Trastuzumab is an HER2-targeted monoclonal antibody that improves survival in the adjuvant setting. Despite the efficacy of trastuzumab in the adjuvant setting, up to 25% of patients experience disease recurrence within 8 to 10 years.
Neratinib is a potent, irreversible tyrosine kinase inhibitor of HER1, HER2, and HER4, and is currently under development. Neratinib irreversibly binds to the intercellular signaling domain of HER1, HER2, and HER3, and inhibits phosphorylation and several HER downstream signaling pathways. The result is decreased proliferation and increased cell death. Clinical studies have shown that intracellular inhibition of HER signaling by neratinib is a more effective means of suppressing HER-mediated tumor growth and overcoming tumor escape mechanisms experienced with current HER2-targeted therapies.
ExteNET is an ongoing, phase 3, multicenter, randomized, placebo-controlled, double-blind study examining the efficacy, safety, and ability of neratinib to reduce the risk for recurrence in patients with early-stage, HER2-positive breast cancer after receiving trastuzumab in the adjuvant setting. Inclusion criteria for this study were HER2-positive breast cancer, prior adjuvant trastuzumab and chemotherapy, lymph node–positive, –negative, or residual invasive disease after neoadjuvant therapy, and hormone receptor (HR)-positive or -negative disease.
The primary study end point was invasive disease-free survival (iDFS). Secondary efficacy end points were disease-free survival including ductal carcinoma in situ, time to distant recurrence, distant disease-free survival, cumulative incidence of central nervous system recurrences, and overall survival (OS).
Women with HER2-positive breast cancer, completed surgery, and trastuzumab-based adjuvant therapy within <1 year were randomly assigned to receive oral neratinib 240 mg daily or matching placebo for 1 year. Concurrent adjuvant therapy for HR-positive disease was recommended. The intention-to-treat population included 2840 patients, with 1420 patients receiving neratinib and 1420 patients receiving placebo.
The primary 2-year analysis revealed significant iDFS benefit with 12 months of neratinib, resulting in 2.3% absolute improvement in iDFS compared with placebo (hazard ratio, 0.67; 95% confidence interval, 0.50-0.91; P = .009). There was also a 33% reduction in the risk for recurrence or death with neratinib compared with placebo. Neratinib was shown to have a manageable and tolerable safety profile and a low incidence of grade 3 or 4 adverse events. Diarrhea was the most common adverse event, with a grade 3 incidence rate of 39.8% and a grade 4 incidence rate of 0.1%.
The median follow-up time for the interim 5-year analysis of iDFS was 4.3 years. At the cutoff date for this 5-year interim analysis, 1952 patients—69% of the intention-to-treat population—had reconsented to longer-term follow-up. At this point, there was a 26% reduction in the risk for invasive-disease recurrence or death with neratinib compared with placebo. The 5-year iDFS rates were 90.4% for patients receiving neratinib and 87.9% for patients receiving placebo. The absolute benefit of 2.5% was maintained for 5 years, and a 4.8% absolute benefit occurred in the HR-positive cohort.
Patients who initiated neratinib treatment ≤1 year after completing adjuvant trastuzumab therapy experienced a further reduction in the risk for invasive-disease recurrence or death. Patients who initiated neratinib ≤1 year after completing adjuvant trastuzumab therapy and whose tumors were HER2-positive experienced a 35% reduction in the risk for iDFS compared with placebo. In the subgroup of patients with HR-positive disease, neratinib resulted in a 41% reduction in the risk for iDFS compared with placebo. The 5-year iDFS in this subgroup was 91.7% with neratinib and 86.9% with placebo, indicating an absolute benefit of 4.8% with neratinib.
The 5-year interim analysis confirms sustained benefit with neratinib. Patients with early-stage, HER2-positive breast cancer who were previously treated with trastuzumab in the adjuvant setting experienced significant iDFS after a 1-year course of neratinib compared with those receiving placebo. Patients with HR-positive disease experienced greater benefit as a result of dual inhibition of HER2 and estrogen-receptor crosstalk. The final 5-year iDFS findings are expected in the second quarter of 2017, and OS data are not yet mature.
Martin M, et al. ONS Abstract IS-16.