Background: Resistance to trastuzumab may occur through activation of the PI3K/Akt/mTOR signaling pathway, the inhibition of which may restore trastuzumab sensitivity. BOLERO-3, a phase 3, double-blind, international trial involving 569 patients with trastuzumab-resistant, HER2-positive (HER2+), advanced breast cancer pretreated with a taxane, recently reported that adding everolimus (EVE; an mTOR inhibitor) to vinorelbine and trastuzumab significantly improved progression-free survival (PFS) vs placebo (PBO) plus vinorelbine and trastuzumab (hazard ratio [HR] = 0.78; log-rank P = .0067). As EVE pharmacokinetics and, therefore, clinical effects may be different in Asian patients, we analyzed the efficacy and safety data from BOLERO-3 for the Asian population.

Methods: Eligible women with trastuzumab-resistant, HER2+, advanced breast cancer who received prior taxane therapy were randomized (1:1) to EVE (5 mg/day) or matching PBO in combination with weekly vinorelbine (25 mg/m2) and trastuzumab (2 mg/kg after 4-mg/kg loading dose). The primary endpoint was PFS by investigator. Secondary endpoints included safety.

Results: Among 569 patients enrolled in this study, 166 (29%) patients were Asian; 88 and 78 were assigned to EVE or PBO arms, respectively. In this subpopulation, adding EVE to vinorelbine and trastuzumab prolonged median PFS compared with the PBO arm (8.3 vs 6.8 months, respectively; HR = 0.83; 95% confidence interval, 0.59 - 1.18). In general, the incidence of all grade adverse events was similar for Asian versus non-Asian patients in the EVE arm (stomatitis, 71% vs 59%; pneumonitis, 7% vs 5%; and infections, 58% vs 70%) and the PBO arm (stomatitis, 31% vs 26%; pneumonitis, 1% vs 4%; and infections, 48% vs 49%). Serious adverse events had a low incidence and included febrile neutropenia (9.1%), neutropenia (2.3%), stomatitis (2.3%), anemia (2.3%), and cataract (2.3%) as the most common among Asian patients in the EVE arm. The incidence of serious pneumonitis was low: Asian (1.1%) versus non-Asian patients (0%) in the EVE arm and 0% versus 1.5%, respectively, in the PBO arm.

Conclusions: Asian patients in the BOLERO-3 trial treated with EVE plus vinorelbine and trastuzumab showed PFS benefits similar to the overall population and had a comparable manageable safety profile. Thus, EVE in combination with vinorelbine and trastuzumab may be considered as a new therapeutic option for Asian women with trastuzumab-resistant, HER2+, advanced breast cancer progressing after taxane-based therapies.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-19.