medwireNews: Premenopausal women with hormone receptor-positive, HER2-negative, advanced breast cancer derive a significant progression-free survival (PFS) benefit from the addition of everolimus to first-line letrozole, shows the MIRACLE trial.
The phase 2 study included 199 patients with resistance to selective estrogen receptor modulators who were randomly assigned to receive the mTOR inhibitor everolimus at a dose of 10 mg daily plus the aromatase inhibitor letrozole 2.5 mg daily (n=101) or letrozole monotherapy at the same dose (n=98).
As reported in JAMA Oncology, PFS was significantly better with the combination than with letrozole alone, at a median of 19.4 and 12.9 months, respectively, and a hazard ratio for progression or death of 0.64.
Similarly, the objective response rate (ORR) was higher in the combination than letrozole alone group, at 50.0% versus 39.3%, while the clinical benefit rate (CBR) was significantly higher, at 72.7% versus 47.5%.
The trial permitted patients in the letrozole group who experienced disease progression to crossover at their physician’s discretion and additionally receive everolimus. Among the 57.1% of patients who crossed over, the median PFS was 5.5 months, ORR was 13.2%, and CBR was 58.5%.
“The addition of everolimus to the same endocrine agent was effective even after disease progression,” which demonstrates “the role of everolimus in overcoming endocrine resistance,” say Binghe Xu (Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing) and team.
Reporting on the safety profile, they note that “everolimus plus letrozole resulted in a relatively high incidence of metabolic disorders, including hypercholesterolemia, hypertriglyceridemia, and hyperglycemia,” with grade 3 or worse events occurring in 1.0%, 12.9%, and 2.0% of patients, respectively. The corresponding rates with letrozole alone were 0.0%, 3.3%, and 2.2%.
Overall, adverse events led to a dose reduction in 33.7% of the combination group, 1.1% of the monotherapy group, and 12.5% of the crossover group, while treatment delays occurred in 53.5%, 4.3%, and 32.1% of participants, respectively, and treatment discontinuation in 8.9%, 0.0%, and 3.8%.
Xu et al highlight some limitations of the study, such as the lack of a placebo control and quality of life assessments, as well as the inability to conduct a phase 3 trial of the combination “because CDK4/6 inhibitors are now the standard first-line therapy” for this patient population.
Nevertheless, they conclude: “Even though the treatment landscape for HR-positive, [HER2]-negative breast cancer has recently expanded to include CDK4/6 inhibitors, our results show that everolimus has therapeutic value and remains an important part of the armamentarium for this disease.”
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