Clinical potential of necitumumab in non-small cell lung carcinoma

Abstract

Despite significant progress, new therapeutic approaches for advanced non-small cell lung cancer (NSCLC) are highly needed, particularly for the treatment of patients with squamous cell carcinoma. The epidermal growth factor receptor (EGFR) is often overexpressed in NSCLC and represents a relevant target for specific treatments. Although EGFR mutations are more frequent in non-squamous histology, the receptor itself is more often overexpressed in squamous NSCLC. Necitumumab is a human monoclonal antibody that is able to inhibit the EGFR pathway and cause antibody-dependent cell cytotoxicity. This drug has been studied in combination with first-line chemotherapy for advanced NSCLC in two Phase III trials, and a significant survival benefit was reported in squamous NSCLC (SQUIRE trial); by contrast, necitumumab did not prove itself beneficial in non-squamous histotype (INSPIRE trial). On the basis of the SQUIRE results, necitumumab was approved in combination with cisplatin and gemcitabine as a first-line treatment for advanced squamous NSCLC, both in the US and Europe, where its availability is limited to patients with EGFR-expressing tumors. The aim of this review is to describe the tolerability and the efficacy of necitumumab by searching the available published data and define its potential role in the current landscape of NSCLC treatment.

Keywords: EGFR; H-score; monoclonal antibody; necitumumab; non-small cell lung cancer.

Figure 1

In normal conditions, the extracellular interaction between EGFR and its ligand, EGF, leads to dimerization of the receptor, binding with ATP in the intracellular region of the receptor, and activation of two main pathways, the first being RAS-RAF-MEK-ERK and the second being PI3K-AKT-mTORc (which is inhibited by PTEN). Notes: Both pathways ultimately lead to proliferative and anti-apoptotic signals. In tumor cells with overexpressed or mutated EGFR, this mechanism is generally overactivated. Necitumumab binds the extracellular region of EGFR, preventing its interaction with EGF and the following downstream cascade. Additionally, the necitumumab–EGFR complex can induce ADCC by various types of immune system cells, such as T lymphocytes, NK lymphocytes, and macrophages; in the example, an activated cytotoxic T-cell releases ADCC effectors (the perforin/granzyme system), ultimately leading to the death of the target cell. The figure shows also the different mechanism of action of EGFR–TKIs, which inhibit the binding with ATP in the intracellular space and consequent activation of the aforementioned cascade. Abbreviations: ADCC, antibody-dependent cell cytolysis; AKT, protein kinase B; ATP, adenosine triphosphate; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; MEK, mitogen-activated protein kinase kinase; mTORc, mammalian target of rapamycin complex; NK, natural killer; PI3K, phosphatidylinositol-3-kinase; PTEN, phosphatase and tensin homolog; RAF, rapidly accelerated fibrosarcoma; RAS, rat sarcoma; TKI, tyrosine kinase inhibitor.