Resistance to HER2-targeted Therapies

General mechanisms of resistance to HER2-targeted therapies occur at three levels.22 The first includes mechanisms intrinsic to the target, such as molecular changes in the target receptor;23 the expression of p95HER2, which is a truncated HER2 receptor;24,25 and HER2 gene amplification.26

Resistance involving parallel signaling pathways bypassing HER2 inhibition, such as increased activation of HER3,2731 aberrant activation of pathways downstream of the receptor,3234 and compensatory crosstalk with other pathways, might also occur.23,3538 Resistance from defects in the apoptosis pathway in tumor cells or in extrinsic host factors participating in the action of the drugs is another potential mechanism of resistance to HER2-targeted therapy.22

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Current Treatment Options for HER2-resistant Breast Cancer

Lapatinib and trastuzumab emtansine (T-DM1) are licensed treatments for use in the setting of trastuzumab resistance.39,40 Lapatinib is a dual HER2 and epidermal growth factor receptor (EGFR)/HER1-specific tyrosine kinase inhibitor that binds to the intracellular domain of HER2, allowing it to inhibit both full-length HER2 and truncated p95HER2.24,41

Lapatinib monotherapy and lapatinib in combination with capecitabine were shown to provide the same clinical benefit, including progression-free survival (PFS), clinical benefit rate, and overall response rate (ORR), regardless of p95HER2 expression in breast tumors from the first- and second-line lapatinib clinical development program.25

Lapatinib in combination with capecitabine is approved for patients with HER2+ metastatic breast cancer that has progressed with trastuzumab, based on a phase-3, randomized study of 324 patients with HER2+, advanced or metastatic breast cancer who received previous treatment with an anthracycline, a taxane and trastuzumab ( identifier NCT00078572).39,42

Patients were randomly assigned to receive either lapatinib plus capecitabine or capecitabine alone.42 At a planned interim analysis, time to progression, the primary end point of the study, significantly favored the combination treatment arm (8.4 months with combination therapy versus 4.4 months with monotherapy; hazard ratio [HR] 0.49, 95% CI 0.34–0.71, P < 0.001), and a non-significant trend toward decreased CNS metastases with lapatinib therapy was observed.

The significant time to progression results at the interim analysis prompted early termination of the study and subsequent crossover of the study arms. Although final exploratory analyses of OS (median OS, 75.0 vs 64.7 weeks; HR 0.87, 95% CI 0.71–1.08, P = 0.210) showed a trend toward a survival advantage with lapatinib plus capecitabine, premature termination of enrollment and subsequent crossover resulted in insufficient power to detect significant differences.43

T-DM1 is an antibody–drug conjugate incorporating the HER2-targeted antitumor properties of trastuzumab with the cytotoxic activities of DM1, a microtubule agent that is a derivative of maytansine.44 T-DM1 as a single agent is indicated for the treatment of patients with HER2+ metastatic breast cancer in patients who previously received trastuzumab and a taxane.40

Approval of T-DM1 is based on the EMILIA study ( identifier NCT00829166), which is a phase 3, randomized, open-label study of 991 patients with HER2+ advanced breast cancer who received previous trastuzumab and taxane therapy.44

Patients were randomly assigned to receive T-DM1 or lapatinib plus capecitabine, and the primary end points included PFS and OS, with two interim OS analyses completed. The median PFS was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine (HR 0.65, 95% CI 0.55–0.77, P < 0.001), and the median OS at the second interim analysis crossed the stopping boundary for efficacy (30.9 vs 25.1 months; HR 0.68, 95% CI 0.55–0.85, P < 0.001).

Results from the phase 3 TH3RESA study ( identifier NCT01419197) of T-DM1 in patients who received prior treatment with both trastuzumab and lapatinib for advanced disease have recently been reported, reaffirming the results from the EMILIA study in 602 patients with previously treated HER2+advanced breast cancer.45

Patients with HER2+ advanced breast cancer who had received at least two prior HER2-directed therapies for advanced breast cancer were randomized to receive T-DM1 or physician’s choice of therapy, with optional crossover to T-DM1 in the control arm upon disease progression. The median PFS significantly favored T-DM1 compared with control (6.2 vs 3.3 months; HR 0.528, 95% CI 0.422–0.661, P < 0.0001). Although the interim OS analysis favored T-DM1 (HR 0.552, 95% CI 0.369–0.826, P = 0.0034), the efficacy stopping boundary was not crossed.

Investigational Options for HER2+ Therapy-resistant Breast Cancer

In addition to development of further novel HER-targeted therapies, several investigational treatments to manage resistance to HER2-targeted therapies are under development (Table 1; click on table to enlarge).

Maintaining HER2-targeted therapy, but switching chemotherapeutic agents, has been considered in the setting of HER2 resistance because some tumors that display resistance continue to depend on HER2-mediated signaling,46 and there are preliminary reports of the benefits of trastuzumab therapy beyond progression.47–53 It is also suggested that the use of trastuzumab after diagnosis of CNS metastases may lead to improved overall survival when compared with patients who discontinue trastuzumab after diagnosis of metastases or who do not receive trastuzumab at all.13,54

(For a larger image of Table 1, click here.)

Benefits of combination therapy with HER2 inhibitors have also been investigated. In a phase 3 study in patients with metastatic breast cancer resistant to trastuzumab therapy, trastuzumab in combination with lapatinib significantly improved PFS compared with lapatinib alone (median PFS, 12.0 vs 8.1 weeks; HR 0.73, 95% CI 0.57–0.93, P = 0.08).55