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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2020/10/12 09:45:29」(JST)

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Afatinib, sold under the brand name Gilotrif among others, is a medication used to treat non-small cell lung carcinoma (NSCLC).^[1]^[2]^[3] It belongs to the tyrosine kinase inhibitor family of medications.^[4] It is taken by mouth.^[4]

It is mainly used to treat cases of NSCLC that harbour mutations in the epidermal growth factor receptor (EGFR) gene.^[5]

Medical uses

It has received regulatory approval for use as a treatment for non-small cell lung cancer,^[6]^[4]^[7]^[8] although there is emerging evidence to support its use in other cancers such as breast cancer.^[9]

Adverse effects

Adverse effects by frequency include:^[6]^[4]^[7]^[8]^[10]

Very common (>10% frequency)

Diarrhea (>90%)
Rash/dermatitis acneform
Stomatitis
Paronychia
Decreased appetite
Nose bleed
Itchiness
Dry skin

Common (1–10% frequency)

Dehydration
Taste changes
Dry eye
Cystitis
Cheilitis
Fever
Runny/stuffy nose
Low amount of potassium in the blood
Conjunctivitis
Increased ALT
Increased AST
Hand-foot syndrome
Muscle spasms
Kidney impairment and/or failure

Uncommon (0.1-1% frequency)

Keratitis
Interstitial lung disease

Mechanism of action

Like lapatinib and neratinib, afatinib is a protein kinase inhibitor that also irreversibly inhibits human epidermal growth factor receptor 2 (Her2) and epidermal growth factor receptor (EGFR) kinases. Afatinib is not only active against EGFR mutations targeted by first generation tyrosine-kinase inhibitors (TKIs) like erlotinib or gefitinib, but also against less common mutations which are resistant to these drugs. However, it is not active against the T790M mutation which generally requires third generation drugs like osimertinib.^[11] Because of its additional activity against Her2, it is being investigated for breast cancer as well as other EGFR and Her2 driven cancers.^[2]

Afatinib covalently binds to cysteine number 797 of the epidermal growth factor receptor (EGFR) via a Michael addition (IC₅₀ = 0.5 nM).^[12]

Clinical trials

In March 2010 a Phase III trial in NSCLC patients called Lux-Lung 5 began with this drug.^[13] Fall 2010 interim results suggested the drug extended progression-free survival threefold compared to placebo, but did not extend overall survival.^[14] In May 2012, the Phase IIb/III trial Lux-Lung 1 came to the same conclusion.^[15]

In January 2015 a Phase III trial in people with NSCLC suggested the drug extended life expectancy in stage IV NSCLC adenocarcinoma with EGFR Mutation type del 19-positive tumors, compared to cisplatin-based chemotherapy by a year (33 months vs. 21 months).^[16] It also shows strong activity against exon 18 mutations (particularly G719) and is currently the preferred EGFR-TKI therapy for exon 18 mutations (particularly G719x).^[17]^{[verification needed]}

Phase II results for breast cancer that over-expresses the protein human epidermal growth factor receptor 2 (Her2-positive breast cancer) were described as promising by the authors, with 19 of 41 patients achieving benefit from afatinib.^[9] Double-blind Phase III trials are under way to confirm or refute this finding. Her2-negative breast cancers showed limited or no response to the drug.^[18]

Brand names

In Bangladesh under the trade name Afanix.

References

^ Spreitzer H (13 May 2008). "Neue Wirkstoffe – Tovok". Österreichische Apothekerzeitung (in German) (10/2008): 498.
^ ^a ^b Minkovsky N, Berezov A (December 2008). "BIBW-2992, a dual receptor tyrosine kinase inhibitor for the treatment of solid tumors". Current Opinion in Investigational Drugs. 9 (12): 1336–46. PMID 19037840.
^ "Afatinib". US Food and Drug Administration. 12 July 2013.
^ ^a ^b ^c ^d "GIOTRIF® Afatinib (as afatinib dimaleate)" (PDF). TGA eBusiness Services. Boehringer Ingelheim Pty Limited. 7 November 2013. Retrieved 28 January 2014.
^ Vavalà T (2017). "Role of afatinib in the treatment of advanced lung squamous cell carcinoma". Clinical Pharmacology. 9: 147–157. doi:10.2147/CPAA.S112715. PMC 5709991. PMID 29225480.
^ ^a ^b "GILOTRIF (afatinib) tablet, film coated [Boehringer Ingelheim Pharmaceuticals, Inc.]". DailyMed. Boehringer Ingelheim Pharmaceuticals, Inc. November 2013. Retrieved 28 January 2014.
^ ^a ^b "Giotrif 20 mg film-coated tablets – Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Boehringer Ingelheim Limited. 20 January 2014. Retrieved 28 January 2014.
^ ^a ^b "Giotrif : EPAR -Product Information" (PDF). European Medicines Agency. Boehringer Ingelheim International GmbH. 16 October 2013. Retrieved 28 January 2014.
^ ^a ^b Lin NU, Winer EP, Wheatley D, Carey LA, Houston S, Mendelson D, et al. (June 2012). "A phase II study of afatinib (BIBW 2992), an irreversible ErbB family blocker, in patients with HER2-positive metastatic breast cancer progressing after trastuzumab". Breast Cancer Research and Treatment. 133 (3): 1057–65. doi:10.1007/s10549-012-2003-y. PMC 3387495. PMID 22418700.
^ "Gilotrif (afatinib) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 28 January 2014.
^ Li D, Ambrogio L, Shimamura T, Kubo S, Takahashi M, Chirieac LR, et al. (August 2008). "BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models". Oncogene. 27 (34): 4702–11. doi:10.1038/onc.2008.109. PMC 2748240. PMID 18408761.
^ Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel Frühjahr 2013. (in German)
^ Clinical trial number NCT01085136 for "LUX-Lung 5: BIBW 2992 Plus Weekly Paclitaxel Versus Investigator's Choice of Single Agent Chemotherapy Following BIBW 2992 Monotherapy in Non-small Cell Lung Cancer Patients Failing Erlotinib or Gefitinib" at ClinicalTrials.gov
^ "Afatinib (BIBW 2992*) Triples Progression Free Survival in Phase III Study in Lung Cancer Patients". BusinessWire. 11 October 2010.
^ Miller VA, Hirsh V, Cadranel J, Chen YM, Park K, Kim SW, et al. (May 2012). "Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial". The Lancet. Oncology. 13 (5): 528–38. doi:10.1016/S1470-2045(12)70087-6. PMID 22452896.
^ Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, et al. (February 2015). "Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials" (PDF). The Lancet. Oncology. 16 (2): 141–51. doi:10.1016/s1470-2045(14)71173-8. PMID 25589191.
^ Kobayashi Y, Togashi Y, Yatabe Y, Mizuuchi H, Jangchul P, Kondo C, et al. (December 2015). "EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Augmented Sensitivity to Afatinib or Neratinib as Compared with First- or Third-Generation TKIs". Clinical Cancer Research. 21 (23): 5305–13. doi:10.1158/1078-0432.CCR-15-1046. PMID 26206867.
^ Schuler M, Awada A, Harter P, Canon JL, Possinger K, Schmidt M, et al. (August 2012). "A phase II trial to assess efficacy and safety of afatinib in extensively pretreated patients with HER2-negative metastatic breast cancer". Breast Cancer Research and Treatment. 134 (3): 1149–59. doi:10.1007/s10549-012-2126-1. PMC 3409367. PMID 22763464.

External links

"Afatinib". Drug Information Portal. U.S. National Library of Medicine.

UpToDate Contents

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1. 上皮成長因子受容体変異を有する進行非小細胞肺癌に対する全身療法 systemic therapy for advanced non small cell lung cancer with an activating mutation in the epidermal growth factor receptor
2. 進行非小細胞肺癌の治療の役割 overview of the treatment of advanced non small cell lung cancer
3. 進行非小細胞肺癌に対する遺伝子型による個別治療 personalized genotype directed therapy for advanced non small cell lung cancer
4. 分子標的剤およびその他の生物製剤を用いた癌治療による皮膚合併症 cutaneous complications of molecularly targeted therapy and other biologic agents used for cancer therapy
5. 化学療法剤の腸管毒性 enterotoxicity of chemotherapeutic agents

English Journal

Sustained Inhibition of HER3 and EGFR Is Necessary to Induce Regression of HER2-Amplified Gastrointestinal Carcinomas.

Leto SM1, Sassi F2, Catalano I1, Torri V3, Migliardi G1, Zanella ER1, Throsby M4, Bertotti A5, Trusolino L6.
Clinical cancer research : an official journal of the American Association for Cancer Research.Clin Cancer Res.2015 Dec 15;21(24):5519-31. doi: 10.1158/1078-0432.CCR-14-3066. Epub 2015 Aug 21.
PURPOSE: Preclinical studies in HER2-amplified gastrointestinal cancer models have shown that cotargeting HER2 with a monoclonal antibody and a small molecule is superior to monotherapy with either inhibitor, but the underlying cooperative mechanisms remain unexplored. We investigated the molecular
PMID 26296355

Afatinib, an Irreversible EGFR Family Inhibitor, Shows Activity Toward Pancreatic Cancer Cells, Alone and in Combination with Radiotherapy, Independent of KRAS Status.

Huguet F1,2,3,4,5,6, Fernet M7,8, Giocanti N7,8, Favaudon V7,8, Larsen AK9,10,11.
Targeted oncology.Target Oncol.2015 Dec 15. [Epub ahead of print]
BACKGROUND: Pancreatic adenocarcinoma is characterized by a high frequency of KRAS mutations and frequent deregulation of the epidermal growth factor receptor (EGFR) and other EGFR family members such as HER2/ErbB2. The EGFR inhibitor erlotinib is approved for treatment of pancreatic cancer, but has
PMID 26668065

A Phase Ib/II Study of Afatinib in Combination with Nimotuzumab in Non-Small Cell Lung Cancer Patients with Acquired Resistance to Gefitinib or Erlotinib.

Lee JY1, Sun JM1, Lim SH1, Kim H1, Yoo KH1, Jung KS1, Song HN1, Ku BM2, Koh J2, Bae YH3, Lee SH1, Ahn JS4, Park K5, Ahn MJ6.
Clinical cancer research : an official journal of the American Association for Cancer Research.Clin Cancer Res.2015 Dec 14. pii: clincanres.1653.2015. [Epub ahead of print]
PURPOSE: In this phase Ib/II study, we aimed to assess the safety and efficacy of afatinib (A) plus nimotuzumab (N) in advanced non-small cell lung cancer (NSCLC) patients with acquired resistance to gefitinib or erlotinib.EXPERIMENTAL DESIGN: In phase Ib stage, patients received A (40mg or 30mg onc
PMID 26667485

Japanese Journal

EGFR-TKIによる治療 (特集肺癌治療の進歩 : 最新の基礎と臨床研究状況) -- (最新の臨床研究)

日本臨床 = Japanese journal of clinical medicine 75(7), 1073-1078, 2017-07
NAID 40021246463

Afatinibと同時に放射線治療によって切迫麻痺を防止し得たEGFR変異陽性肺腺がんの1例

呼吸器内科 = Respiratory medicine 31(4), 381-386, 2017-04
NAID 40021188516

Osimertinibの治療反応性が病変部位ごとに大きく異なった肺腺癌の1例

肺癌 57(3), 211-215, 2017
NAID 130005708207

「アファチニブ」

Afatinib
Clinical data
Trade names	Gilotrif, Giotrif, Afanix
Other names	BIBW 2992
AHFS/Drugs.com	Multum Consumer Information
License data	EU EMA: by INN; US FDA: Afatinib;
Pregnancy; category	AU: C; US: D (Evidence of risk); ;
Routes of; administration	Oral
ATC code	L01XE13 (WHO) ;
Legal status
Legal status	AU: S4 (Prescription only) ; CA: ℞-only ; UK: POM (Prescription only) ; US: ℞-only ;
Pharmacokinetic data
Protein binding	95%
Metabolism	CYP not involved
Elimination half-life	37 hours
Excretion	Faeces (85%), urine (4%)
Identifiers
	IUPAC name N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide;
CAS Number	850140-72-6 [Drugbank];
PubChem CID	10184653;
IUPHAR/BPS	5667;
DrugBank	DB08916 ;
ChemSpider	8360155 ;
UNII	41UD74L59M;
KEGG	D09724 ;
ChEBI	CHEBI:61390 ;
ChEMBL	ChEMBL1173655 ;
CompTox Dashboard (EPA)	DTXSID20893451 ;
ECHA InfoCard	100.239.035
Chemical and physical data
Formula	C24H25ClFN5O3
Molar mass	485.94 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CN(C)C\C=C\C(=O)Nc3cc1c(Nc(cc2Cl)ccc2F)ncnc1cc3OC4COCC4;
	InChI InChI=1S/C24H25ClFN5O3/c1-31(2)8-3-4-23(32)30-21-11-17-20(12-22(21)34-16-7-9-33-13-16)27-14-28-24(17)29-15-5-6-19(26)18(25)10-15/h3-6,10-12,14,16H,7-9,13H2,1-2H3,(H,30,32)(H,27,28,29)/b4-3+/t16-/m0/s1 ; Key:ULXXDDBFHOBEHA-CWDCEQMOSA-N ;
	(what is this?) (verify)

　　[★]

英: afatinib
商: ジオトリフ

[Spreitzer-1] Spreitzer H (13 May 2008). "Neue Wirkstoffe – Tovok". Österreichische Apothekerzeitung (in German) (10/2008): 498.

[Minkovsky-2] Minkovsky N, Berezov A (December 2008). "BIBW-2992, a dual receptor tyrosine kinase inhibitor for the treatment of solid tumors". Current Opinion in Investigational Drugs. 9 (12): 1336–46. PMID 19037840.

[FDA-3] "Afatinib". US Food and Drug Administration. 12 July 2013.

[TGA-4] "GIOTRIF® Afatinib (as afatinib dimaleate)" (PDF). TGA eBusiness Services. Boehringer Ingelheim Pty Limited. 7 November 2013. Retrieved 28 January 2014.

[5] Vavalà T (2017). "Role of afatinib in the treatment of advanced lung squamous cell carcinoma". Clinical Pharmacology. 9: 147–157. doi:10.2147/CPAA.S112715. PMC 5709991. PMID 29225480.

[DM-6] "GILOTRIF (afatinib) tablet, film coated [Boehringer Ingelheim Pharmaceuticals, Inc.]". DailyMed. Boehringer Ingelheim Pharmaceuticals, Inc. November 2013. Retrieved 28 January 2014.

[EMC-7] "Giotrif 20 mg film-coated tablets – Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Boehringer Ingelheim Limited. 20 January 2014. Retrieved 28 January 2014.

[EMA-8] "Giotrif : EPAR -Product Information" (PDF). European Medicines Agency. Boehringer Ingelheim International GmbH. 16 October 2013. Retrieved 28 January 2014.

[Lin-9] Lin NU, Winer EP, Wheatley D, Carey LA, Houston S, Mendelson D, et al. (June 2012). "A phase II study of afatinib (BIBW 2992), an irreversible ErbB family blocker, in patients with HER2-positive metastatic breast cancer progressing after trastuzumab". Breast Cancer Research and Treatment. 133 (3): 1057–65. doi:10.1007/s10549-012-2003-y. PMC 3387495. PMID 22418700.

[MSR-10] "Gilotrif (afatinib) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 28 January 2014.

[11] Li D, Ambrogio L, Shimamura T, Kubo S, Takahashi M, Chirieac LR, et al. (August 2008). "BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models". Oncogene. 27 (34): 4702–11. doi:10.1038/onc.2008.109. PMC 2748240. PMID 18408761.

[12] Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel Frühjahr 2013. (in German)

[LUX-Lung_5-13] Clinical trial number NCT01085136 for "LUX-Lung 5: BIBW 2992 Plus Weekly Paclitaxel Versus Investigator's Choice of Single Agent Chemotherapy Following BIBW 2992 Monotherapy in Non-small Cell Lung Cancer Patients Failing Erlotinib or Gefitinib" at ClinicalTrials.gov

[businesswire-14] "Afatinib (BIBW 2992*) Triples Progression Free Survival in Phase III Study in Lung Cancer Patients". BusinessWire. 11 October 2010.

[Miller-15] Miller VA, Hirsh V, Cadranel J, Chen YM, Park K, Kim SW, et al. (May 2012). "Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial". The Lancet. Oncology. 13 (5): 528–38. doi:10.1016/S1470-2045(12)70087-6. PMID 22452896.

[16] Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, et al. (February 2015). "Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials" (PDF). The Lancet. Oncology. 16 (2): 141–51. doi:10.1016/s1470-2045(14)71173-8. PMID 25589191.

[17] Kobayashi Y, Togashi Y, Yatabe Y, Mizuuchi H, Jangchul P, Kondo C, et al. (December 2015). "EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Augmented Sensitivity to Afatinib or Neratinib as Compared with First- or Third-Generation TKIs". Clinical Cancer Research. 21 (23): 5305–13. doi:10.1158/1078-0432.CCR-15-1046. PMID 26206867.

[Schuler-18] Schuler M, Awada A, Harter P, Canon JL, Possinger K, Schmidt M, et al. (August 2012). "A phase II trial to assess efficacy and safety of afatinib in extensively pretreated patients with HER2-negative metastatic breast cancer". Breast Cancer Research and Treatment. 134 (3): 1149–59. doi:10.1007/s10549-012-2126-1. PMC 3409367. PMID 22763464.

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afatinib