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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Developed by Lilly Oncology, necitumumab (PortrazzaTM) is a fully human IgG1 antibody designed to block the ligand binding site of EGFR. In 2013, Lilly announced that SQUIRE, a Phase III clinical study on 1,093 patients with Stage IV metastatic squamous non-small-cell lung cancer (NSCLC), met its primary endpoint in finding that patients had increased overall survival when given necitumumab in combination with gemcitabine and cisplatin as a first-line treatment, in comparison to chemotherapy alone. This led to FDA approval of necitumumab in 2015, the first biological therapy to be approved for patients with squamous cell lung cancer, one of the leading causes of cancer deaths worldwide. Furthermore, NSCLC is more common than other types of lung cancer, and accounts for 85% of all lung cancer cases. Patients with squamous cell carcinoma represent about 30% of those affected by NSCLC
Main Classes of Drugs
Published in Jerome Z. Litt, Neil H. Shear, Litt's Drug Eruption & Reaction Manual, 2017
Epidermal growth factor receptor (EGFR) inhibitorCetuximabErlotinibGefitinibLapatinibNecitumumabNilotinibPanitumumabPazopanibSorafenibSunitinib
A patent review of mTOR inhibitors for cancer therapy (2011–2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Han-Yue Qiu, Peng-Fei Wang, Min Zhang
As LY3023414 exhibited interesting pharmacological characters, a great effort has been paid to evaluate its potential in therapeutic processes [41]. While the high solubility of LY3023414 at pH 2-7 indicates the chance to be developed as an oral administrating drug, the extremely specific kinome selectivity toward PI3K isoforms, mTOR, and DNA-PK over approximately 260 kinases further elevate the possibility. In various studies, LY3023414 was found effective to different cancer types, facilitating its access to clinical trials [42,43]. By the end of 2020, the results of several phase I and phase II studies have been made public (www.clinicaltrials.gov). In the first-in-human phase I trial in patients with advanced cancers, LY3023414 was well tolerated and efficient at the dose of 200mg twice daily while adverse events (AEs) tended to be mostly mild and moderate (NCT02536586). In another phase II trial on pretreated tumors, LY3023414 showed promising single-agent activities in certain histotypes (NCT02549989). The combination of LY3023414 with Abemaciclib in trials proved to enhance antitumor activity (NCT02079636 and NCT02981342). Still, another trial on LY3023414 with Necitumumab in squamous lung cancer treatment has been terminated due to lack of efficacy, suggesting the importance of mapping out applicable therapeutic indications (NCT02443337)
Emerging drugs for EGFR-mutated non-small cell lung cancer
Published in Expert Opinion on Emerging Drugs, 2019
Vineeth Sukrithan, Lei Deng, Alexander Barbaro, Haiying Cheng
The development of 4th generation TKIs with activity against C797S mutations is in progress. EAI001 and EAI045 are fourth-generation EGFR TKIs that are non-ATP binding and allosterically inhibit mutant EGFR. EAI045 is not equally efficacious against the two EGFR subunits in their dimerized form and therefore needs to be combined with an EGFR dimerization inhibitor such as cetuximab for potent synergistic activity [53]. Novel agents targeting compound mutations involving T790M (T790M/C797S/L858R), (del 19/T790M/C797S) and (T790M/L858R) are in pre-clinical development [54–56]. Brigatinib, a dual EGFR and ALK kinase inhibitor also has been reported to have activity against triple mutated EGFR [57]. Necitumumab is a humanized antibody that binds to the extracellular region of EGFR, preventing dimerization and downstream signaling of the EGFR receptor. A Phase I trial of necitumumab with osimertinib is recruiting (NCT02496663).
Necitumumab in the treatment of non-small-cell lung cancer: clinical controversies
Published in Expert Opinion on Biological Therapy, 2018
Vincenzo di Noia, Ettore D’Argento, Sara Pilotto, Giulia Grizzi, Mario Caccese, Roberto Iacovelli, Giampaolo Tortora, Emilio Bria
Necitumumab is an IgG1 monoclonal antibody directed against the domain III of the extracellular region of EGFR, exerting its inhibitory activity through the block of the ligand-binding site [26]. Specifically, it binds to similar epitopes than cetuximab, but with different chemical interactions, and it is additionally able to interact with the majority of the EGFR variants usually resistant to cetuximab and panitumumab [27]. Moreover, different from cetuximab (a human-murine chimeric mAb), necitumumab is a fully humanized mAb, leading to fewer hypersensitivity reactions. Its binding to EGFR induces a configuration change in the receptor, which prevents its dimerization and the subsequent signaling cascades of mitogen-activated protein kinase (MAPK) and PI3K/Akt, eventually blocking tumor cells proliferation and survival [28]. Furthermore, necitumumab is able to induce antibody-dependent cellular cytotoxicity (ADCC) as other components of the IgG1 class [29]. Similar to other mAb in clinical practice, necitumumab is featured by oral unavailability, slow distribution in tissues, and low volume of distribution due to its large molecular size and proteolytic degradation. As the drug exposure is not influenced by liver and renal function, no dose adjustments are necessary in case of hepatic or renal failure [30,31].