A multicentre, randomised, double-blind, phase II study to evaluate the tolerability of an induction dose escalation of everolimus in patients with metastatic breast cancer (DESIREE)

Abstract

Background: Stomatitis is one of the main reasons to discontinue everolimus in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC). To decrease stomatitis and subsequently early treatment discontinuations or dose reductions, the DESIREE trial investigated the use of a stepwise dose-escalation schedule of everolimus (EVE esc).

Patients and methods: DESIREE is a phase II, multicentre, randomised, double-blind, placebo-controlled trial in patients with HR+/HER2- mBC and progression/relapse after nonsteroidal aromatase inhibitor treatment. Patients were randomised to EVE esc (2.5 mg/day, week 1; 5 mg/day, week 2; 7.5 mg/day, week 3; 10 mg/day, weeks 4-24) or everolimus 10 mg/day (EVE 10mg) for 24 weeks plus exemestane. The primary endpoint was the incidence of stomatitis episodes grade ≥2 within 12 weeks of treatment. The secondary endpoints included toxicity, relative total dose intensity (RTDI) and quality of life (QoL).

Results: A total of 160 patients were randomised and 156 started treatment (EVE esc: 80; EVE 10mg: 76). The median age of patients was 64 years (range 33-85), 56.3% patients in the EVE esc arm versus 42.1% in the EVE 10mg arm had liver metastasis (P = 0.081) and 62.5% versus 51.3% received over one metastatic therapy line (P = 0.196). Within 12 weeks, the incidence of stomatitis episodes grade ≥2 was significantly lower in the EVE esc arm compared with the EVE 10mg arm (28.8% versus 46.1%; odds ratio 0.47, 95% confidence interval 0.24-0.92; P = 0.026). Toxicity was in line with the known safety profile without new safety concerns. The median RTDI was 91.1% in the EVE esc arm versus 80.0% in the EVE 10mg arm (P = 0.329). Discontinuation rate in the first 3 weeks was 6.3% versus 15.8%, respectively (P = 0.073). QoL was comparable between the two treatment arms.

Conclusions: A dose-escalation schema of everolimus over 3 weeks can be successfully used to reduce the incidence of high-grade stomatitis in the first 12 weeks of treatment in patients with HR+/HER2- mBC.

Trial registration: ClinicalTrials.govNCT02387099; https://clinicaltrials.gov/ct2/show/NCT02387099.

Keywords: everolimus; exemestane; metastatic breast cancer; stomatitis.

Figure 1

CONSORT diagram. AE, adverse event; esc, escalated; EVE, everolimus.

Figure 2

Stomatitis episodes grade ≥2 within (A) 12 and (B) 24 weeks of treatment as well as (C) time to onset of stomatitis grade ≥2 within 24 weeks. (A) Incidence of stomatitis episodes grade ≥2 within 12 weeks considering stomatitis grade <2 and premature treatment discontinuation due to adverse events, patient’s decision or investigator’s decision. ∗Primary endpoint design: type I error 20%. (B) Incidence of stomatitis episodes grade ≥2 within 24 weeks considering stomatitis grade <2 and premature treatment discontinuation due to adverse events, patient’s decision or investigator’s decision. (C) Time to onset of stomatitis grade ≥2 within 24 weeks was assessed post hoc. Competing events were defined as discontinuation of study treatment due to adverse event, patient’s decision or investigator’s decision, progression or death without stomatitis grade ≥2. CI, confidence interval; esc, escalated; EVE, everolimus; OR, odds ratio.