Journal name: OncoTargets and Therapy Article Designation: Review Year: 2016 Volume: 9 OncoTargets and Therapy Dovepress Running head verso: Genova and Hirsch Running head recto: Necitumumab in non-small cell lung carcinoma open access to scientific and medical research DOI: http://dx.doi.org/10.2147/OTT.S114039 Open Access Full Text Article REVIEW Clinical potential of necitumumab in non-small cell lung carcinoma Carlo Genova1–3 Abstract: Despite significant progress, new therapeutic approaches for advanced non-small Fred R Hirsch1 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 overex- 1Division of Medical Oncology, Department of Medicine, University pressed in NSCLC and represents a relevant target for specific treatments. Although EGFR of Colorado Cancer Center, Aurora, mutations are more frequent in non-squamous histology, the receptor itself is more often CO, USA; 2Lung Cancer Unit, IRCCS AOU San Martino IST, 3Department of overexpressed in squamous NSCLC. Necitumumab is a human monoclonal antibody that Internal Medicine, School of Medicine, is able to inhibit the EGFR pathway and cause antibody-dependent cell cytotoxicity. This University of Genoa, Genoa, Italy 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 For personal use only. 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: necitumumab, EGFR, non-small cell lung cancer, monoclonal antibody, H-score Introduction Non-small cell lung cancer (NSCLC) accounts for a significant proportion of the global cancer-related deaths in spite of continuous therapeutic improvements. Most patients are diagnosed with advanced disease and, because curative treatments are OncoTargets and Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 15-Sep-2018 not available at this stage, the only available option is palliative systemic therapy, which aims at prolonging survival and improving symptoms.1 Different histologic subtypes of NSCLC can be identified, the most representative being adenocarci- noma (ADC) and squamous cell carcinoma (SCC). Currently, therapeutic options for SCC are more limited compared to ADC, as the latter subtype can be treated with “new” agents like pemetrexed and bevacizumab, as well as specific targeted therapies when sensitizing mutations of the epidermal growth factor receptor (EGFR) gene or rearrangements involving the anaplastic lymphoma kinase (ALK) gene are identified.2 Notably, although activating mutations of the EGFR gene are more typical of Correspondence: Fred R Hirsch non-squamous histology, the EGFR protein itself is often highly expressed in both Department of Medicine, Division histologic subtypes, and it has been reported that its over-expression in SCC is even of Medical Oncology, University of Colorado Cancer Center, 12801 E. more pronounced than in ADC (82% vs 44%);3 hence, it has been postulated that 17th Avenue, 80045 Aurora, CO, USA EGFR could represent an eligible target for both histotypes. Cetuximab, a chimeric Tel +1 303 807 9853 Email [email protected] murine/human monoclonal antibody (mAB) targeting EGFR, currently registered for submit your manuscript | www.dovepress.com OncoTargets and Therapy 2016:9 5427–5437 5427 Dovepress © 2016 Genova and Hirsch. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you http://dx.doi.org/10.2147/OTT.S114039 hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Powered by TCPDF (www.tcpdf.org) 1 / 1 Genova and Hirsch Dovepress the treatment of colorectal and head and neck cancers, was class, it retains the ability to induce antibody-dependent cell studied in combination with first-line chemotherapy in an cytotoxicity (ADCC) by stimulating response from adaptive open-label, Phase III trial involving patients with advanced immune cells (such as lymphocytes), which exert their activ- NSCLC who were not selected for histology (FLEX trial), ity on opsonized neoplastic cells (eg, activating the perforin/ achieving a significant advantage in terms of overall survival granzymes mechanism), resulting in immune-mediated cell (OS) compared to chemotherapy alone (11.3 vs 10.1 months; lysis.10,11 The mechanisms of action of necitumumab are hazard ratio [HR]=0.871; P=0.044);4 a retrospective analysis summarized in Figure 1. suggested that the OS advantage achieved with the addition of cetuximab to chemotherapy was limited to patients with high Pharmacokinetics expression of EGFR, while this benefit was not confirmed in Necitumumab shares common pharmacokinetic features with patients with low expression of the protein.5 other therapeutic mABs, which are unavailable by oral route Necitumumab (IMC-11F8, LY3012211) is a second- and get distributed in tissues at slow speed and low volumes, generation human mAB directed against the extracellular resulting in increased half-life compared to non-antibody region of EGFR, developed by Eli Lilly & Co (Indianapolis, drugs; additionally, the elimination routes of such agents IN, USA); other agents in the same drug class include cetux- are only partially documented, and involve degradation to imab and panitumumab, which are available for clinical use peptides after being internalized into their target cells, pro- in other solid malignancies.6 teolysis within the liver or the reticuloendothelial system, Recently, significant data regarding activity, efficacy, and as well as nonspecific endocytosis. In a first-in-human, tolerability of necitumumab in NSCLC have been collected dose-escalation, Phase I trial, the maximum tolerated dose and the aim of this review is to define the potential role of of necitumumab was identified to be 800 mg; at this dose, this drug in the treatment of NSCLC by exploring the avail- the half-life of necitumumab was ≈7 days; additionally, its able literature; for this purpose, relevant articles indexed in mean clearance decreased in a less than dose-proportional PubMed and abstracts from major oncology conferences pattern, while its maximum serum concentration and area For personal use only. have been considered. under the concentration versus time curve extrapolated from time 0 to infinity values increased disproportionately to the Pharmacology dose of necitumumab. These nonlinear pharmacokinetics Pharmacodynamics findings suggest a saturable clearance mechanism for this Under normal conditions, when EGFR interacts with its drug; additionally, its metabolism is not apparently related ligand, the epidermal growth factor, the former undergoes to height or weight, indicating fixed dose as the most suitable dimerization and subsequent phosphorylation, leading choice for necitumumab.12,13 to the activation of downstream signaling pathways that involve a number of subsequent protein-based cascades, Preclinical data such as the Kirsten rat sarcoma/rapidly accelerated Necitumumab was able to inhibit in vitro proliferation of a OncoTargets and Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 15-Sep-2018 fibrosarcoma/mitogen-activated protein kinase pathway series of tumor cell lines characterized by overexpression of and the phosphatidylinositol-3-kinase/protein kinase B EGFR, including epidermal, pancreatic, and colorectal cell pathway; these signaling cascades ultimately lead to the lines.14 Additionally, the binding and ADCC activities of promotion of cell proliferation and survival. While this necitumumab were subjects of comparisons with cetuximab process has a physiologic role in the development of tissues and panitumumab; in colorectal cells, necitumumab showed and organs, it is also a key player in the growth of several an EGFR binding activity similar to cetuximab and signifi- types of neoplasms, including lung cancer.7 Necitumumab cantly higher than panitumumab, although panitumumab had contains an antigen-binding fragment, known as FAB-11F8, a higher affinity for the receptor;15 in NSCLC cells, necitu- with high affinity for one of the ligand-binding extracel- mumab and cetuximab, both belonging to the IgG1 class, lular domains of EGFR;8 as a consequence of competitive were rapidly internalized into target cells and were able to binding, the mAB prevents the dimerization of EGFR and induce a relevant ADCC at 1.0 nM with a magnitude directly the subsequent signaling cascade, resulting in internaliza- proportional