Targeted Therapy Drugs: Necitumumab

Targeted Therapy Drugs: Necitumumab-Introduction

Necitumumab, developed by Eli Lilly, is a recombinant human IgG1 monoclonal antibody that binds to the human epidermal growth factor receptor (EGFR) and blocks the binding of EGFR to its ligands. It is applied in combination with gemcitabine and cisplatin for first-line treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC).

Targeted Therapy Drugs: Necitumumab-Target

The target of this drug is EGFR. EGFR belongs to a family of receptor tyrosine kinases (TKs) that includes EGFR, ERBB2 (also known as HER2), ERBB3 (also known as HER3) and ERBB4 (also known as HER4). Structurally, each receptor is composed of an extracellular ligand-binding domain, a transmembrane domain and an intracellular domain. All family members have intrinsic TK activity, except ERBB3. The receptors exist as inactive monomers. On binding to ligands, such as EGF and transforming growth factor-α, the receptors undergo conformational changes that facilitate homodimerization or heterodimerization. Growth factor-induced receptor dimerization of EGFR is followed by intermolecular autophosphorylation of key tyrosine residues in the activation loop of catalytic TK domains through the transfer of γ-phosphates from bound adenosine triphosphate (ATP). Subsequently, appropriate adaptor or signalling molecules with SRC homology 2 and protein tyrosine-binding domains bind to carboxy-terminal phosphotyrosines and recruit proteins involved in downstream signalling events that control multiple cellular processes, including proliferation and survival. Selective blockade of EGFR and ERBB2 has been shown to be an effective therapeutic approach against multiple epithelial cancers.

Targeted Therapy Drugs: Necitumumab-Disease

Necitumumab is applied for treating metastatic squamous non-small cell lung cancer (NSCLC). Lung cancer is the leading cause of cancer death in the United States. NSCLC, as the main type of this cancer can be divided into squamous cell and non-squamous cell cancer. Today, further subcategrization can be handled due to the various molecular criteria, which can also be regarded as a strategy for cancer treatment. The distinct subsets of cancer may have some driving mutations in genes that encode proteins are crucial for the cellular proliferation and survival. Targeting the activity of these mutant proteins can lead to cell death and therapeutic benefit. NSCLC harbours activating mutations in the epidermal growth factor receptor (EGFR) gene. So the EGFR protein act as a vital target in NSCLC therapy

Targeted Therapy Drugs: Necitumumab-Efficacy

The safety and efficacy of Necitumumab were evaluated in a multicenter, randomized, open-label clinical study of 1,093 participants with advanced squamous NSCLC who received the chemotherapies gemcitabine and cisplatin with or without Portrazza. Those taking Necitumumab plus gemcitabine and cisplatin lived longer on average (11.5 months) compared to those only taking gemcitabine and cisplatin (9.9 months). Necitumumab was not found to be an effective treatment in patients with non-squamous NSCLC.

Targeted Therapy Drugs: Necitumumab-Side Effect

The most common side effects of Necitumumab are skin rash and magnesium deficiency (hypomagnesemia), which can cause muscular weakness, seizure, irregular heartbeats and can be fatal. Necitumumab includes a boxed warning to alert health care providers of serious risks of treatment with Necitumumab, including cardiac arrest and sudden death, as well as hypomagnesemia.

Targeted Therapy Drugs: Necitumumab-Reference

Pao W, Chmielecki J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer[J]. Nature Reviews Cancer, 2010, 10(11): 760-774.