Disease progression in patients with HER2-positive breast cancer receiving Trastuzumab ( Herceptin ) might be associated with activation of the PI3K/Akt/mTOR intracellular signalling pathway.
A study has assessed whether the addition of the mTOR inhibitor Everolimus ( Afinitor ) to Trastuzumab might restore sensitivity to Trastuzumab.
In this randomised, double-blind, placebo-controlled, phase 3 trial, BOLERO-3, researchers recruited women with HER2-positive, Trastuzumab-resistant, advanced breast carcinoma who had previously received taxane therapy.
Eligible patients were randomly assigned ( 1:1 ) using a central patient screening and randomisation system to daily Everolimus ( 5 mg/day ) plus weekly Trastuzumab ( 2 mg/kg ) and Vinorelbine [ Navelbine ] ( 25 mg/m2 ) or to placebo plus Trastuzumab plus Vinorelbine, in 3-week cycles, stratified by previous Lapatinib use.
The primary endpoint was progression-free survival by local assessment in the intention-to-treat population.
Researchers have reported the final analysis for progression-free survival; overall survival follow-up is still in progress.
During the period 2009-2012, 569 patients were randomly assigned to Everolimus ( n=284 ) or placebo ( n=285 ). Median follow-up at the time of analysis was 20.2 months.
Median progression-free survival was 7.00 months with Everolimus and 5.78 months with placebo ( hazard ratio, HR=0.78; p=0.0067 ).
The most common grade 3-4 adverse events were neutropenia ( 73% in the everolimus group vs 62% in the placebo group ), leucopenia ( 38% vs 29% ), anaemia ( 19% vs 6% ), febrile neutropenia ( 16% vs 4% ), stomatitis ( 13% vs 1% ), and fatigue ( 12% vs 4% ).
Serious adverse events were reported in 117 ( 42% ) patients in the Everolimus group and 55 ( 20% ) in the placebo group; two on-treatment deaths due to adverse events occurred in each group.
In conclusion, 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. ( Xagena )
André F et al, The Lancet Oncology 2014; 15: 580-591