Mechanism of Action Magnifier – 2016 Desk Reference

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Necitumumab: an Epidermal Growth Factor Receptor Antibody

Overexpression of the epidermal growth factor receptor (EGFR) is correlated with poor prognosis in many human cancers.1 EGFR is a member of the ErbB family of receptor tyrosine kinases (TKs). EGFR activation occurs in response to ligand stimulation and/or genetic alterations of the EGFR gene, such as somatic mutations, amplifications, or deletions. Activated EGFR induces downstream signaling through the MAPK, PI3K/AKT, and PLCγ signal transduction pathways that mediate cell proliferation, cell survival, and cell migration, respectively, thereby contributing to neoplastic transformation and tumor growth.2-4

Two main classes of anticancer agents affect the EGFR: those targeting the extracellular ligand-binding domain and those blocking the intracellular TK domain.1 Cetuximab is a mouse/human chimeric monoclonal antibody that targets the ligand-binding domain of the EGFR, whereas erlotinib and gefitinib are small molecule TK inhibitors.

Necitumumab (IMC-11F8) is a recombinant, fully human IgG1 monoclonal antibody that binds to the extracellular domain of the human EGFR and blocks interaction between EGFR and its ligands.5-7 A critical difference between necitumumab and cetuximab that is important for the use of these antibodies as anticancer drugs is that the variable domains of necitumumab are of human origin, while the variable region of cetuximab is of mouse origin.6 A particular challenge of treatment with a chimeric antibody is the immune system’s habit of recognizing them as nonself and eliminating them from the body. Cetuximab has already shown its value in the clinic but suffers from the problems associated with immune sensitivity to mouse-derived antibody sequences. Necitumumab, as a mechanistically very similar, but fully human, antibody is likely to reproduce all of cetuximab’s promise but lack its disadvantages.6

The antitumor effects of necitumumab in combination with cisplatin plus gemcitabine, pemetrexed, or paclitaxel were evaluated in mouse tumor models. Results from these preclinical studies showed that the combination of necitumumab and cisplatin/gemcitabine was particularly effective, although interestingly, the mechanisms underlying these benefits were model dependent. For example, increased tumor cell apoptosis contributed toward combination efficacy in the A549 model, in association with increased expression of hsa-miR-29b and reduced expression of anti­apoptotic genes, including DNA methyltransferase DNMT3B, commonly upregulated in patients with non–small cell lung cancer (NSCLC). Such inverse effects of combination therapy on DNMT3B and hsa-miR-29b expression were found in multiple models. Importantly, in the A549 model, hsa-miR-29b downregulation of DMNT3b reduced promoter methylation of tumor suppressor genes such as cell adhesion molecule 1 (CADM1), Ras-associated (RalGDS/AF-6) domain family member 1 (RASSF1), and fragile histidine triad gene (FHIT), increasing their expression. These results provided the rationale for clinical studies combining necitumumab and cisplatin/gemcitabine in patients with NSCLC.7

In a phase 3 study (SQUIRE) in patients with stage IV squamous NSCLC, the combination of necitumumab and the chemotherapy agents gemcitabine and cisplatin was compared with the 2 chemotherapy agents alone as first-line therapy.8 Results showed that the addition of necitumumab resulted in a median overall survival of 11.5 months compared with 9.9 months with the 2 chemotherapies alone.

References

  1. Lenz HJ. Anti-EGFR mechanism of action: antitumor effect and underlying cause of adverse events. Oncology (Williston Park). 2006;20(5 suppl 2):5-13.
  2. Yarden Y, Pines G. The ERBB network: at last, cancer therapy meets systems biology. Nat Rev Cancer. 2012;12:553-563.
  3. Arteaga CL, Engelman JA. ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell. 2014;25:282-303.
  4. Yarden Y, Shilo BZ. SnapShot: EGFR signaling pathway. Cell. 2007;131:1018.
  5. Lu D, Zhang H, Koo H, et al. A fully human recombinant IgG-like bispecific antibody to both the epidermal growth factor receptor and the insulin-like growth factor receptor for enhanced antitumor activity. J Biol Chem. 2005;280:19665-19672.
  6. Li S, Kussie P, Ferguson KM. Structural basis for EGF receptor inhibition by the therapeutic antibody IMC-11F8. Structure. 2008;16:216-227.
  7. Samakoglu S, Deevi DS, Li H, et al. Preclinical rationale for combining an EGFR antibody with cisplatin/gemcitabine for the treatment of NSCLC. Cancer Genomics Proteomics. 2012;9:77-92.
  8. Thatcher N, Hirsch FR, Luft AV, et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2015;16:763-774.
Web Exclusives - August 30, 2018

Next-Generation Sequencing More Cost-Effective and Faster Than Single-Gene Testing

A new study presented at ASCO 2018 showed that the use of next-generation sequencing of metastatic non–small-cell lung cancer tumors to test for all known cancer-related genetic mutations was more cost-effective and provided faster results than testing for a single genetic mutation.

Emerging Therapies, Web Exclusives - November 5, 2018

TLR9 Agonist plus Immunotherapy May Overcome Resistance to PD-1 Inhibition

According to data from a preliminary phase 1b clinical trial, a novel approach using the investigational toll-like receptor 9 (TLR-9) agonist CMP-001 in combination with pembrolizumab may have the potential to reverse resistance to anti–PD-1 therapy.