EGFR-targeted Related Drugs

Introduction of EGFR

EGFR is the expression product of proto-oncogene C-ERBB1, the receptor of EGF cell proliferation and signal transduction. It is a member of epidermal growth factor receptor (HER) family, which includes HER1 (erbB1, EGFR), HER2 (erbB2, NEU), HER3 (erbB3),and HER4 (erbB4). Mutation or over-expression of EGFR usually leads to tumorigenesis. EGFR gene is located on the short arm of chromosome 7, EGFR is a glycoprotein, belongs to tyrosine kinase type receptor, a membrane through, molecular weight 170KDa.

EGFR Signal Pathway

The EGFR protein is a transmembrane protein, an extracellular EGFR monomer without the activity of ammonia kinase, which binds to the ligand. In the absence of a ligand, the EGFR monomer on the surface of the cell membrane is continuously ingested into the cell. When there is an excess of EGFR monomer, two EGFR monomers will polymerize into a dimer without ligand. And this EGFR dimer activates itself and further activates downstream cellular signaling pathways. In the presence of ligands, two EGFR monomers with ligands combine to form a kinase-active dimer, and the dimer phosphokinase phosphorylates the EGFR dimer itself. Phosphorylated residues are binding sites that recruit adaptors and additional tyrosine kinase substrates to enhance tyrosine kinase activity, phosphorylate proteins in downstream signaling pathways, and activate downstream signaling pathways. Including MAPK, Akt and JNK pathway, induced cell proliferation. EGFR may also polymerize with other members of the ErbB receptor family (ErbB2/Her2/neu) to activate it.

The tyrosine kinase active site of EGFR is mainly located between exon 18 and exon 24, such as deletion mutation of EGFR exon 19 and L858R mutation, which leads to the change of amino acid residue 858 from Leucine to Arginine. As a result, the two monomers of EGFR bind directly in the absence of ligands, forming a self-activating dimer that continuously activates tyrosine kinase activity. There are two main signal transduction pathways downstream of EGFR: one is Ras/ Raf/MEK/ERK-MAPK pathway, the other is PI3K/Akt/mTOR pathway. The gene mutation of the key genes K-Ras, BRAF, PIK3CA downstream of the EGFR signal transduction system, and the inactivation of the tumor suppressor gene PTEN are the focus of drug research.

EGFR and Disease

EGFR-TKIs (Epidermal growth factor receptor tyrosine kinase inhibitors) is widely used in advanced non-small cell lung cancer (non-small cell lung cancer, NSCLC), especially in patients with lung adenocarcinoma with epidermal growth factor receptor EGFR gene mutation. On the one hand, macromolecular targeted drugs specifically recognize the antibody of EGFR-ligand binding site in the extracellular domain, and block the binding of the ligand to EGFR by competing with the ligand for EGFR to block the ligand-induced activation of EGFR. On the other hand, the amount of EGFR on the cell surface was decreased by inducing the endocytosis of EGFR. Small molecule targeted drugs inhibit the activation of downstream biological signaling pathways by competing with ATP for the tyrosine kinase active site of EGFR.

Targeted drugs targeting EGFR approved by FDA

Drug Name Trade Name Indication Listing Date
Gefitinib Iressa metastatic non-small cell lung cancer with deletion of exon 19 or mutation of exon 21 of the EGFR gene 2003
Erlotinib Tarceva First-line treatment of metastatic non-small Cell Lung Cancer with deletion of Exon 19 or mutation of Exon 21 of EGFR Gene 2004
Cetuximab Erbitux Combined radiotherapy for local or regional advanced squamous cell carcinoma of head and neck, chemotherapy based on 5-fluorouracil and platinum for locally recurrent or metastatic squamous cell carcinoma of head and neck 2004
Panitumumab Vectibix Treatment of metastatic Colorectal Cancer with KRAS Wild-type (mCRC) 2006
Icotinib Kemena First-line treatment of locally advanced or metastatic non-small cell lung cancer with EGFR-sensitive mutation (NSCLC) 2011
Nimotuzumab taxinson Combined radiotherapy for stage Ⅲ / Ⅳ nasopharyngeal carcinoma with EGFR expression 2012
Afatinib Gilotrif FDA-approved first-line treatment for metastatic non-small Cell Lung Cancer with deletion of Exon 19 or substitution mutation of Exon 21 of the EGFR Gene 2013
Osimertinib Tagrisso Treatment of non-small cell lung cancer with EGFR T790M mutation 2015
Necitumumab Portrazza Combination of gemcitabine and cisplatin in the treatment of metastatic squamous cell lung cancer 2015
Olmutinib Olita Treatment of non-small cell lung cancer with EGFR T790M mutation approved by South Korea for locally advanced or metastatic non-small cell lung cancer previously treated with EGFR TKI 2016

 

Phase Code Name (CD) Drug Name (CD, GN, BN) Organization Condition
Phase I AG-1517; PD-153035; SU-5271; WHI-P79; ZM-252868 AG-1517; PD-153035; SU-5271; WHI-P79; ZM-252868 Pfizer (Originator); Sugen (Originator); Psoriasis; Cancer
Phase I BIBX-1382; BIBX-1382BS BIBX-1382; BIBX-1382BS, Falnidamol (Rec INN) Boehringer Ingelheim (Originator); Cancer
Phase I P-54-FP P-54-FP Medical Research Council (MRC) (Originator); Cancer
Phase I AV-412; MP-412 AV-412; MP-412 Mitsubishi Tanabe Pharma (Originator); AVEO Pharma; Cancer, solid tumor; Cancer
Phase I AC-480; BMS-599626 (former code) AC-480; BMS-599626 (former code) Bristol-Myers Squibb (Originator); Daiichi Sankyo; Cancer, solid tumor; Glioma
Phase I JNJ-26483327 JNJ-26483327 Johnson & Johnson (Originator); Cancer, solid tumor
Phase I 806; Antibody 806; ch806; mAb806 806; Antibody 806; ch806; mAb806 Ludwig Institute for Cancer Research (Originator); Abbott; Life Science Pharmaceuticals; Cancer, solid tumor; Cancer
Phase I AT-13387A; AT-13387AU; 66226JUH2I (UNII code); AT-13387 (free base) AT-13387A; AT-13387AU; 66226JUH2I (UNII code); AT-13387 (free base), Onalespib lactate (USAN; Rec INN) Astex Pharmaceuticals (Originator); National Cancer Institute; Cancer, head and neck (squamous cell carcinoma); Cancer, breast; Cancer, prostate (castration-resistant); Cancer, lung (non-small cell) (NSCLC); Melanoma; Gastrointestinal stromal tumor (GIST)
Phase I D2C7-(scdsFv)-PE38 KDEL; D2C7-IT; scds-D2C7-PE38KDEL D2C7-(scdsFv)-PE38 KDEL; D2C7-IT; scds-D2C7-PE38KDEL Duke University (Originator); US Department of Health & Human Services (Originator); Carcinoma, squamous cell; Glioblastoma multiforme
Phase I AL-6802; SIM-6802 AL-6802; SIM-6802, Simotinib hydrochloride Advenchen Laboratories (Originator); Simcere Pharmaceutical; Cancer, lung (non-small cell) (NSCLC); Cancer
Phase I EGFR-ECD/VSSP/MONT EGFR-ECD/VSSP/MONT Centro de Inmunologia Molecular (CIM) (Originator); Cancer, prostate
Phase I 11C-PD-153035; [11C]PD-153035; [Methoxy-11C]PD-153035 11C-PD-153035; [11C]PD-153035; [Methoxy-11C]PD-153035 Karolinska Institutet (KI) (Originator); Shandong Tumor Hospital; Cancer, lung (non-small cell) (NSCLC); Cancer
Phase I AVL-292; CC-292; DRU6NG543J (UNII code) AVL-292; CC-292; DRU6NG543J (UNII code), Spebrutinib (USAN; Rec INN) Celgene (Originator); Lymphoma, diffuse large B-cell; Lymphoma, follicular; Rheumatoid arthritis; Lymphoma, B-cell; Autoimmune disease; Small lymphocytic lymphoma; Leukemia, chronic lymphocytic
Phase I HKI-357; PB-357; PF-5208766; WAY-178357 HKI-357; PB-357; PF-5208766; WAY-178357 Pfizer (Originator); Puma Biotechnology; Cancer
Phase I QLNC-120; 6Q2E32HVE7 (UNII code) QLNC-120; 6Q2E32HVE7 (UNII code), Selatinib ditosilate Qilu Pharmaceutical (Originator); Cancer, breast
Phase I DBPR-112 DBPR-112 National Health Research Institutes (Originator); Cancer, head and neck (squamous cell carcinoma); Cancer, lung (non-small cell) (NSCLC)
Phase I 18F-Fluoro-PEG6-IQPA; [18F]F-PEG6-IPQA 18F-Fluoro-PEG6-IQPA; [18F]F-PEG6-IPQA Kanazawa University (Originator); M.D. Anderson Cancer Center (Originator); Diagnostics; Cancer, lung
Phase I/II AEE-788; NVP-AEE-788 AEE-788; NVP-AEE-788 Novartis (Originator); Glioblastoma multiforme; Cancer, solid tumor; Cancer, colorectal metastatic
Phase I/II MDX-214 MDX-214 Bristol-Myers Squibb (Originator); Cancer, solid tumor; Immunological Disorders
Phase I/II INCB-007839; INCB-7839 INCB-007839; INCB-7839, Aderbasib (Prop INN; USAN) University of Minnesota; Incyte (Originator); Cancer, breast; Cancer, solid tumor; Lymphoma, non-Hodgkin
Phase I/II HMPL-813 HMPL-813, Epitinib succinate Hutchison China MediTech (Chi-Med) (Originator); Glioblastoma multiforme; Cancer, solid tumor
Phase I/II CEP-32496; RXDX-105 CEP-32496; RXDX-105, Agerafenib hydrochloride (Prop INNM) Roche; Teva (Originator); Daiichi Sankyo (Originator); Cancer
Phase I/II S-222611; 60OIK33ZQR (UNII code) S-222611; 60OIK33ZQR (UNII code), Epertinib (Rec INN) Shionogi (Originator); Cancer, breast metastatic; Cancer, solid tumor
Phase II BIO-300; G-2535; PTI-G4660; SIPI-9764-I BIO-300; G-2535; PTI-G4660; SIPI-9764-I, 4′,5,7-Trihydroxyisoflavone; Genistein, Bonistein National Cancer Institute; Bausch & Lomb; Astellas Pharma; Humanetics; National Institutes of Health; US Army Med Res Inst of Chemical Defense; Uniformed Services University; Universita degli Studi di Messina; SurModics; Renal failure, chronic; Fibrosis, cystic; Cancer, bladder; Cancer, breast; Cancer, prostate; Melanoma, metastatic; Eye Disorders; Poisoning; Cancer, lung (non-small cell) (NSCLC); Erectile dysfunction; Cancer, endometrium; Cancer, kidney (renal cell carcinoma, clear cell); Fibroids, uterine (myoma); Infection, HIV; Osteopenia; Endometrial hyperplasia; Acute radiation syndrome
Phase II IdB-1056 IdB-1056, Delphinidin; Delphinidin chloride; Delphinidol; Ephdine Indena; Other cardiovascular disorders; Cancer
Phase II VK3 VK3, Menadione (Rec INNM; BAN; USAN); Vitamin K3, Kappaxin; Thyloquinone Albert Einstein College of Medicine; Sanofi (Originator); Bristol-Myers Squibb (Originator); Talon Therapeutics; Lilly (Originator); Hemorrhage; Cancer
Phase II CI-1033; PD-183805 (free base) CI-1033; PD-183805 (free base), Canertinib dihydrochloride (Rec INNM; USAN) Pfizer (Originator); Cancer, breast metastatic; Cancer, lung (non-small cell) (NSCLC)
Phase II CP-547632; OSI-632 CP-547632; OSI-632 Pfizer (Originator); Astellas Pharma (Originator); Cancer, lung (non-small cell) (NSCLC); Cancer, ovary
Phase II EKB-569; WAY-EKB-569 EKB-569; WAY-EKB-569, Pelitinib (USAN; Rec INN) National Cancer Institute; Pfizer (Originator); Cancer, lung (non-small cell) (NSCLC); Cancer, solid tumor; Cancer, mouth; Cancer, colorectal
Phase II TP-38 TP-38, Cervene Duke University (Originator); Teva; Glioblastoma multiforme; Cancer, brain
Phase II EXEL-7647; KD-019; KD-020; XL-647; F6XM2TN5A1 (UNII code) EXEL-7647; KD-019; KD-020; XL-647; F6XM2TN5A1 (UNII code), Tesevatinib (USAN; Rec INN) Symphony Evolution; Kadmon; Exelixis (Originator); Cancer, metastatic; Glioblastoma; Cancer, lung (non-small cell) (NSCLC); Cancer, metastatic (to brain); Polycystic kidney, autosomal dominant; Polycystic kidney, autosomal recessive
Phase II 823296; GW-823296 823296; GW-823296, Orvepitant (USAN; Rec INN) GlaxoSmithKline (Originator); NeRRe Therapeutics; Anxiety disorder; Depression; Cough, chronic; Stress, post-traumatic; Pruritus
Phase II AZD-8931 AZD-8931, Sapitinib (Rec INN) AstraZeneca (Originator); Cancer, gastrointestinal; Cancer, breast; Cancer, lung (non-small cell) (NSCLC); Cancer, solid tumor; Cancer, colorectal
Phase II Anti-EGFR ILs-DOX; C225-ILS-DOX Anti-EGFR ILs-DOX; C225-ILS-DOX Universitaetsspitals Basel (USB) (Originator); SAKK; Glioblastoma multiforme; Cancer, breast; Cancer, solid tumor
Phase II BMS-690514 BMS-690514 Bristol-Myers Squibb (Originator); Cancer, breast metastatic; Cancer, lung (non-small cell) (NSCLC); Cancer, solid tumor
Phase II ARQ-197 ARQ-197, Tivantinib (Prop INN; USAN) National Cancer Institute; Istituto Oncologico Veneto; ArQule (Originator); Kyowa Hakko Kirin; Dana-Farber Cancer Institute; Daiichi Sankyo; Cancer, breast metastatic; Cancer, pancreas; Cancer, liver (hepatocellular carcinoma); Cancer, lung (small cell) (SCLC); Cancer, lung (non-small cell) (NSCLC); Cancer, solid tumor; Cancer, colorectal metastatic; Mesothelioma, malignant; Cancer, stomach; Cancer, kidney metastatic; Cancer, germ cells; Cancer, prostate metastatic
Phase II GT-MAb 2.5-GEX GT-MAb 2.5-GEX, Gatipotuzumab (Rec INN), PankoMab; PankoMab-GEX Glycotope (Originator); Cancer, ovary (epithelial); Cancer, breast; Cancer, lung (non-small cell) (NSCLC); Cancer, solid tumor; Cancer, colorectal; Cancer, fallopian tube; Cancer, peritoneum
Phase II GA-201; R-7160; RG-7160; RO-5083945 GA-201; R-7160; RG-7160; RO-5083945, Imgatuzumab (USAN; Rec INN) Roche (Originator); Cancer, head and neck (squamous cell carcinoma); Cancer, lung (non-small cell) (NSCLC); Lymphoma; Cancer, solid tumor; Cancer, colorectal
Phase II BIBW-2948; BIBW-2948 BS BIBW-2948; BIBW-2948 BS Boehringer Ingelheim (Originator); Chronic obstructive pulmonary disease (COPD)
Phase II Sym-004 Sym-004, Futuximab/modotuximab (Rec INN) Symphogen (Originator); Cancer, head and neck (squamous cell carcinoma); Gliosarcoma; Glioblastoma multiforme; Cancer, lung (non-small cell) (NSCLC) (squamous cell carcinoma); Esophageal carcinoma (squamous cell); Cancer, colorectal
Phase II HM-781-36; HM-781-36B; NOV-1201; NOV-120101 HM-781-36; HM-781-36B; NOV-1201; NOV-120101, Poziotinib (Rec INN) Spectrum Pharmaceuticals; Luye Pharma; Hanmi (Originator); Cancer, breast metastatic; Cancer, lung (non-small cell) (NSCLC) (adenocarcinoma); Cancer, breast; Cancer, lung; Cancer, head and neck; Cancer, stomach
Phase II GT-MAb 5.2-GEX GT-MAb 5.2-GEX, Tomuzotuximab (Rec INN), CetuGEX Glycotope (Originator); Female reproductive system cancer; Cancer, head and neck (squamous cell carcinoma); Cancer, breast; Cancer, lung (non-small cell) (NSCLC); Cancer, solid tumor; Cancer, colorectal
Phase II DL11f; MEHD-7945A; RG-7597 DL11f; MEHD-7945A; RG-7597, Duligotumab (Rec INN); Duligotuzumab (Prop INN; USAN) Genentech (Originator); Cancer, head and neck (squamous cell carcinoma); Cancer, solid tumor; Cancer, colorectal metastatic
Phase II BB-401; pNGVL1-U6-EGFR-AS; pNGVL1-U6-EGFRAS BB-401; pNGVL1-U6-EGFR-AS; pNGVL1-U6-EGFRAS NantWorks; University of Pittsburgh (Originator); Benitec Biopharma; Cancer, head and neck (squamous cell carcinoma)
Phase II ABT-806; W984C353CG (UNII code) ABT-806; W984C353CG (UNII code), Depatuxizumab (Rec INNM; Rec INN) Ludwig Institute for Cancer Research (Originator); Life Science Pharmaceuticals; AbbVie; Cancer, gastrointestinal; Cancer, solid tumor; Glioma
Phase II PYM PYM, Bleomycetin; Bleomycin A5 hydrochloride; Pingyangmycin; Zhengguangmycin A5 Beijing Stomatol Hosp Capital Med Univ; Chinese Academy of Medical Sciences; Shanghai Jiao Tong University; Affiliated Hospital Xuzhou Medical Coll; Nanfang Hospital Southern Medical Univ; Malformation, vascular; Cancer, cervix; Cancer, mouth (squamous cell); Hemangioma, hepatic; Cancer, esophagus
Phase II BI-836845 BI-836845, Xentuzumab MorphoSys; Boehringer Ingelheim (Originator); Cancer, breast; Cancer, prostate (castration-resistant); Cancer, lung (non-small cell) (NSCLC)
Phase II/III AR-00334543; ARRY-334543; ARRY-543; ASLAN-001; QBT-01; SPS-4370 AR-00334543; ARRY-334543; ARRY-543; ASLAN-001; QBT-01; SPS-4370, Varlitinib tosylate (Prop INNM; USAN) Array BioPharma (Originator); ASLAN Pharmaceuticals; Hyundai Pharm; Cancer, breast metastatic; Cancer, pancreas; Cholangiocarcinoma; Cancer, biliary; Cancer, liver (hepatocellular carcinoma); Cancer, solid tumor; Cancer, gastroesophageal junction; Cancer, stomach
Phase III CHIR-258; CHIR-258 lactate; CHIR-258LC; GFKI-258; NVP-TKI258; TKI-258 CHIR-258; CHIR-258 lactate; CHIR-258LC; GFKI-258; NVP-TKI258; TKI-258, Dovitinib lactate (USAN) Novartis (Originator); Samsung Medical Center; Oncology Venture; Cancer, breast metastatic; Cancer, pancreas; Leukemia, acute myeloid; Cancer, head and neck (adenoid cystic carcinoma); Endocrine cancer; Glioblastoma multiforme; Cancer, liver (hepatocellular carcinoma); Multiple myeloma; Cancer, prostate (castration-resistant); Cancer, lung (non-small cell) (NSCLC); Cancer, endometrium; Cancer, kidney (renal cell carcinoma); Cancer, stomach; Melanoma; Gastrointestinal stromal tumor (GIST); Cancer, colorectal; Mesothelioma, pleural; Von Hippel-Lindau disease; Pheochromocytoma; Cancer, bladder (urothelial carcinoma); Cancer, salivary glands (adenoid cystic carcinoma)
Phase III 2F8 2F8, Zalutumumab (Prop INN; USAN), HuMax-EGFr Bristol-Myers Squibb (Originator); Genmab; Cancer, head and neck (squamous cell carcinoma); Cancer, lung (non-small cell) (NSCLC); Cancer, head and neck; Cancer, colorectal
Phase III ASP-7487; OSI-906; OSI-906AA ASP-7487; OSI-906; OSI-906AA, Linsitinib (Prop INN; USAN) National Cancer Institute; Multiple Myeloma Research Foundation; Astellas Pharma (Originator); Vanderbilt University; University of Colorado; Cancer, breast metastatic; Sarcoma, Ewing; Cancer, liver (hepatocellular carcinoma); Multiple myeloma; Cancer, lung (non-small cell) (NSCLC); Gastrointestinal stromal tumor (GIST); Cancer, colorectal; Cancer, ovary (epithelial recurrent); Cancer, prostate metastatic; Carcinoma, adrenocortical

Conclusion

The epidermal growth factor receptor (EGFR) belongs to the ErbB family of receptor tyrosine kinases (RTK). There is evidence that cooperation between multiple ErbB receptors and homologs is necessary to induce cell transformation. In particular, the growth and survival of cancer cells appear to be maintained by the receptor/ligand network of the ErbB family. This phenomenon is also important for treatment because the response of anti-EGFR drugs may depend on the overall level of expression of ErbB receptors and ligands in tumor cells.

References

1. Normanno, N., De Luca, A., Bianco, C., Strizzi, L., Mancino, M., Maiello, M. R., … & Salomon, D. S. (2006). Epidermal growth factor receptor (EGFR) signaling in cancer. Gene366(1), 2-16.

2. Blobel, C. P. (2005). ADAMs: key components in EGFR signalling and development. Nature reviews Molecular cell biology6(1), 32.

3. Soria, J. C., Ohe, Y., Vansteenkiste, J., Reungwetwattana, T., Chewaskulyong, B., Lee, K. H., … & Okamoto, I. (2018). Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. New England journal of medicine378(2), 113-125.

Related Products

Gefitinib         Cetuximab            Panitumumab          Icotinib           Olmutinib

Erlotinib          Nimotuzumab       Afatinib                    Osimertinib