Adding Everolimus to Trastuzumab/Vinorelbine Prolongs Progression-Free Survival but Increases Toxicity in Trastuzumab-Resistant Advanced Breast Cancer
Disease progression in HER2-positive breast cancer treated with trastuzumab (Herceptin) may be associated with PI3K/Akt/mTOR pathway activation, and use of an mTOR inhibitor might restore trastuzumab sensitivity. In the double-blind phase III BOLERO-3 trial reported in The Lancet Oncology, André et al assessed the addition of the mTOR inhibitor everolimus (Afinitor) to trastuzumab plus vinorelbine in women with HER2-positive, trastuzumab-resistant advanced breast cancer who had previously received taxane therapy. The addition of everolimus to the combination significantly prolonged progression-free survival but also resulted in higher rates of hematologic and nonhematologic toxicities.
Study Details
In the trial, 569 patients were randomly assigned to receive weekly trastuzumab at 2 mg/kg and vinorelbine at 25 mg/m² plus everolimus at 5 mg/d (n = 284) or placebo (n = 285) every 3 weeks with stratification by previous lapatinib (Tykerb) treatment. Trastuzumab resistance was defined as recurrence during or within 12 months of adjuvant therapy or progression during or within 4 weeks of treatment for advanced disease. The primary endpoint was progression-free survival on local radiologic review.
The everolimus and placebo groups were generally balanced for age (median, 54.5 and 54 years), ethnicity (69% white in both, 24% and 22% Asian), Eastern Cooperative Oncology Group performance status (0 in 68% and 67%, 1 in 31% in both), estrogen receptor status (positive in 53% in both), progesterone receptor status (positive in 37% in both), metastasis site (bone in 44% and 40%, visceral in 79% and 75%, including liver in 43% and 47%, central nervous system in 7% and 2%), previous lines of chemotherapy in metastatic setting (zero for 16% in both, one for 40% and 42%, two for 34% and 29%, three for 8% and 12%), and previous treatments (eg, radiotherapy in 100% in both, surgery in 86% and 84%, hormonal therapy in 43% and 40%, anthracyclines in 64% and 62%, cyclophosphamide in 61% and 60%, lapatinib in 27% in both).
Increased Progression-Free Survival
After a median follow-up of 20.2 months, median progression-free survival was 7.00 months in the everolimus group vs 5.78 months in the placebo group (hazard ratio [HR] = 0.78, P = .0067). Subgroup analyses showed that hazard ratios consistently favored everolimus and were significant for patients aged < 65 years (0.77, 95% confidence interval [CI] = 0.62–0.95), European sites (0.72, 95% CI = 0.53–0.99), no prior lapatinib (0.78, 95% CI = 0.62–0.99), prior adjuvant or neoadjuvant trastuzumab (0.65, 95% CI = 0.48–0.87), hormone receptor–negative/progesterone receptor–negative status (0.65, 95% CI = 0.48–0.87), and no visceral involvement (0.48, 95% CI = 0.30–0.76). Exploratory analysis indicated greater progression-free survival benefit with everolimus according to PTEN low status (HR = 0.40, 95% CI = 0.20–0.82) and pS6 high status (HR = 0.48, 95% CI =0.24–0.96).
Objective response occurred in 41% of everolimus patients and 37% of placebo patients (P = .2108). Overall survival data were not mature at the time of progression-free survival analysis and are to be reported at a later date.
Increased Toxicity
The most common grade 3 or 4 adverse events in the everolimus vs placebo groups were neutropenia (73% vs 62%), leukopenia (38% vs 29%), anemia (19% vs 6%), febrile neutropenia (16% vs 4%), stomatitis (13% vs 1%), and fatigue (12% vs 4%). Serious adverse events occurred in 42% vs 20%, with the most common being febrile neutropenia (10% vs 1%), pyrexia (5% vs 2%), neutropenia (4% vs 1%), anemia (4% vs 1%), and stomatitis (3% vs < 1%). Hospitalization was required for 27 of 29 everolimus patients and each of 4 placebo patients with febrile neutropenia as a serious adverse event.
All study treatment was discontinued due to adverse events in 10% vs 5% of patients, with those leading to discontinuation in > 2% of patients consisting of decreased ejection fraction (4% vs < 1%), neutropenia (3% vs 2%), fatigue (3% vs 1%), and stomatitis (2% vs 0%). Two deaths in each group were considered related to adverse events, consisting of death due to unknown cause and acute respiratory distress syndrome in the everolimus patients and acute respiratory failure and pneumonia in the placebo patients.
The investigators concluded, “The addition of everolimus to trastuzumab plus vinorelbine significantly prolongs [progression-free survival] in patients with trastuzumab-resistant and taxane-pretreated, HER2-positive, advanced breast cancer. The clinical benefit should be considered in the context of the adverse event profile in this population.”
Luca Gianni, MD, of Ospedale San Raffaele Scientific Institute, Milan, is the corresponding author for The Lancet Oncology article.
The study was funded by Novartis Pharmaceuticals. For full disclosures of the study authors, visit www.thelancet.com.
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