A Phase II, Multicenter, Randomized, Double-Blind Study to Assess the Tolerability of Escalating Induction Doses of Everolimus in Patients with Metastatic Breast Cancer (DESIREE)

Stomatitis represents a primary cause for discontinuing everolimus therapy among individuals diagnosed with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer. The DESIREE study explored a gradual dose-increase approach for everolimus (EVE esc) to mitigate mucositis and reduce premature discontinuations or dosage adjustments. This phase II, multicenter, randomized, double-blind, placebo-controlled investigation involved participants with HR+/HER2– advanced breast cancer who experienced disease progression or recurrence following nonsteroidal aromatase inhibitor therapy. Subjects were allocated to either EVE esc (starting at 2.5 mg daily in week 1, increasing to 5 mg in week 2, 7.5 mg in week 3, and 10 mg from weeks 4 to 24) or standard everolimus at 10 mg daily (EVE 10mg), both combined with exemestane over 24 weeks. The main outcome measure was the occurrence of grade ≥2 mucositis events during the initial 12 weeks. Additional outcomes encompassed adverse effects, relative total dose intensity (RTDI), and patient-reported quality of life (QoL). In total, 160 individuals were allocated randomly, with 156 initiating therapy (EVE esc: 80; EVE 10mg: 76). The average patient age was 64 years (ranging from 33 to 85); liver metastases were present in 56.3% of the EVE esc group compared to 42.1% in the EVE 10mg group (P = 0.081), and more than one prior metastatic treatment line was noted in 62.5% versus 51.3% (P = 0.196). Over the first 12 weeks, grade ≥2 mucositis events occurred less frequently in the EVE esc group than in the EVE 10mg group (28.8% vs. 46.1%; odds ratio 0.47, 95% confidence interval 0.24-0.92; P = 0.026). Adverse event profiles aligned with established data, showing no novel concerns. Median RTDI reached 91.1% for EVE esc versus 80.0% for EVE 10mg (P = 0.329). Early discontinuations within the initial three weeks were 6.3% in EVE esc versus 15.8% in EVE 10mg (P = 0.073). Quality of life measures remained similar across groups. Implementing a three-week gradual increase in everolimus dosing effectively lowers the rate of severe mucositis during the early 12 weeks of therapy in HR+/HER2– advanced breast cancer cases.