A series of studies assessing the effect of previous HER2-targeted therapy on neratinib activity are underway, although inconsistent effects have been reported. In a phase 1/2 study of neratinib in combination with paclitaxel, among the 99 evaluable patients included in the MTD assessment, ORR was 73% (95% CI 62.9–81.2) in the overall population, 71% among patients who experienced up to one previous chemotherapy regimen for metastatic disease and no previous lapatinib therapy, and 77% among those who experienced two or three previous chemotherapy regimens for metastatic disease and in whom prior lapatinib therapy was permitted (ClinialTrials.gov identifier NCT00445458).84

In another phase 1/2 study of neratinib in combination with vinorelbine, ORR was 41% in patients who had not received lapatinib previously and 8% in patients who had experienced prior lapatinib therapy (ClinicalTrials.gov identifier NCT00706030).85

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Phase 2 study results of neratinib monotherapy in 136 patients reported 16-week PFS rates of 59% in patients who had previous trastuzumab therapy and 78% in those who did not, with a median PFS of 22.3 and 39.6 weeks, respectively, and with an ORR of 24% and 56% (ClinialTrials.gov  identifier NCT00300781).86

Additionally, a phase 2 trial of neratinib for patients with HER2+ breast cancer and brain metastases is currently recruiting (ClinialTrials.gov  identifier NCT01494662).87

Afatinib (BIBW 2992) is an irreversible tyrosine kinase inhibitor undergoing clinical investigation in HER2-resistant disease. Phase 2 results of afatinib monotherapy in 41 patients with HER2+ metastatic breast cancer that progressed after trastuzumab therapy have shown a median PFS of 15.1 weeks (95% CI 8.1–16.7) and a median OS of 61.0 weeks (95% CI 56.7–not evaluable), with 10% of patients achieving a partial response and 37% having stable disease, with an overall clinical benefit rate of 46% (ClinialTrials.gov identifier NCT00431067).88

There are a series of ongoing studies of afatinib in trastuzumab- or lapatinib-resistant breast cancer, which include LUX-Breast 1 (ClinialTrials.gov identifier NCT01125566), a phase 3 study assessing afatinib in combination with vinorelbine versus trastuzumab plus vinorelbine in patients with metastatic breast cancer in whom one round of previous trastuzumab therapy was ineffective.89

The study began June 2010, with an estimated enrollment of 508 patients and a planned completion date of June 2014. LUX-Breast 2 (ClinialTrials.gov identifier NCT01271725) is a phase 2 study assessing afatinib monotherapy followed by afatinib in combination with paclitaxel or vinorelbine upon progression in patients with metastatic breast cancer who experienced progression while taking previous trastuzumab or lapatinib therapy,90 and LUX-Breast 3 (ClinialTrials.gov identifier NCT01441596) is a phase 2 study assessing afatinib alone or in combination with vinorelbine versus investigator choice of treatment in patients with HER2+ breast cancer and progressive brain metastases after trastuzumab- or lapatinib-based therapy.91

Hsp90 inhibitors

Hsp90 is a chaperone protein that promotes protein folding and stabilization and prevents rapid protein degradation. Pre-clinical data show that HER2 is chaperoned by Hsp90.92 In a phase 2 study of 31 patients with trastuzumab-refractory HER2+ breast cancer, combination therapy with an Hsp90 inhibitor (tanespimycin; development of which was discontinued because of a corporate decision) and trastuzumab provided a clinical benefit rate of 59%, and a median PFS and OS of 6 and 17 months, respectively (ClinicalTrials.gov identifier NCT00773344).92

Phase 1/2 clinical investigation of other Hsp90 inhibitors in patients with HER2-resistant breast cancer includes AUY922 and ganetespib. Phase 2 clinical investigation of retaspimycin was terminated because of lack of efficacy at an interim analysis (ClinicalTrials.gov identifier NCT00817362).93

Telomerase inhibitors

Telomerase expression is necessary for cellular proliferation, with telomerase overexpression correlated with tumorigenesis, and with telomerase inhibition resulting in apoptosis or cell senescence.94 In a trastuzumab-resistant cell line, the telomerase inhibitor imetelstat (GRN163L) restored trastuzumab sensitivity.

A phase 1 study of imetelstat in patients with trastuzumab-resistant breast cancer has been completed, and, in an initial report of 10 patients with trastuzumab-refractory HER2+ metastatic breast cancer enrolled in the study, no objective responses were reported; however, two patients achieved stable disease (ClinicalTrials.gov identifier NCT01265927).95

VEGF inhibitors

HER2 induction of VEGF expression is believed to play a role in the pathogenesis of HER2-amplified breast cancer.96 In human breast cancer xenografts transplanted into mice, trastuzumab-resistant clones showed elevated VEGF expression, and sensitivity to trastuzumab was restored upon treatment with bevacizumab, which is a monoclonal antibody against VEGF,97 and with bevacizumab in combination with trastuzumab plus pertuzumab.98

Although bevacizumab has been investigated as first-line therapy in patients with HER2+metastatic breast cancer,99 planned or ongoing clinical studies of bevacizumab in patients with HER2-resistant breast cancer have not been reported.

Phase 2 results for pazopanib, an oral therapy approved for use in advanced renal cell carcinoma and advanced soft tissue sarcoma,100 in combination with lapatinib versus lapatinib monotherapy have been reported in patients with HER2+ inflammatory breast cancer, including those who experienced relapse after trastuzumab therapy (if the therapy was considered readily available) (ClinicalTrials. gov identifier NCT00558103).101

ORR for patients treated with lapatinib 1500 mg, lapatinib 1000 mg plus pazopanib 400 mg, and pazopanib 800 mg was 47%, 58%, and 31%, respectively, and median PFS was 16.0, 16.0, and 11.4 weeks, respectively. There was no consistent effect of prior trastuzumab therapy on response rate in the lapatinib-containing treatment arms.