Although a large number of treatment regimens have been studied for HR+, ERBB2/HER2- MBC, there have been few head-to-head trials comparing the efficacy of these regimens.

In order to rank first-line therapy for HR+/ERBB2- MBC, researchers conducted an information theoretic network meta-analysis, which is a graph theory–based approach for regimen ranking that takes into account effect size and temporality of evidence for a given regimen. This type of meta-analysis offers advantages over traditional meta-analyses, which do not account for time-varying trends, such as advances in therapy, and that require that the same clinical endpoint be studied.

The meta-analysis adds the dimensions of "charge," which correlates directly with a drug regimen's ranking and "impedance of the transmission line" between regimens, which correlates with both how recent the evidence is as well as with surrogacy of the comparison.

To be included in this meta-analysis, all randomized, controlled trials (RCTs) of first-line systemic treatments of HR+, ERBB2- MBC that were referenced on or that appeared in a previous systematic review and network meta-analysis were analyzed. All phase III RCTs, phase II RCTs with regimens that were considered to be standard of care and/or were given regulatory approval by the FDA, and older trials that did not specify breast cancer subtype were included in the analysis.

Studies were ranked based on P value and effect size for the least surrogate outcome with P <.10, number of patients enrolled in each group, and an aging coefficient to account for the salience of a particular regimen. An effect size was calculated based on factors such as overall survival, progression-free survival, response rates, and median survival times. The lower the aging coefficient, the more likely that a regimen was discarded over time in favor of a more effective one. Regimens were given an overall score that could be positive, meaning these were recommended regimens; negative, representing nonrecommendable regimens; or 0 or near 0 scores, which indicated that these regimens were of indeterminate value.

The information theoretic network meta-analysis included 203 RCTs that were published between 1974 to 2019 and accounted for a total of 63,629 patients. Of these RCTs, 134 were phase III, 27 were phase II, and 42 studies did not specify a trial phase. This represented 252 unique regimens, including 149 cytotoxic chemotherapeutic agents, 37 endocrine therapies (ETs), 15 combination ETs and targeted therapies, 31 combination cytotoxic chemotherapy and targeted therapies, 17 combination chemotherapy and ETs, and three other therapies, including observation.

The investigators determined that there were 151 main regimens used in 2019, of which four of the five top first-line regimens contained combinations of ET and cyclin-dependent kinase 4 and 6 inhibitors. These included (in ranking order): 1) letrozole plus palbociclib, 3) letrozole plus ribociclib, 4) anastrozole plus ribociclib, and 5) fulvestrant plus ribociclib.

An aging coefficient was generated for each regimen. Of the 151 regimens, 54 regimens had an aging coefficient of >0.5. The lowest ranking regimens that had an aging coefficient >0.5, included monotherapy with either ET (e.g., letrozole or anastrozole), vinorelbine plus capecitabine, or weekly ixabepilone plus bevacizumab.

The authors also examined patterns of first-line treatment for MBC in 1976, 1992, 2017, and 2015; the first drug therapy RCT for MBC was published in 1974.

This study provides pharmacists with insight into the rank order of first-line treatments of HR+/ERBB2- MBC, which can be used to help optimize patient care.

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