Abstract P3-15-03: Safety analysis of BOLERO-3: A phase 3 trial of daily everolimus (EVE) vs placebo (PBO), both with weekly trastuzumab (TRAS) and vinorelbine in trastuzumab-resistant, advanced breast cancer
Authors: Jerusalem G , Masuda N , André F , Fein L , Fasolo A , O'Regan R , Wilks S , Isaacs C , Zhang Y , Taran T , Toi M 
Published: August 2014

Abstract
Background: Activation of the PI3K/mTOR pathway is thought to be involved in resistance to TRAS. BOLERO-3 is a randomized phase 3, double-blind, placebo-controlled, international, clinical trial evaluating the addition of the mTOR inhibitor EVE (5 mg/day) to TRAS plus vinorelbine (25 mg/m2) in patients with HER2+ advanced breast cancer resistant to TRAS and who were previously treated with a taxane. A total of 569 adult women were randomized 1:1 to receive EVE (n = 284) or PBO (n = 285). Study treatment represented the 2nd, 3rd, or 4th line of chemotherapy-containing regimen for 83% of patients in the metastatic setting. The primary endpoint, progression-free survival based on local radiologic assessment, was significantly longer in the EVE arm versus PBO (HR = 0.78; P = .0067) at a median follow-up of 20 months.
Methods: Study drugs were continued until disease progression or unacceptable toxicity. Incidences of adverse events (AEs) were monitored continuously. Dose modifications and discontinuations were recorded.
Results: The median duration of exposure to study treatment was similar across treatment groups: 24.8 weeks for EVE, 25.1 weeks for TRAS, and 24.0 weeks for vinorelbine (EVE arm); and 22.9 weeks for PBO, 24.0 weeks for TRAS, and 23.1 weeks for vinorelbine (PBO arm). The AEs were consistent with known drug-safety profiles. Class-effect AEs with mTOR inhibitors (including stomatitis, rash, noninfectious pneumonitis, and hyperglycemia) were higher in the EVE arm and were mainly grade 1/2. Grade 3 class-effect AEs each occurred in &lt;15% of patients (stomatitis [13%], hyperglycemia [2%], and noninfectious pneumonitis [&lt;1%]). Grade 4 noninfectious pneumonitis (&lt;1%) was uncommon; there were no grade 4 events of stomatitis or hyperglycemia, and no grade 3/4 events of rash. The incidence and grade of hematologic AEs were increased in the EVE arm vs the PBO arm, including all grade neutropenia (81% vs 70%), anemia (49% vs 29%), febrile neutropenia (17% vs 4%) and thrombocytopenia (14% vs 2%); grade 3/4 hematologic AEs included neutropenia (grade 3: 35% vs 32%; grade 4: 38% vs 30%), anemia (grade 3: 17% vs 6%; grade 4: 2% vs &lt;1%), febrile neutropenia (grade 3: 11% vs 3%; grade 4: 5% vs 1%), and thrombocytopenia (grade 3: 3% vs &lt;1%; grade 4: 1% vs 0). The incidences and grades of changes in liver enzymes and hyperlipidemia were similar between arms. Serious AEs were reported in 42% of patients in the EVE arm and 20% of patients in the PBO arm (26% and 6% were attributed to study treatments, respectively). A higher percentage of patients discontinued treatment because of AEs in the EVE arm versus PBO (10% vs 5%). In all, 83% of patients required at least 1 EVE dose interruption and/or reduction; 96% of these were attributed to AEs. There were fewer deaths in the EVE arm (37%) compared with PBO (41%).
Conclusions: The safety of the combination of EVE, TRAS, and vinorelbine was considered manageable in this heavily pretreated patient population. Overall, the results from BOLERO-3 demonstrate that EVE can be combined with TRAS and chemotherapy to improve efficacy in TRAS-resistant HER2+ advanced breast cancer previously treated with a taxane.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-15-03.