Emerging treatments for HER2-positive early-stage breast cancer: focus on neratinib

Abstract

Over the last decades, a better understanding of breast cancer heterogeneity provided tools for a biologically based personalization of anticancer treatments. In particular, the overexpression of the human epidermal growth factor receptor 2 (HER2) by tumor cells provided a specific target in these HER2-positive tumors. The development of the monoclonal antibody trastuzumab, and its approval in 1998 for the treatment of patients with metastatic disease, radically changed the natural history of this aggressive subtype of breast cancer. These findings provided strong support for the continuous research in targeting the HER2 pathway and implementing the development of new anti-HER2 targeted agents. Besides trastuzumab, a series of other anti-HER2 agents have been developed and are currently being explored for the treatment of breast cancer patients, including those diagnosed with early-stage disease. Among these agents, neratinib, an oral tyrosine kinase inhibitor that irreversibly inhibits HER1, HER2, and HER4 at the intracellular level, has shown promising results, including when administered to patients previously exposed to trastuzumab-based treatment. This article aims to review the available data on the role of the HER2 pathway in breast cancer and on the different targeted agents that have been studied or are currently under development for the treatment of patients with early-stage HER2-positive disease with a particular focus on neratinib.

Neratinib in Early-Stage Breast Cancer: A Profile of Its Use in the EU

“…In early-stage HER2-positive breast cancer, standard adjuvant therapy with chemotherapy and trastuzumab for 1 year was associated with an absolute improvement of 6–12% in disease-free survival and 6–9% in overall survival during longer-term follow-up (8–12 years); however, 15–20% of patients had disease recurrence [3]. Several options have been explored to escalate standard adjuvant therapy, including extending trastuzumab treatment to 2 years and combining trastuzumab with lapatinib (dual HER1 and HER2 inhibitor) or bevacizumab (anti-vascular endothelial growth factor monoclonal antibody) [3, 4]. However, no significant clinical benefit was demonstrated with these treatments [3].…”

“…However, no significant clinical benefit was demonstrated with these treatments [3]. The search for alternative therapies led to the development of the oral, irreversible, pan-HER tyrosine kinase inhibitor neratinib (Nerlynx ® ) as an extended adjuvant treatment for patients with early-stage, HER2-positive breast cancer who have completed trastuzumab-based adjuvant therapy [4, 5]. This review focuses on the clinical evidence for its use in the extended adjuvant setting, with a particular focus on the patient population for which it is approved in the EU, i.e.…”

Prognostic role of distant disease-free interval from completion of adjuvant trastuzumab in HER2-positive early breast cancer: analysis from the ALTTO (BIG 2-06) trial

“…In addition, real-world data from the currently ongoing registries in the advanced setting should also be considered an important source of data to explore this unmet medical need. [26][27][28][29] With the current availability of several effective targeted agents as (neo)adjuvant and post-neoadjuvant treatment for patients with HER2-positive breast cancer, [30][31][32][33][34] defining the optimal performance of first-line anti-HER2 therapies in those relapsing after prior exposure in the early setting is becoming a clinically relevant research area. The present analysis has some limitations that should be acknowledged.…”

Novel treatment strategies for patients with HER2‑positive breast cancer who do not benefit from current targeted therapy drugs (Review)

“…A more important role of neratinib was observed when combined with paclitaxel in treating patients who received prior taxane, trastuzumab and lapatinib therapies (71). Neratinib was effective as a single agent or in combination with different chemotherapy drugs in the treatment of HER2+ MBC patients and early BC patients (68,(72)(73)(74). In a multicenter, randomized, double-blind and placebo-controlled phase III trial (ExteNET), which involved 2,840 women, a total of invasive disease-free survival events of 70 patients in the neratinib group and 109 patients in the placebo group occurred, corresponding to 93.9 and 91.6% 2-year invasive disease-free survival rates, respectively (75).…”