Abstract
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.
Graphical Abstract
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[http://dx.doi.org/10.1200/JCO.2016.67.1487] [PMID: 27217461]
[http://dx.doi.org/10.1016/S0140-6736(16)32419-9] [PMID: 27939057]
[http://dx.doi.org/10.1177/1758834015608993] [PMID: 26557899]
[http://dx.doi.org/10.1016/j.annonc.2020.09.010] [PMID: 32979513]
[http://dx.doi.org/10.6004/jnccn.2021.0023] [PMID: 34794122]
[http://dx.doi.org/10.5306/wjco.v5.i5.990] [PMID: 25493235]
[http://dx.doi.org/10.1200/JCO.2017.73.7585] [PMID: 28580882]
[http://dx.doi.org/10.1001/jamaoncol.2019.4782] [PMID: 31563959]
[http://dx.doi.org/10.1177/1758835920963925] [PMID: 33149768]
[http://dx.doi.org/10.1634/theoncologist.2017-0072] [PMID: 28652278]
[http://dx.doi.org/10.1056/NEJMoa1810527] [PMID: 30345905]
[http://dx.doi.org/10.1200/JCO.2018.78.9909] [PMID: 29860922]
[http://dx.doi.org/10.1056/NEJMoa1911149] [PMID: 31826360]
[http://dx.doi.org/10.1016/S1470-2045(19)30164-0] [PMID: 31036468]
[http://dx.doi.org/10.1007/s12325-013-0060-1] [PMID: 24158787]
[http://dx.doi.org/10.1093/annonc/mdu456] [PMID: 25231953]
[http://dx.doi.org/10.1056/NEJMoa1813904] [PMID: 31091374]
[http://dx.doi.org/10.1016/j.annonc.2020.11.011] [PMID: 33246021]
[http://dx.doi.org/10.1016/S1470-2045(21)00034-6] [PMID: 33794206]
[http://dx.doi.org/10.1016/S1470-2045(21)00727-0] [PMID: 34922646]
[http://dx.doi.org/10.1158/1078-0432.CCR-20-2114] [PMID: 33722897]
[http://dx.doi.org/10.1016/j.annonc.2021.08.548]
[http://dx.doi.org/10.1136/bmj.d5928]
[http://dx.doi.org/10.1016/j.jclinepi.2010.03.016] [PMID: 20688472]
[http://dx.doi.org/10.1200/JCO.2010.34.4879] [PMID: 22010023]
[http://dx.doi.org/10.1186/bcr3039] [PMID: 22114931]
[http://dx.doi.org/10.1038/nrclinonc.2013.29] [PMID: 23459626]
[http://dx.doi.org/10.1038/nrd4360] [PMID: 25131830]
[http://dx.doi.org/10.1038/nrc3265] [PMID: 22576165]
[http://dx.doi.org/10.1097/MD.0000000000013909] [PMID: 30608416]
[http://dx.doi.org/10.1016/S1470-2045(19)30420-6] [PMID: 31494037]
[http://dx.doi.org/10.4048/jbc.2020.23.e55] [PMID: 33154823]
[http://dx.doi.org/10.1038/s41591-021-01562-9] [PMID: 34737452]
[http://dx.doi.org/10.1016/j.annonc.2021.08.2086]
[http://dx.doi.org/10.1200/JCO.21.00944] [PMID: 34357781]
[http://dx.doi.org/10.1016/S1470-2045(14)71159-3] [PMID: 25524798]
[http://dx.doi.org/10.1186/s13058-016-0721-5] [PMID: 27349747]
[http://dx.doi.org/10.1056/NEJMoa1607303] [PMID: 27959613]
[http://dx.doi.org/10.1056/NEJMoa1609709] [PMID: 27717303]
[http://dx.doi.org/10.1093/annonc/mdy155] [PMID: 29718092]
[http://dx.doi.org/10.1016/S1470-2045(18)30292-4] [PMID: 29804902]
[http://dx.doi.org/10.1056/NEJMoa1903765] [PMID: 31166679]
[http://dx.doi.org/10.1200/JCO.2017.75.6155] [PMID: 28968163]
[http://dx.doi.org/10.1016/j.annonc.2020.12.013] [PMID: 33385521]
[http://dx.doi.org/10.1016/S1470-2045(13)70322-X] [PMID: 23902874]
[http://dx.doi.org/10.1200/JCO.2007.13.5822] [PMID: 18316794]
[http://dx.doi.org/10.1200/JCO.2002.10.057] [PMID: 12177099]
[http://dx.doi.org/10.1200/JCO.2002.10.058] [PMID: 12177098]
[http://dx.doi.org/10.1093/jnci/djt337] [PMID: 24317176]