Patterns of treatment with everolimus exemestane in hormone receptor-positive HER2-negative metastatic breast cancer in the era of targeted therapy

Abstract

Background There is currently no clinical trial data regarding the efficacy of everolimus exemestane (EE) following prior treatment with CDK4/6 inhibitors (CDK4/6i). This study assesses the use and efficacy of everolimus exemestane in patients with metastatic HR+ HER2− breast cancer previously treated with endocrine therapy (ET) or endocrine therapy + CDK4/6i. Methods Retrospective analysis of electronic health record-derived data for HR+ HER2− metastatic breast cancer from 2012 to 2018. The proportion of patients receiving EE first-line, second-line, or third-line, and the median duration of EE prior to next line of treatment (TTNT) by line of therapy was calculated. OS for patients receiving EE first-line, second-line, or third-line, indexed to the date of first-line therapy initiation and stratified by prior treatment received, was calculated with Kaplan-Meier method with multivariable Cox proportional hazards regression analysis. Results Six hundred twenty-two patients received EE first-line (n = 104, 16.7%), second-line (n = 273, 43.9%) or third-line (n = 245, 39.4%). Median TTNT was 8.3 months, 5.5 months, and 4.8 months respectively. Median TTNT of EE second-line was longer following prior ET alone compared to prior ET + CDK4/6i (6.2 months (95% CI 5.2, 7.3) vs 4.3 months (95% CI 3.2, 5.7) respectively, p = 0.03). Similarly, EE third-line following ET alone vs ET + CDK4/6i in first- or second-line resulted in median TTNT 5.6 months (95% CI 4.4, 6.9) vs 4.1 months (95% CI 3.6, 6.1) respectively, although this was not statistically significant (p = 0.08). Median OS was longer for patients who received EE following prior ET + CDK4/6i. EE second-line following ET + CDK 4/6i vs ET alone resulted in median OS 37.7 months vs. 32.7 months (p = 0.449). EE third-line following ET + CDK4/6i vs prior ET alone resulted in median OS 59.2 months vs. 40.8 months (p < 0.010). This difference in OS was not statistically significant when indexed to the start of EE therapy. Conclusion This study suggests that EE remains an effective treatment option after prior ET or ET + CDK4/6i use. Median TTNT of EE was longer for patients who received prior ET, whereas median OS was longer for patients who received prior ET + CDK4/6i. However, this improvement in OS was not statistically significant when indexed to the start of EE therapy suggesting that OS benefit is primarily driven by prior CDK4/6i use. EE remains an effective treatment option regardless of prior treatment option.

ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer

“…40 None of the patients enrolled in this trial had previously received CDK4/6 inhibitors, although retrospective analyses suggest that prior exposure to CDK4/6 inhibitor therapy may not impact survival outcomes for patients receiving everolimuseexemestane. 41,42 In patients with tumours harbouring an ESR1 mutation, substituting the exemestane backbone with fulvestrant is favoured [ESCAT score: II-A; off label]. 43 If everolimus is used, appropriate prophylaxis, such as dexamethasone oral solution, should be prescribed to prevent the incidence and severity of stomatitis.…”

Targeted Therapy in HR+ HER2− Metastatic Breast Cancer: Current Clinical Trials and Their Implications for CDK4/6 Inhibitor Therapy and beyond Treatment Options

“…It is notable that in the BOLERO-2 study, the benefit from everolimus was not influenced by the presence of PIK3CA tumor mutations [ 77 ]. A recent retrospective comparative analysis showed a higher efficacy of everolimus plus exemestane in patients with prior CDK4/6 inhibitor plus endocrine therapy than in patients with prior endocrine therapy alone [ 78 ]. A potential selection bias caused by patients with CDK4/6 inhibitor resistance due to PIK3CA mutations who benefit from a second- or third-line therapy with everolimus has to be considered.…”

“…However, everolimus remains a second- or third-line treatment option in patients with HR+, HER2− MBC. This is especially true for patients with PIK3CA mutations who show a disease progression on PI3K inhibitor therapy or who experience contraindications to PI3K inhibitors [ 78 ].…”

Biomarkers of everolimus efficacy in breast cancer therapy

“…11 The combination of exemestane with everolimus as a second line or third line treatments following hormonal therapy and CDK inhibitors is associated with shorter times to next treatment compared with exemestane and everolimus treatment following hormonal therapy alone. 12 A better characterization of patient groups with tumors more sensitive to everolimus treatments would facilitate the reintegration of the drug in earlier treatment of ER positive, HER2 negative metastatic breast cancer and rekindle earlier efforts to introduce everolimus in the therapy of other breast cancer sub-types. This paper discusses predictive factors for everolimus efficacy in breast cancer with the goal to reposition its use in patients more likely to benefit.…”

“…11 The combination of exemestane with everolimus as a second line or third line treatments following hormonal therapy and CDK inhibitors is associated with shorter times to next treatment compared with exemestane and everolimus treatment following hormonal therapy alone. 12…”