Noah S. Kornblum, MD
Everolimus demonstrated strong potential as an effective tool for overcoming endocrine resistance in postmenopausal women with ER-positive, HER2-negative metastatic breast cancer resistant to aromatase inhibitor (AI) therapy.
Results from the PrE0102 trial published in the Journal of Clinical Oncology
showed that adding the mTOR inhibitor to fulvestrant (Faslodex) in this patient population resulted in a median progression-free survival (PFS) of 10.3 months compared with 5.1 months for fulvestrant plus placebo (HR, 0.61; 95% CI, 0.40-0.92; stratified log-rank P
“Our findings provide additional evidence that everolimus plus antiestrogen therapy is more efficacious than is antiestrogen therapy alone in patients with metastatic, hormone receptor–positive, HER2-negative breast cancer resistant to AI therapy, and that the fulvestrant/everolimus combination represents a new therapeutic option for AI-resistant disease,” first author Noah Kornblum, MD, Department of Oncology, Montefiore Medical Center, and colleagues wrote.
PFS results were first presented at the 2016 San Antonio Breast Cancer Symposium. With additional follow-up, the data cutoff was March 2017, investigators determined that everolimus did not improve median overall survival (28.3 vs 31.4 months; HR, 1.31; 95% CI, 0.72-2.38; stratified log-rank P
= .37). However, investigators noted that the study was not powered to detect an improvement in survival.
From May 2013 to November 2015, 131 postmenopausal women enrolled in the randomized, double-blind, placebo-controlled, phase II PrE0102 trial at 23 institutions. Eligible patients had histologically- or cytologically-confirmed, unresectable, locally advanced or metastatic, ER-positive, HER2-negative breast cancer, and AI-resistant disease. Kornblum et al defined AI resistance as “either as relapse while receiving adjuvant AI therapy or disease progression while receiving an AI for metastatic disease.’’ Only 1 prior chemotherapy regimen for metastatic disease was allowed.
Sixty-six women were randomly assigned to 10 mg of daily everolimus plus fulvestrant while 65 were assigned to fulvestrant plus placebo. All patients received 500 mg of fulvestrant on days 1 and 15 of cycle 1, then on day 1 of each subsequent 28-day cycle.
Treatment continued for a maximum of 12 cycles (48 weeks) or until progression, unacceptable toxicity, or withdrawal of consent. Patients who did not progress by week 48 underwent unblinding of the treatment arm. At the time of unblinding, all patients originally assigned to everolimus continued on open-label everolimus.
All women in the study are included in the efficacy analysis. All women from the placebo arm and 64 women from the everolimus arm were included in the updated safety results. One patient withdrew consent and another was deemed ineligible because of performance status deterioration. Neither woman received the protocol treatment.
Twelve patients (18.2%; 95% CI, 9.8-29.6) in the experimental arm had an objective response compared with 8 (12.3%; 95% CI, 5.5-22.8) in the placebo arm, but the difference was nonsignificant (P
= .47). Investigators observed a significant difference (P
= .01) in clinical benefit rate favoring the experimental arm (63.6% vs 41.5%).
In the experimental arm, the median duration of treatment was 5.1 months (range, 0-28.6) for everolimus and 6.9 months (range, 1.4-29.8) for fulvestrant. The median duration was 4.6 months for both fulvestrant and placebo in the control arm.
Patients in the experimental arm were more likely to require any dose modification (66% vs 37%), dose held (45% vs 22%), or dose reduced (23% vs 3%), and more likely to miss a dose due to noncompliance (14% vs 9%).
Progression was the most common reason for treatment discontinuation. Thirty-seven (58%) 37 patients in the everolimus arm and 49 (75%) in the placebo arm discontinued treatment due to progression.
Thirteen (20%) patients discontinued due to adverse events (AEs) in the experimental arm compared with 5 (8%) in the placebo arm.
Everolimus was associated with increased toxicity. The most common (≥5%) grade ≥3 or higher treatment-related AEs in the everolimus arm compared with the placebo arm were oral mucositis (11% vs 0%), fatigue (6% vs 5%), and pneumonitis (6% vs 0%). One patient in the placebo arm experienced grade 4 elevated AST. There were no grade 4 AEs recorded in the experimental arm.
There were 3 deaths during the study or within 30 days of completing protocol therapy, 2 in the everolimus arm (sepsis and cardiac arrest) and 1 cardiac arrest in the placebo arm. There were no deaths attributed to study treatment.
In their concluding remarks, the authors addressed the emergence of CDK4/6 inhibitors as an effective treatment option for overcoming endocrine resistance.
“This study was completed before the availability of the CDK4/6 inhibitors, which are effective when added to both first-line AI therapy and second-line fulvestrant in AI-resistant disease,” wrote Kornblum et al. “Given the activity of the CDK4/6 inhibitors such as palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio), in combination with AIs as first-line endocrine therapy, the use of everolimus may represent an option for combination with fulvestrant as second-line therapy in AI-resistant disease.”
Kornblum N, Zhao F, Manola J, et al. Randomized phase II trial of fulvestrant plus everolimus or placebo in postmenopausal women with hormone receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer resistant to aromatase inhibitor therapy: results of PrE0102 [published online April 17, 2018]. J Clin Oncol. doi: 10.1200/JCO.2017.76.9331.