The primary efficacy analysis based on local radiological assessment resulted in an estimated 22% risk reduction in PFS (HR 0.78, 95% CI 0.65–0.95, P = 0.0067), corresponding to a modest 1.22-month prolongation in median PFS, from 5.78 months in the placebo arm to 7.00 months in the everolimus arm.70

The PFS benefit of everolimus was observed across patient subgroups defined by demographic characteristics, previous therapy, and disease characteristics, and patients with hormone receptor–negative tumors had better PFS outcomes with everolimus. Secondary end points included ORR, which was similar between treatment arms; OS data are not yet mature.

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The non-hematological AE profile of everolimus in combination with trastuzumab and vinorelbine was consistent with the known safety profile of the individual drugs, and no new unexpected AEs were observed.45,70 AEs typical of mTOR inhibitors occurred more frequently with everolimus and included stomatitis, non-infectious pneumonitis, rash, and hyperglycemia, whereas the incidence and grade of other non-hematological AEs were similar between treatment arms (everolimus plus trastuzumab and vinorelbine vs placebo plus trastuzumab and vinorelbine), with the exception of grade 3/4 stomatitis (13% vs 1%) and fatigue (12% vs 4%). The most common hematological AEs with everolimus plus trastuzumab and vinorelbine treatment were neutropenia (81%), anemia (49%), febrile neutropenia (17%), and thrombocytopenia (14%).

Other mTOR inhibitors under development in HER2-resistant breast cancer include temsirolimus and INK128, both with ongoing phase 1/2 studies. Investigational PI3K inhibitors include buparlisib (BKM120), BYL719, GDC-0941, and XL147; and investigational Akt inhibitors include MK2206, all under investigation in phase 1/2 clinical studies in patients with HER2+ breast cancer who either experienced progression while taking trastuzumab or received prior trastuzumab therapy.

In a phase 1/2 study of the PI3K inhibitor buparlisib, in combination with trastuzumab in patients resistant to trastuzumab-containing therapy, the maximum tolerated dose (MTD) of buparlisib was reported to be 100 mg/day, with grade 3 AEs of asthenia, altered mood, rash, γ-glutamyl transpeptidase increase, hypokalemia, and hypersensitivity (in one patient each), and no grade 4 events were reported (Clinical identifier NCT01132664).76

In the 17 enrolled patients (18 were initially enrolled), two achieved partial response and seven achieved disease stabilization. An additional phase 1/2 study evaluating safety and efficacy of buparlisib plus lapatinib in HER2+ trastuzumab-resistant advanced breast cancer in patients with evidence of activation of the PI3K/Akt/mTOR pathway is currently recruiting ( identifier NCT01589861).77

Therapies targeting downstream pathways—IGF1R inhibitors

It is hypothesized that crosstalk between IGF1R and HER2 might occur in breast cancer cells, leading to receptor heterodimerization and causing tumor cells to escape trastuzumab toxicity.37 In preclinical models, IGF1R overexpression led to trastuzumab resistance,36 and the combination of an IGF1R inhibitor and trastuzumab resulted in greater cell death than did treatment with trastuzumab alone.37

BMS-754807 and cixutumumab are IGF1R inhibitors undergoing phase 1/2 clinical investigation in patients with HER2-resistant breast cancer ( identifiers NCT00788333 and NCT00684983, respectively). A phase 2 study of linsitinib (OSI-906), a dual inhibitor of IGF1R and the insulin receptor,78 in patients with metastatic breast cancer was terminated because of severe toxicity and lack of efficacy ( identifier NCT01205685).

Therapies targeting downstream pathways—other tyrosine kinase inhibitors

Neratinib (HKI-272) is an irreversible multi-tyrosine kinase inhibitor of EGFR/HER1, HER2, and HER4, which has undergone clinical investigation in treatment of patients with HER2-resistant disease.79 Phase 1/2 study results in 72 patients who underwent previous HER2-targeted therapy and later were treated with neratinib in combination with capecitabine found that of the 22 patients evaluable for efficacy during the interim analysis, 11 achieved partial response (ORR of 50%) and two maintained stable disease for less than 24 weeks ( identifier NCT00741260).80

In a phase 1 study of neratinib in combination with trastuzumab and paclitaxel in patients with metastatic HER2+ breast cancer who had previously been treated with anti-HER agents and a taxane, the recommended phase 2 dose of neratinib in combination with trastuzumab and paclitaxel was determined to be 200 mg/day, and common grade 3/4 AEs were diarrhea (38%), dehydration (14%), electrolyte imbalance (19%), and fatigue (19%) ( identifier NCT01423123).81

Objective responses (two patients with complete response; six patients with partial response) were achieved in 38% of patients, and the median time to disease progression was 3.7 months. In an ongoing phase 1/2 study of neratinib in combination with temsirolimus in patients who previously received trastuzumab therapy, six patients treated at the MTD (8 mg intravenous) were evaluable for response, four achieved partial response, and one had stable disease ( identifier NCT01111825).82

Phase 2 study results in 117 patients with advanced breast cancer who received no more than two prior trastuzumab regimens and who were randomly assigned to receive neratinib or lapatinib plus capecitabine have been reported.83 For neratinib and combination therapy, median PFS was 4.5 and 6.8 months (HR 1.3, 95% CI 1.0–1.8, P = 0.091) and median OS was 19.4 and 19.0 months, respectively (P = 0.180; and ORR was 29% and 41%, P = 0.067), indicating that neratinib monotherapy was not as effective as lapatinib plus capecitabine (  identifier NCT00777101).