Efficacy of everolimus in patients with hormone receptor positive, HER2 negative, metastatic breast cancer pretreated with CDK4/6 inhibitors.

CONTEXT AND AIMS: Everolimus was approved in 2012 for the treatment of advanced hormone-receptor-positive, HER2-negative metastatic breast cancer (MBC) in combination with exemestane. Since then, the first line treatment for these cancers has evolved with the development of CDK4/6 inhibitors.

METHODS: Patients with histologically proved MBC and who received everolimus between 2012 and 2022 were included in a multicentric retrospective cohort. Prior exposure to CDK4/6 inhibitors was documented. The purpose of the study was to evaluate the efficacy of everolimus plus endocrine therapy in patients previously treated with CDK4/6 inhibitors and to identify factors associated with improved PFS on everolimus. The primary endpoint was PFS. Secondary outcomes included overall survival (OS), factors associated with improved efficacy, and grade III-IV toxicities.

RESULTS: From 2012 to December 30, 2022, 325 patients were included. Of these, 75 patients (23%) had been pretreated by CDK4/6 inhibitors. In the overall population, median PFS was 6.4 months (95% CI, 5.5-7.1), with a median OS of 25 months (95% CI, 21.8-28.1). Among those previously exposed to CDK4/6 inhibitors, median PFS was 5.3 months (95% CI, 4.6-7.1), compared to 6.7 months (95% CI, 5.8-7.6) for those who had not received CDK4/6 inhibitors (p = 0.046) and the median OS was 27.3 months without CDK4/6 inhibitors before everolimus (95% CI, 23.2-30.2) versus 21.8 months (95% CI,18.5-25.5) when pretreated by CDK4/6 inhibitors (p = 0.01). Sixty-eight patients (21%) had a PFS greater than 12 months. Factors associated with an improved PFS were the lack of liver metastases (p < 0.001), no prior exposure to metastatic chemotherapy (p = 0.001), a lower tumor grade (p = 0.005), no prior treatment with CDK4/6 inhibitors (p = 0.006), and a better performance status (p = 0.008). 89 patients (28%) discontinued everolimus due to toxicity rather than disease progression or death and 23 (25%) patients treated with exemestane alone, after everolimus exposure, maintained a stable disease for at least 6 months.

CONCLUSION: Patients who had prior exposure to CDK4/6 inhibitors experienced a shorter median PFS benefit from everolimus based-treatment compared to those who were CDK4/6 inhibitor-naive. In this study, they also demonstrated shorter OS, likely due to a more pronounced endocrine-resistant profile. Although a reduction in PFS is expected with successive lines of therapy, the use of everolimus after exposure to CDK4/6 inhibitors and aromatase inhibitors remains an option and allows to propose another endocrine-based therapy and to postpone the use of chemotherapy. Managing endocrine resistance remains challenging and further research is needed to identify predictive biomarkers for improved outcomes.