| Reference | [1]. Recent Results Cancer Res. 2018;211:199-215. doi: 10.1007/978-3-319-91442-8_14.<br />
Afatinib.<br />
Wecker H(1), Waller CF(2).<br />
Author information: (1)Department of Haematology, Oncology and Stem Cell Transplantation, University Medical Centre Freiburg, and Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany. (2)Department of Haematology, Oncology and Stem Cell Transplantation, University Medical Centre Freiburg, and Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany. [email protected].<br />
Afatinib (BIBW 2992, US: GilotrifTM, other countries: Giotrif©) is an irreversible blocker of the ErbB family, acting at the tyrosine kinases of these proteins. In 2013, it was approved by the FDA and the EMA for the treatment of adults with advanced, EGFR mutation-positive non-small-cell lung cancer. Further investigations for the treatment of many other tumors with afatinib, e.g., HNSCC and breast cancer, are ongoing.<br />
DOI: 10.1007/978-3-319-91442-8_14 PMID: 30069769 [Indexed for MEDLINE]<br />
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[2]. J Oncol Pharm Pract. 2020 Sep;26(6):1461-1474. doi: 10.1177/1078155220931926. Epub 2020 Jun 20.<br />
Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings.<br />
Harvey RD(1)(2)(3), Adams VR(4), Beardslee T(3), Medina P(5).<br />
Author information: (1)Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, USA. (2)Department of Pharmacology, Emory University School of Medicine, Atlanta, USA. (3)Winship Cancer Institute of Emory University, Atlanta, USA. (4)Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, Lexington, USA. (5)College of Medicine, Stephenson Cancer Center, University of Oklahoma, Norman, USA.<br />
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors represent the standard of care in patients with EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC). The availability of several EGFR tyrosine kinase inhibitors approved for use in the first-line or later settings in NSCLC warrants an in-depth understanding of the pharmacological properties of, and clinical data supporting, these agents. The second-generation, irreversible ErbB-family blocker, afatinib, has been extensively studied in the context of EGFRm+ NSCLC. Results from the LUX-Lung 3 and 6 studies showed that afatinib was more active and better tolerated than chemotherapy in patients with tumors harboring EGFR mutations. Subanalysis of these trials, along with real-world data, indicates that afatinib is active in patients with certain uncommon EGFR mutations (S768I/G719X/L861Q) as well as common mutations (Del19/L858R), and in patients with active brain metastases. In LUX-Lung 7, a head-to-head phase IIb trial, afatinib improved progression-free survival and time-to-treatment failure versus the first-generation reversible EGFR tyrosine kinase inhibitor, gefitinib, albeit with a higher incidence of serious treatment-related adverse events. Nevertheless, afatinib is generally well tolerated, and adverse events are manageable through supportive care and a well-defined tolerability-guided dose adjustment scheme. In this review, we provide a detailed overview of the pharmacology, efficacy, and safety of afatinib, discuss treatment sequencing strategies following emergence of different resistance mechanisms, and shed light on the economic impact of afatinib. We also provide a comparison of afatinib with the available EGFR tyrosine kinase inhibitors and discuss its position within treatment strategies for patients with EGFRm+ NSCLC.<br />
DOI: 10.1177/1078155220931926 PMCID: PMC7448811 PMID: 32567494 [Indexed for MEDLINE]<br />
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[3]. Expert Opin Pharmacother. 2018 Dec;19(18):2055-2062. doi: 10.1080/14656566.2018.1540591. Epub 2018 Nov 3.<br />
Afatinib and Erlotinib in the treatment of squamous-cell lung cancer.<br />
Tagliamento M(1), Genova C(1)(2), Rijavec E(1), Rossi G(1), Biello F(1), Dal Bello MG(1), Alama A(1), Coco S(1), Boccardo S(1), Grossi F(3).<br />
Author information: (1)a Lung Cancer Unit , Ospedale Policlinico San Martino , Genoa , Italy. (2)b Department of Internal Medicine and Medical Specialties (DIMI) , University of Genoa , Genoa , Italy. (3)c Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Medical Oncology , Milan , Italy.<br />
Erratum in Expert Opin Pharmacother. 2018 Dec;19(18):9.<br />
INTRODUCTION: Squamous-cell carcinoma (SCC) of the lung represents around 20% of non-small cell lung cancers. Although activating mutations of EGFR are rare in this subtype, its overexpression occurs in more than half the cases. Consequently, many epidermal growth factor receptor (EGFR)-targeted agents have been investigated in patients with SCC. AREAS COVERED: This review summarizes the potential roles of erlotinib and afatinib in SCC of the lung. The authors explore the rationale of targeting EGFR in SCC and the pharmacological properties of erlotinib and afatinib. Subsequently, they describe the most relevant clinical data involving each agent with regard to their safety profile and antineoplastic activity. Particular focus is given to the LUX-Lung 8 trial, which compared erlotinib and afatinib as a second-line treatment in a population of patients affected by advanced SCC of the lung. EXPERT OPINION: Despite being overcome by new therapeutic strategies – in particular immune checkpoint inhibitors – afatinib and erlotinib still represent potential treatment options down the line in lung SCC because they have a more manageable toxicity profile compared to chemotherapy.<br />
DOI: 10.1080/14656566.2018.1540591 PMID: 30392436 [Indexed for MEDLINE]<br />
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[4]. Ann Oncol. 2020 Dec;31(12):1693-1703. doi: 10.1016/j.annonc.2020.08.2335. Epub 2020 Sep 9.<br />
NRG1 fusion-driven tumors: biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents.<br />
Laskin J(1), Liu SV(2), Tolba K(3), Heining C(4), Schlenk RF(5), Cheema P(6), Cadranel J(7), Jones MR(8), Drilon A(9), Cseh A(10), Gyorffy S(11), Solca F(12), Duruisseaux M(13).<br />
Author information: (1)Division of Medical Oncology, Department of Medicine, University of British Columbia, BC Cancer, Vancouver, BC, Canada. Electronic address: [email protected]. (2)Georgetown University Medical Center, Washington, USA. (3)Oregon Health and Science University, Portland, OR, USA. (4)Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), Dresden, Germany; Center for Personalized Oncology, NCT Dresden and University Hospital Carl Gustav Carus Dresden at Technical University Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany. (5)National Center of Tumor Diseases Heidelberg, Heidelberg University Hospital and German Cancer Research Center, Heidelberg, Germany. (6)William Osler Health System, University of Toronto, Toronto, ON, Canada. (7)Assistance Publique Hôpitaux de Paris, Hôpital Tenon and Sorbonne Université, Paris, France. (8)QIAGEN Digital Insights, QIAGEN Inc., Redwood City, CA, USA. (9)Memorial Sloan Kettering Cancer Center, New York, NY, USA. (10)Boehringer Ingelheim International GmbH, Ingelheim, Germany. (11)AstraZeneca Canada Ltd, Mississauga, ON, Canada. (12)Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria. (13)Hospices Civils de Lyon Cancer Institute, Anticancer Antibodies Lab Cancer Research Center of Lyon INSERM 1052 CNRS 528, Université Claude Bernard Lyon 1, Lyon, France.<br />
Oncogenic gene fusions are hybrid genes that result from structural DNA rearrangements, leading to deregulated activity. Fusions involving the neuregulin-1 gene (NRG1) result in ErbB-mediated pathway activation and therefore present a rational candidate for targeted treatment. The most frequently reported NRG1 fusion is CD74-NRG1, which most commonly occurs in patients with invasive mucinous adenocarcinomas (IMAs) of the lung, although several other NRG1 fusion partners have been identified in patients with lung cancer, including ATP1B1, SDC4, and RBPMS. NRG1 fusions are also present in patients with other solid tumors, such as pancreatic ductal adenocarcinoma. In general, NRG1 fusions are rare across different types of cancer, with a reported incidence of <1%, with the notable exception of IMA, which represents ≈2%-10% of lung adenocarcinomas and has a reported incidence of ≈10%-30% for NRG1 fusions. A substantial proportion (≈20%) of NRG1 fusion-positive non-small-cell lung cancer cases are nonmucinous adenocarcinomas. ErbB-targeted treatments, such as afatinib, a pan-ErbB tyrosine kinase inhibitor, are potential therapeutic strategies to address unmet treatment needs in patients harboring NRG1 fusions.<br />
DOI: 10.1016/j.annonc.2020.08.2335 PMID: 32916265 [Indexed for MEDLINE]<br />
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[5]. Semin Oncol. 2019 Jun;46(3):271-283. doi: 10.1053/j.seminoncol.2019.08.004. Epub 2019 Sep 11.<br />
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in non-small cell lung cancer harboring uncommon EGFR mutations: Focus on afatinib.<br />
Masood A(1), Kancha RK(2), Subramanian J(3).<br />
Author information: (1)Rush Precision Oncology Program and Research, Rush University Medical Center, Chicago, IL. (2)Molecular Medicine and Therapeutics Laboratory, Centre for Plant Molecular Biology, Osmania University, Hyderabad, India. (3)Division of Oncology, Saint Luke's Cancer Institute, Kansas City, MO; Center for Precision Oncology, Saint Luke's Cancer Institute, Kansas City, MO.<br />
The development of first-, second-, and third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of patients with non-small cell lung cancer (NSCLC) harboring mutations in the EGFR. However, limited data are available regarding the activity of available EGFR TKIs against uncommon EGFR mutations. This is an important question because improvements in screening techniques are facilitating the identification of patients with uncommon mutations for whom optimal treatment has not yet been clarified. This uncertainty reflects the fact that most prospective clinical trials of EGFR TKIs have been restricted to patients with tumor harboring common (Del19 or L858R) mutations. In this article, we discuss the nature of EGFR mutation heterogeneity in NSCLC and review recent preclinical and clinical data that have assessed the sensitivity of different mutations to different EGFR TKIs. Recent preclinical data indicate that second-generation ErbB family blockers, such as afatinib, have a broad activity profile across uncommon EGFR mutations. Emerging evidence indicates that the preclinical data for afatinib are reflected in the clinic. Subanalysis of clinical trials, and real-world data, demonstrate that EGFRs with defined, but uncommon mutations such as G719X, S768I, and L861Q are sensitive to afatinib, which is now approved for tumors harboring these mutations. A recent clinical trial has demonstrated that EGFRs harboring some of these less common mutations also appear to be sensitive to the third-generation EGFR TKI, osimertinib. Treatment options for tumors with other uncommon mutations, notably exon 20 insertion, remain an area of unmet need, although osimertinib has shown preclinical activity in this setting, and early clinical activity has been seen with the dual EGFR/HER2 TKIs, poziotinib and TAK-788. Further data are required to help drive appropriate treatment decisions in patients whose tumors harbor these uncommon EGFR mutations. To see an abstract video summarising the content of the paper, please visit http://usscicomms.com/oncology/masood/seminars-in-oncology/.<br />
DOI: 10.1053/j.seminoncol.2019.08.004 PMID: 31558282 [Indexed for MEDLINE]
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