C43Everolimus-exemestane (EE) vs palbociclib-letrozole (PL) or palbociclib-fulvestrant (PF) in the treatment of metastatic HR+, HER2- breast cancer. Indirect comparisons with network meta-analysis for daily clinical practice

Background: To compare the efficacy of EE to PF or PL in the treatment of metastatic HR+, HER2- breast cancer pre-treated or untreated with aromatase-inhibitors (AI) for advanced disease. Methods: An indirect comparison with a network meta-analysis comparing EE with PL or PF in the treatment of metastatic HR+, HER2- breast cancer pre-treated or untreated with AI for advanced disease was performed. The Progression-Free-Survival (PFS) was the primary end point of all our indirect comparisons. The indirect comparison was performed both for patients pre-treated with AI and for patients never treated with AI for advanced disease. Efficacy data were expressed as Hazard Ratio (HR) and 95% Confidence Interval (95CI), assuming an α-error of 5% as index of statistical significance. Results: All the data of the BOLERO-2 trial, the Bachelot et al network meta-analysis (Breast Cancer Treat Rep 2014), the PALOMA-2 and the Paloma-3 trial were analyzed and indirectly compared in a network meta-analysis. 2 orders of comparison were performed: EE vs PL for patients never treated with AI for advanced disease and EE vs PF for patients pre-treated with AI for advanced disease. The pooled HR and 95%CI were respectively 0.597 (0.355-1.005, p = 0.89) and 1.1 (0.7-1.6, p = 0.97) for EE vs PL (never treated with AI) and EE vs PF (pre-treated with AI). No major reasons of clinical and methodological heterogeneity were detected in an independent qualitative analysis, while a moderate quantitative heterogeneity was detected using the I2 test. Conclusions: Till today EE and PL or PF represent active treatments for patients with metastatic HR+, HER2- breast cancer treated or untreated with AI, and no direct comparisons between EE and PL or PF exist in literature. Although our data have not the power to detect any definitive difference in PFS between EE and PL or PF (probably with the exception of EE vs PL, where a trend in favor of EE could be hypothesized), EE, PL or PF seem to be comparable in terms of PFS; it follows that the better safety profile or the economic profile could help physicians in daily clinical practice.