abemaciclib plus Ful500.

Conclusion: For second-line endocrine therapy in HR+/HER2- advanced/metastatic breast cancer, CDK4/6i is a better choice than mTORi, PI3Ki, HDACi, and Ful; it shows good PFS and OS outcomes and a low probability for serious adverse events.

Comments:

The network meta-analysis you conducted aimed to determine the optimal second-line therapy for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) advanced or metastatic breast cancer. The study included 12 phase III clinical trials with a total of 6,120 patients. The analysis compared the efficacy of different treatment regimens based on progression-free survival (PFS), overall survival (OS), and the objective response rate (ORR).

The results of the analysis indicated that cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) in combination with 500 mg fulvestrant (Ful500) had the best PFS results. Among the CDK4/6i drugs, palbociclib ranked first with the highest surface under the cumulative ranking (SUCRA) value of 94.99%. The combination of mammalian target of rapamycin inhibitor (mTORi) and everolimus ranked second with a SUCRA value of 73.07%, followed by phosphoinositide 3-kinase inhibitor (PI3Ki) plus Ful500 (SUCRA=66.73%), Ful500 alone (SUCRA=44.55%), and histone deacetylase inhibitor (HDACi) plus exemestane (SUCRA=43.49%). However, there was no significant difference in PFS rates between CDK4/6i, mTORi, and PI3Ki.

For overall survival (OS), CDK4/6i plus Ful500 was ranked first, with ribociclib, abemaciclib, and palbociclib having SUCRA values of 86.20%, 83.98%, and 78.52%, respectively. The combination of alpelisib and Ful500 ranked second (SUCRA=66.91%), but it was not statistically different from CDK4/6i. The mTORi plus everolimus group had the best objective response rate (SUCRA=88.73%).

In terms of safety, it was noted that 81.56% of patients in the tucidinostat plus exemestane regimen developed neutropenia, indicating significant hematological toxicity. Additionally, 13.40% of patients experienced grade 3-4 diarrhea after using abemaciclib plus Ful500.

Based on these findings, the study concluded that for second-line endocrine therapy in HR+/HER2- advanced/metastatic breast cancer, CDK4/6i is a better choice compared to mTORi, PI3Ki, HDACi, and Ful alone. CDK4/6i showed favorable outcomes in terms of both PFS and OS while having a low probability of serious adverse events.