BOLERO-3 Safety Analysis Finds Everolimus Regimen Is Manageable

Guy Jerusalem, MD, PhD

The combination of everolimus, trastuzumab, and vinorelbine, as given in the BOLERO-3 trial in patients with pretreated HER2-positive advanced breast cancer, is adequately tolerated, and adverse events are manageable, according to a safety analysis of the international phase III study presented at the 2013 San Antonio Breast Cancer Symposium.

The findings build upon earlier efficacy data indicating that adding the mTOR inhibitor everolimus slows tumor progression in patients who have become resistant to trastuzumab, defined as recurrence while taking the HER2-targeting agent or within four to 12 weeks since last infusion depending on the treatment setting.

BOLERO-3 evaluated the efficacy and safety of adding everolimus (5 mg/day) to trastuzumab (2 mg/kg weekly), and vinorelbine (25 mg/m²), compared with placebo, trastuzumab, and vinorelbine in 569 women with trastuzumab-resistant HER2-positive advanced breast cancer previously treated with a taxane. As presented at the 2013 Annual Meeting of the American Society of Clinical Oncology, the primary efficacy endpoint, progression-free survival (PFS), was longer in the everolimus arm compared with the placebo arm (median: 7.0 months vs 5.78 months; HR = 0.78; P = .0067) at a median follow-up of 20 months.

Study drugs were continued until disease progression or unacceptable toxicity. Incidences of adverse events were monitored continuously. Cardiac imaging was assessed at screening and every 12 weeks. The safety population included all patients who received at least one daily dose of study treatment and who had at least one valid post-baseline safety assessment.

Treatment in BOLERO-3 represented the second, third, or fourth line of chemotherapy for 84% of patients in the metastatic setting. One-fourth of the patients in each group had a treatment history that included the anti-HER2 agent lapatinib.

The median duration of exposure to study treatment was similar across the treatment groups, and ranged from 22.9 weeks for placebo to 25.1 weeks for trastuzumab in the experimental arm.

Guy Jerusalem, MD, head of Medical Oncology at the University of Liege in Belgium, presented the safety results at the symposium.

Class-effect adverse events (AEs) associated with mTOR inhibitors (eg, stomatitis, rash, noninfectious pneumonitis, and hyperglycemia) occurred more frequently in the everolimus arm, and most were grade 1/2.

The incidences of serious AEs suspected to be treatment-related were 26.4% in the everolimus arm and 6.4% in the placebo arm. Grade 3 class-effect AEs in the everolimus arm each occurred in less than 15% of patients: (stomatitis, 13%; hyperglycemia, 4%).

“We added a targeted agent and we expect to add some toxicity, so we have somewhat more neutropenic fever and also stomatitis, which of course is a typical side effect associated with everolimus,” said Jerusalem. “Vinorelbine also produces stomatitis, so giving both together will give an even higher incidence of stomatitis.”

At 6% for all grades, the incidence of noninfectious pneumonitis was less than it was in other clinical trials of everolimus. “Noninfectious pneumonitis is generally reported to be 15% with everolimus, with a 3% incidence of grade 3 toxicity,” he said. “One possible explanation is the dose used in this study—5 mg. But other factors may contribute. Corticosteroids are sometimes given as antiemetic treatments during cancer chemotherapy. There may also be an immunosuppressive effect of the chemotherapy added.”

Grade 4 noninfectious pneumonitis occurred in less than 1%, and there were no grade 4 events of stomatitis or hyperglycemia, and no grade 3/4 events of rash, according to the abstract.

There were 10 instances of a decrease in ejection fraction that caused treatment discontinuation in everolimus-treated patients and one in the placebo group.

The increased toxicity in the everolimus arm did not affect quality of life or performance status. The median time to deterioration in European Cooperative Oncology Group performance status was 32.66 months in the everolimus arm versus 21.55 months in the placebo arm, a nonsignificant difference.

As per protocol, patient-reported, health-related quality-of-life (HRQoL) data were a part of a separate analysis reported here. This analysis showed no negative impact of everolimus on overall and functional HRQoL scores. There was no significant difference in the median time to definitive deterioration (TTD) of HRQoL between treatment arms, while the median TTD in global health status score was 8.3 months in the everolimus arm and 7.3 months in the placebo arm, a nonsignificant difference.

A subanalysis of the 166 Asian patients included in BOLERO-3 demonstrated a similar benefit to everolimus on PFS in Asians compared with the overall study population and a comparable manageable safety profile.

Jerusalem G, Masuda N, André F, et al. 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. Presented at: 2013 San Antonio Breast Cancer Symposium; December 10-14, 2013; San Antonio, TX. Abstract S2-02. Abstract P3-15-03.

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