Let us review management options, first for patients eligible to receive first-line therapy, and then for those whose disease progresses or relapses after first-line treatment.
There are three distinct options approved by the FDA in the first-line HER2-positive setting:
- chemotherapy with trastuzumab,
- docetaxel/trastuzumab/pertuzumab, and
- lapatinib/letrozole for patients with ER+/HER2+ advanced breast cancer.
Added to these FDA-approved specifics, even the recently approved T-DM1 (see next section) could theoretically be considered as an option for some patients eligible to receive first-line metastatic treatment).
An anti-estrogen alone could theoretically be considered for patients with indolent advanced ER+/HER2+disease, but I have essentially not recommended that strategy in view of data from three randomized phase III trials demonstrating the benefit of anti-estrogens plus anti-HER2 therapies (either trastuzumab or lapatinib in this setting, as well as very poor response and median progression-free survival for patients randomized to anti-estrogen therapy alone).
However, even in this setting of HER2+/ER+ metastatic breast cancer, most times we recommend combination chemotherapy plus anti-HER2 therapies for at least four to six months, and then discontinue the chemotherapy, add the anti-estrogen, and maintain the anti-HER2 approach until a change is required due to tumor progression or poor tolerability. The rationale for this approach is that the typical progression-free survival with anti-estrogen + anti-HER2 therapy is in the range of seven months, whereas it has been well documented to be 1.0 to 1.5+ years when combination chemotherapy-anti-HER2 treatment is utilized.
The chemotherapy combination regimens most commonly utilized before the results of the CLEOPATRA trial became available in late 2011 were taxane with trastuzumab (we have also extensively used the weekly paclitaxel + weekly carboplatin + trastuzumab regimen). However, data from CLEOPATRA have changed the consideration of best first-line therapy for patients with advanced HER2+ metastatic breast cancer.
This study showed that the combination of trastuzumab, pertuzumab, and docetaxel is now a preferred regimen (with category 1 evidence) in the first-line setting for metastatic HER2-positive breast cancer with no previous exposure to trastuzumab. The median progression-free survival was significantly longer in the group randomized to the triple regimen (docetaxel, trastuzumab, and pertuzumab) compared with the group who received trastuzumab plus docetaxel (18.5 months vs. 12.4 months; P<0.001).
Moreover, the overall survival analysis from this trial demonstrated a statistically significant improvement for patients treated with the triple-drug combination (HR=0.66; 95% CI, 0.52-0.84; P=0.0008). An interesting fact of CLEOPATRA was that only 10 percent or so of patients had received adjuvant trastuzumab -- which is different from the typical situation we observe in the U.S. and most parts of the world, where a vast majority of patients received trastuzumab-containing adjuvant regimens.
As the febrile neutropenia and diarrhea were higher than preferred, weekly paclitaxel is also an acceptable taxane to combine with trastuzumab and pertuzumab in the first-line setting. But we realize that it is important to evaluate other chemotherapy options as backbone to the combined anti-HER2 monoclonal antibodies. Thus, we are conducting the VELVET trial, a global phase II study in which we are investigating the use of vinorelbine + trastuzumab + pertuzumab in the first-line setting. This strategy is based on the fairly similar efficacy demonstrated in the HERNATA trial between trastuzumab with either vinorelbine or docetaxel but with less toxicity when vinorelbine was used.
Before discussing second-line options, there are two potential clinical response outcomes from first-line therapy: response or progression. If the patient has a major response, then continuation of anti-HER2 therapy with trastuzumab is classically recommended. If tumor progression occurs, then second-line therapy including an anti-HER2 agent is recommended.
The FDA has approved T-DM1 (now known as ado-trastuzumab emtansine) for patients with previously treated HER2-positive metastatic breast cancer. T-DM1 is now approved for use as a single agent for the treatment of patients with HER2+, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either received prior therapy for metastatic disease or developed disease recurrence during or within six months of completing adjuvant therapy.
T-DM1 combines the anti-HER2 monoclonal antibody trastuzumab with the chemotherapy DM1, and is the first approved antibody-drug conjugate (ADC) for management of breast cancer. So technically, T-DM1 could be appropriate as first-line therapy for patients who develop tumor progression within six months of trastuzumab-containing adjuvant therapy.
The recent regulatory agency approval of T-DM1 was based on the Phase III EMILIA trial, which demonstrated an improved median survival of nearly six months in patients with previously treated HER2+ metastatic breast cancer who received T-DM1 vs. lapatinib and capecitabine (median overall survival was 30.9 months vs. 25.1 months, respectively).
Additionally, the objective response rate was higher with T-DM1 than with the double-agent combination (43.6% vs. 30.8%; P<0.001). The two-year overall survival rates also favored T-DM1 over lapatinib plus capecitabine (65.4% vs. 47.5%). Perhaps as relevant is that patients receiving T-DM1 experienced significantly fewer severe side effects than those receiving lapatinib and capecitabine.
In the second-line setting, clinical data confirm that HER2 remains a valid target. Therapeutic options beyond T-DM1 include the combinations of lapatinib/capecitabine, trastuzumab/capecitabine, and lapatinib/trastuzumab. Based on the updated final analysis of the EGF104900 study, there was a significant 4.5-month median overall survival advantage with the combination of lapatinib and trastuzumab in patients with heavily pretreated HER2-positive metastatic breast cancer compared with lapatinib alone. Nearly 300 women participated in this trial, and Blackwell et al found that improvements in absolute overall survival rates were 10 percent at six months and 15 percent at 12 months in the combination arm compared with the lapatinib-alone arm.
The challenge with applying these data to practice is that lapatinib alone is not the usual comparator we would use in trials or clinical care. Data of pertuzumab with trastuzumab/chemotherapy or even T-DM1 plus pertuzumab/chemotherapy are awaited in the refractory setting, so that we can determine how to potentially incorporate pertuzumab beyond the first-line setting. There is also interest in evaluating other targeted agents with anti-HER2 therapies (in the first-line and refractory settings), which could help expand the therapeutic options for our patients.
In summary, there has been a revolution of improvements in therapies for patients with HER2+ metastatic breast cancer over the last 15 years. These improvements are a result of application of biological and clinical trial principles, patient participation in studies, and the development of novel targeted agents that improve survival. Although more work remains to be done, the progress has been remarkable.