Neratinib is an oral anti-HER2 tyrosine kinase inhibitor that has shown promising activity in the treatment of HER2-positive metastatic breast cancer.1 It differs from monoclonal antibodies such as trastuzumab (Herceptin) because, as a small molecule, neratinib blocks the ATP binding site on the intracellular domain of the HER2 molecule, thereby inhibiting downstream signal transduction through the AKT-PI3 kinase pathway. It also differs from other tyrosine kinase inhibitors such as lapatinib (Tykerb) because it binds not only to HER1 and HER2 but also to HER4 and does so irreversibly. Findings in the ExteNET trial, reported by Chan and colleagues2 and summarized in this issue of The ASCO Post, indicate benefit of neratinib vs placebo after trastuzumab-based adjuvant therapy in early-stage HER2-positive breast cancer.
As the authors of the ExteNET study point out, extending adjuvant trastuzumab to 2 years of treatment, as done in the HERA trial, did not improve disease-free or overall survival compared with 1 year.3 On the other hand, testing a molecule with a different mechanism of action for a second year of anti-HER2 targeted therapy might prove beneficial, particularly for patients with high-risk disease.
The ExteNET investigators have now presented their early 2-year results, with the primary endpoint of invasive disease–free surival.2 This was a large study, opened at 495 centers globally and enrolling 2,840 patients who had completed standard adjuvant treatment with chemotherapy and trastuzumab. Patients were randomly assigned to receive 1 year of neratinib or placebo. Although the trial’s sponsor changed twice, the treatment allocation and events remained blinded to patients, investigators, and sponsors, and the primary endpoint was maintained with the intent-to-treat analysis.
Study Amendments
Two important amendments were instituted during the course of the trial. With the recognition that patients with node-negative disease actually have an excellent prognosis with standard chemotherapy/trastuzumab treatment, eligibility was restricted to patients with node-positive disease, but only after 671 patients with node-negative cancer had been enrolled. This represented 24% of the patients in the final intent-to-treat analysis, and their inclusion may have narrowed slightly the difference between the investigational and control groups.
The second important amendment was to reduce the allowed interval between completion of trastuzumab and enrollment from 2 years to 1 year, thereby capturing patients who might have experienced a recurrence during the second year off therapy. Given these considerations, a 2.3% absolute improvement in invasive disease–free survival is evidence of the activity of neratinib in this population, especially in patients with higher-risk disease.
Curious Finding
There was a curious finding not seen in other HER2 adjuvant trials. Analysis according to the stratification factor of hormone receptor status showed that the benefit of neratinib was more pronounced in patients with hormone receptor–positive breast cancer (hazard ratio = 0.51) vs those with hormone receptor–negative disease (hazard ratio = 0.93). The authors hypothesized that the irreversible binding and different mechanism of action of neratinib in patients who have received maximum trastuzumab benefit may positively modify estrogen receptor sensitivity to hormonal agents in the adjuvant setting. This is conjectural but a potentially important consideration requiring further study.
Toxicity
The primary side effect seen with neratinib was diarrhea, with 40% of patients in the investigational group experiencing grade 3 toxicity. It occurred primarily during the first month of treatment and lasted a median of 5 days (range 2–9 days) but led to discontinuation of neratinib treatment in 17% of the patients. Fortunately, this toxicity was responsive to administration of antidiarrheal agents, and a current trial is evaluating the prophylactic administration of loperamide during the first month of neratinib therapy. Not surprisingly, cardiac toxicity was uncommon in this trial given that all patients had a normal cardiac ejection fraction after having completed prior treatment with trastuzumab and chemotherapy.
Who Will Benefit Most
The early results of the ExteNET trial indicate a potential role for neratinib in a subgroup of patients with significant residual risk for recurrence after completion of standard chemotherapy and HER2-targeted therapy. This is especially true if the gastrointestinal toxicity of neratinib can be minimized. Further study will be important to understand whether this treatment will be most worthwhile for patients whose tumors are not only HER2-positive but also hormone receptor–positive.
One of the welcome challenges for breast cancer researchers today is to identify those patients who might gain the most benefit from new treatment interventions. In the spectrum of adjuvant therapies for malignancy, the bar for HER2-positive breast cancer has been set reasonably high, with 10-year overall survival at 84% in patients with mostly node-positive disease treated in the NSABP B-31/NCCTG N9831 protocol.4 In the patient population in the ExteNET study, the invasive disease–free survival in the placebo arm at 2 years was 91.6%. Ongoing clinical trials are testing whether the incorporation of other new agents along with trastuzumab as dual-targeted anti-HER2 therapy in the neoadjuvant or adjuvant setting will raise the bar further.
Also, we are learning that patients with small node-negative tumors may do very well with much less aggressive therapy.5,6 All of this is good news for our patients, and the ExteNET trial provides an early indication that we have another active and potentially beneficial intervention to offer some of our patients as we move closer to a cure for this disease. How new agents such as neratinib can be incorporated most effectively over time will be a focus of continued interest and research. What we are learning about HER2-positive breast cancer is that one size does not fit all. ■
Disclosure: Dr. Romond reported no potential conflicts of interest.
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