Comparison of the Effectiveness and Clinical Outcome of Everolimus Followed by CDK4/6 Inhibitors with the Opposite Treatment Sequence in Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer

Abstract

In hormone receptor-positive, HER2-negative metastatic breast cancer (HR+ HER2-MBC), the mainstay treatment options include cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and everolimus (EVE) in combination with endocrine treatment. This study aims to compare the outcomes of the following treatment sequences: CDK4/6i followed by EVE and EVE followed by CDK4/6i. Materials and MethodsData from HR+ HER2-MBC patients treated between Jan. 2014 and Nov. 2020 with both CDK4/6i and EVE were retrospectively analyzed. ResultsAmong the 88 patients included in the study, 51 received CDK4/6i before EVE (C→E group), and 37 received EVE before CDK4/6i (E→C group) with endocrine treatment. More patients in the E→C group had endocrine resistance (13.7% vs. 40.5%), experienced palliative chemotherapy (7.8% vs. 40.5%), and were heavily treated (treated as ≥3rd line, 5.9% vs. 40.5%). Median overall survival was 46.8 months in the C→E group and 38.9 months in the E→C group (p=0.151). Median composite progression-free survival, defined as the time from the start of the preceding regimen to disease progression on the following regimen or death, was 24.8 months in the C→E group vs. 21.8 months in the E→C group (p=0.681). Median PFS2/PFS1 ratio did not differ significantly between groups (0.5 in the C→E group, 0.6 in the E→C group; p=0.775). Ten patients (11.4%) discontinued EVE, and 2 patients (2.3%) discontinued CDK4/6i during treatment. ConclusionAlthough the CDK4/6i-based regimen should be considered as an earlier line of treatment, CDK4/6i-and EVE-based treatments can be valid options in circumstances where the other treatment had been already given.

Place in Therapy of Cyclin-Dependent Kinase 4/6 Inhibitors in Breast Cancer: A Targeted Literature Review

“…Two studies compared the clinical effectiveness of different CDK4/6i treatment sequences (ESM) [ 36 , 37 ]. Basile et al reported that patients receiving CDK4/6i combined with chemotherapy in 1L followed by chemotherapy in 2L had significantly worse OS than those receiving CDK4/6i combined with ET in 1L followed by ET in 2L (hazard ratio: 6.95, p = 0.011) [ 36 ].…”

Endocrine therapy in metastatic breast cancer-more than just CDK4/6 inhibitors

“…There was no significant difference in overall survival between the two groups [77] . In contrast, Cook et al showed no influence of prior treatment with a CDK4/6 inhibitor on progression-free survival for patients treated with everolimus plus exemestane compared to patients without prior exposure (3.6 months vs. 4.2 months) [78] . In addition, they reported a numerical improvement in overall survival (15.6 months vs. 11.3 months) for patients previously treated with a CDK4/6 inhibitor [78] .…”

“…In contrast, Cook et al showed no influence of prior treatment with a CDK4/6 inhibitor on progression-free survival for patients treated with everolimus plus exemestane compared to patients without prior exposure (3.6 months vs. 4.2 months) [78] . In addition, they reported a numerical improvement in overall survival (15.6 months vs. 11.3 months) for patients previously treated with a CDK4/6 inhibitor [78] . The discussion of the efficacy of everolimus plus exemestane after treatment with a CDK4/6 inhibitor is accompanied by the discussion of the optimal treatment sequence.…”

Selective protection of normal cells from chemotherapy, while killing drug-resistant cancer cells

“…This is exactly the same type of cancer that is also treated with palbociclib. In some studies, therapies with everolimus and palbociclib were used in sequence: when one of them failed, the other one was used in sequences [57][58][59]. In one trial, palbociclib was given first, followed by everolimus [57].…”