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01-06-2013 | Review Article

Tyrosine Kinase Inhibitors: Their On-Target Toxicities as Potential Indicators of Efficacy

Authors: Devron R. Shah, Rashmi R. Shah, Joel Morganroth

Published in: Drug Safety | Issue 6/2013

Abstract

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of certain forms of cancers, raising hopes for many patients with otherwise unresponsive tumours. While these agents are generally well tolerated, clinical experience with them has highlighted their unexpected association with serious toxic effects on various organs such as the heart, lungs, liver, kidneys, thyroid, skin, blood coagulation, gastrointestinal tract and nervous system. Many of these toxic effects result from downstream inhibition of vascular endothelial growth factor or epidermal growth factor signalling in cells of normal organs. Many of these undesirable effects such as hypertension, hypothyroidism, skin reactions and possibly proteinuria are on-target effects. Since tyrosine kinases are widely distributed with specific functional roles in different organs, this association is not too surprising. Various studies suggest that the development of these on-target effects indicates clinically desirable and effective inhibition of the corresponding ligand-mediated receptor linked with oncogenesis. This is reflected as improved efficacy in the subgroup of patients who develop these on-target adverse effects compared with those who do not. Inevitably, issues arise with respect to the regulatory assessment of efficacy and risk/benefit of the TKIs as well as the clinical approach to managing patients who develop these effects. Routine subgroup analysis of efficacy data from clinical trials (patients with and without on-target toxicity) may enable more effective clinical use of TKIs since (i) discontinuing or reducing the dose of the TKI has a negative impact if the tumour is TKI-responsive; and (ii) it is usually possible to manage these undesirable on-target effects with conventional clinical approaches. Prospective studies are needed to investigate this proposition further.

Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med. 2005;353(2):172–87.PubMedCrossRef

Chen MH, Kerkela R, Force T. Mechanisms of cardiomyopathy associated with tyrosine kinase inhibitor cancer therapeutics. Circulation. 2008;118(1):84–95.PubMedCrossRef

Shah RR, Morganroth J, Shah DR. Cardiovascular safety of tyrosine kinase inhibitors: with a special focus on cardiac repolarization (QT interval). Drug Saf. doi:10.1007/s40264-013-0047-5

Keefe D, Bowen J, Gibson R, et al. Noncardiac vascular toxicities of vascular endothelial growth factor inhibitors in advanced cancer: a review. Oncologist. 2011;16(4):432–44.PubMedCrossRef

Cook KM, Figg WD. Angiogenesis inhibitors: current strategies and future prospects. CA Cancer J Clin. 2010;60(4):222–43.

Gotlink KJ, Verheul HMW. Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action? Angiogenesis. 2010;13(1):1–14.

Laurent-Puig P, Lievre A, Blons H. Mutations and response to epidermal growth factor receptor inhibitors. Clin Cancer Res. 2009;15(4):1133–9.PubMedCrossRef

Elice F, Rodeghiero F, Falanga A, et al. Thrombosis associated with angiogenesis inhibitors. Best Pract Res Clin Haematol. 2009;22(1):115–28.PubMedCrossRef

Sonpavde G, Bellmunt J, Schutz F, et al. The double edged sword of bleeding and clotting from VEGF inhibition in renal cancer patients. Curr Oncol Rep. 2012;14(4):295–306.PubMedCrossRef

10.

Amir E, Seruga B, Martinez-Lopez J, et al. Oncogenic targets, magnitude of benefit, and market pricing of antineoplastic drugs. J Clin Oncol. 2011;29(18):2543–9.PubMedCrossRef

11.

van Cruijsen H, van der Veldt A, Hoekman K. Tyrosine kinase inhibitors of VEGF receptors: clinical issues and remaining questions. Front Biosci. 2009;14(1):2248–68.PubMedCrossRef

12.

Roodhart JM, Langenberg MH, Witteveen E, et al. The molecular basis of class side effects due to treatment with inhibitors of the VEGF/VEGFR pathway. Curr Clin Pharmacol. 2008;3(2):132–43.PubMedCrossRef

13.

Eaby B, Culkin A, Lacouture ME. An interdisciplinary consensus on managing skin reactions associated with human epidermal growth factor receptor inhibitors. Clin J Oncol Nurs. 2008;12(2):283–90.PubMedCrossRef

14.

Asnacios A, Naveau S, Perlemuter G. Gastrointestinal toxicities of novel agents in cancer therapy. Eur J Cancer. 2009;45(Suppl. 1):332–42.PubMedCrossRef

15.

Steeghs N, Gelderblom H, Roodt JO, et al. Hypertension and rarefaction during treatment with telatinib, a small molecule angiogenesis inhibitor. Clin Cancer Res. 2008;14(11):3470–6.PubMedCrossRef

16.

GlaxoSmilthKline. Clinical Study Register. A meta-analysis of the cumulative incidence of hypertension in the first month of treatment with pazopanib across three RCC studies: VEG102616, VEG105192 and VEG107769 (Study number 115227). Available from URL: http://www.gsk-clinicalstudyregister.com/result_detail.jsp?protocolId=115227&studyId=7FE7FADD-D3FA-4BD6-9BF5-0845FF2A2C90&compound=pazopanib&type=Compound&letterrange=L-P. Accessed 25 Oct 2012.

17.

FDA. Label for INLYTA (axitinib) approved on 27 January 2012. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202324lbl.pdf. Accessed 7 Oct 2012.

18.

FDA. Label for BOSULIF (bosutinib) approved on 4 September 2012. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203341lbl.pdf. Accessed 7 Oct 2012.

19.

FDA. Label for XALKORI (crizotinib) approved on 24 February 2012. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202570s003lbl.pdf. Accessed 7 Oct 2012.

20.

FDA. Label for SPRYCEL (dasatinib) approved on 7 October 2011. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021986s009s010lbl.pdf. Accessed 7 Oct 2012.

21.

FDA. Label for TARCEVA (erlotinib) approved on 17 April 2012. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021743s017lbl.pdf. Accessed 7 Oct 2012.

22.

FDA. Label for IRESSA (gefitinib) approved on 17 June 2005. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021399s008lbl.pdf. Accessed 7 Oct 2012.

23.

FDA. Label for GLEEVEC (imatinib) approved on 31 January 2012. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021588s035lbl.pdf. Accessed 7 Oct 2012.

24.

FDA. Label for TYKERB (lapatinib) approved on 14 February 2012. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022059s013lbl.pdf. Accessed 7 Oct 2012.

25.

FDA. Label for TASIGNA (nilotinib) approved on 1 May 2012. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022068s012lbl.pdf. Accessed 7 Oct 2012.

26.

FDA. Label for VOTRIENT (pazopanib) approved on 26 April 2012. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022465s-010S-012lbl.pdf. Accessed 7 Oct 2012.

27.

FDA. Label for STIVARGA (regorafenib) approved on 27 September 2012. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203085lbl.pdf. Accessed 7 Oct 2012.

28.

FDA. Label for JAKAFI (ruxolitinib) approved on 21 June 2012. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202192s001lbl.pdf. Accessed 7 Oct 2012.

29.

FDA. Label for NEXAVAR (sorafenib) approved on 14 October 2011. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021923s012lbl.pdf. Accessed 7 Oct 2012.

30.

Label for SUTENT (sunitinib) approved on 20 April 2012. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021938s019s020lbl.pdf. Accessed 7 Oct 2012.

31.

FDA. Label for CAPRELSA (vandetanib) approved on 22 June 2011. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022405s001lbl.pdf. Accessed 7 Oct 2012.

32.

FDA. Label for ZELBORAF (vemurafenib) approved on 17 August 2011. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202429s000lbl.pdf. Accessed 7 Oct 2012.

33.

Nazer B, Humphreys BD, Moslehi J. Effects of novel angiogenesis inhibitors for the treatment of cancer on the cardiovascular system: focus on hypertension. Circulation. 2011;124(15):1687–91.PubMedCrossRef

34.

Qi WX, Shen Z, Lin F, et al. Incidence and risk of hypertension with vandetanib in cancer patients: a systematic review and meta-analysis of clinical trials. Br J Clin Pharmacol. 2013;75(4):919–30.PubMedCrossRef

35.

Rini BI, Cohen DP, Lu DR, et al. Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst. 2011;103(9):763–73.PubMedCrossRef

36.

George S, Reichardt P, Lechner T, et al. Hypertension as a potential biomarker of efficacy in patients with gastrointestinal stromal tumor treated with sunitinib. Ann Oncol. 2012;23(12):3180–7.PubMedCrossRef

37.

Rini BI, Schiller JH, Fruehauf JP, et al. Diastolic blood pressure as a biomarker of axitinib efficacy in solid tumors. Clin Cancer Res. 2011;17(11):3841–9.PubMedCrossRef

38.

Estfan B, Byrne M, Kim R. Sorafenib in advanced hepatocellular carcinoma: hypertension as a potential surrogate marker for efficacy. Am J Clin Oncol (Epub 2012 Apr 27).

39.

Kim JJ, Vaziri SA, Rini BI, et al. Association of VEGF and VEGFR2 single nucleotide polymorphisms with hypertension and clinical outcome in metastatic clear cell renal cell carcinoma patients treated with sunitinib. Cancer. 2012;118(7):1946–54.PubMedCrossRef

40.

Li XS, Wu X, Zhao PJ, et al. Efficacy and safety of sunitinib in the treatment of metastatic renal cell carcinoma. Chin Med J (Engl). 2011;124(18):2920–4.

41.

Clemons J, Gao D, Naam M, et al. Thyroid dysfunction in patients treated with sunitinib or sorafenib. Clin Genitourin Cancer. 2012;10(4):225–31.PubMedCrossRef

42.

Daimon M, Kato T, Kaino W, et al. Thyroid dysfunction in patients treated with tyrosine kinase inhibitors, sunitinib, sorafenib and axitinib, for metastatic renal cell carcinoma. Jpn J Clin Oncol. 2012;42(8):742–7.PubMedCrossRef

43.

Torino F, Corsello SM, Longo R, et al. Hypothyroidism related to tyrosine kinase inhibitors: an emerging toxic effect of targeted therapy. Nat Rev Clin Oncol. 2009;6(4):219–28.PubMedCrossRef

44.

Sakurai K, Fukazawa H, Arihara Z, et al. Sunitinib-induced thyrotoxicosis followed by persistent hypothyroidism with shrinkage of thyroid volume. Tohoku J Exp Med. 2010;222(1):39–44.PubMedCrossRef

45.

Krouse RS, Royal RE, Heywood G, et al. Thyroid dysfunction in 281 patients with metastatic melanoma or renal carcinoma treated with interleukin-2 alone. J Immunother Emphasis Tumor Immunol. 1995;18(4):272–8.PubMedCrossRef

46.

Schwartzentruber DJ, White DE, Zweig MH, et al. Thyroid dysfunction associated with immunotherapy for patients with cancer. Cancer. 1991;68(11):2384–90.PubMedCrossRef

47.

Wong E, Rosen LS, Mulay M, et al. Sunitinib induces hypothyroidism in advanced cancer patients and may inhibit thyroid peroxidase activity. Thyroid. 2007;17(4):351–5.PubMedCrossRef

48.

Mannavola D, Coco P, Vannucchi G, et al. A novel tyrosine-kinase selective inhibitor, sunitinib, induces transient hypothyroidism by blocking iodine uptake. J Clin Endocrinol Metab. 2007;92(9):3531–4.PubMedCrossRef

49.

Abdulrahman RM, Verloop H, Hoftijzer H, et al. Sorafenib-induced hypothyroidism is associated with increased type 3 deiodination. J Clin Endocrinol Metab. 2010;95(8):3758–62.PubMedCrossRef

50.

Kappers MH, van Esch JH, Smedts FM, et al. Sunitinib-induced hypothyroidism is due to induction of type 3 deiodinase activity and thyroidal capillary regression. J Clin Endocrinol Metab. 2011;96(10):3087–94.PubMedCrossRef

51.

Vesely D, Astil J, Lastuvka P, et al. Serum levels of IGF-I, HGF, TGFβ1, bFGF and VEGF in thyroid gland tumors. Physiol Res. 2004;53(1):83–9.PubMed

52.

Makita N, Miyakawa M, Fujita T, et al. Sunitinib induces hypothyroidism with a markedly reduced vascularity. Thyroid. 2010;20(3):323–6.PubMedCrossRef

53.

Sato S, Muraishi K, Tani J, et al. Clinical characteristics of thyroid abnormalities induced by sunitinib treatment in Japanese patients with renal cell carcinoma. Endocr J. 2010;57(10):873–80.PubMedCrossRef

54.

Kitajima K, Takahashi S, Maeda T, et al. Thyroid size change by CT monitoring after sorafenib or sunitinib treatment in patients with renal cell carcinoma: comparison with thyroid function. Eur J Radiol. 2012;81(9):2060–5.PubMedCrossRef

55.

Riesenbeck LM, Bierer S, Hoffmeister I, et al. Hypothyroidism correlates with a better prognosis in metastatic renal cancer patients treated with sorafenib or sunitinib. World J Urol. 2011;29(6):807–13.PubMedCrossRef

56.

Schmidinger M, Vogl UM, Bojic M, et al. Hypothyroidism in patients with renal cell carcinoma: blessing or curse? Cancer. 2011;117(3):534–44.PubMedCrossRef

57.

Robinson ES, Matulonis UA, Ivy P, et al. Rapid development of hypertension and proteinuria with cediranib, an oral vascular endothelial growth factor receptor inhibitor. Clin J Am Soc Nephrol. 2010;5(3):477–83.PubMedCrossRef

58.

Eskens FA, de Jonge MJ, Bhargava P, et al. Biologic and clinical activity of tivozanib (AV-951, KRN-951), a selective inhibitor of VEGF receptor-1, -2, and -3 tyrosine kinases, in a 4-week-on, 2-week-off schedule in patients with advanced solid tumors. Clin Cancer Res. 2011;17(22):7156–63.PubMedCrossRef

59.

Eremina V, Jefferson JA, Kowalewska J, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med. 2008;358(11):1129–36.PubMedCrossRef

60.

Eremina V, Quaggin SE. Biology of anti-angiogenc therapy-induced thrombotic microangiopathy. Semin Nephrol. 2010;30(6):582–90.PubMedCrossRef

61.

Izzedine H, Massard C, Spano JP, et al. VEGF signalling inhibition-induced proteinuria: Mechanisms, significance and management. Eur J Cancer. 2010;46(2):439–48.PubMedCrossRef

62.

Hattori S, Kanda S, Harita Y. Tyrosine kinase signalling in kidney glomerular podocytes. J Signal Transduct. 2011;2011:317852. doi:10.1155/2011/317852.PubMed

63.

Bertuccio C, Veron D, Aggarwal PK, et al. Vascular endothelial growth factor receptor 2 direct interaction with nephrin links VEGF-A signals to actin in kidney podocytes. J Biol Chem. 2011;286(46):39933–44.PubMedCrossRef

64.

Sugimoto H, Hamano Y, Charytan D, et al. Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt-1) induces proteinuria. J Biol Chem. 2003;278(15):12605–8.PubMedCrossRef

65.

Blanco S, Bonet J, López D, et al. ACE inhibitors improve nephrin expression in Zucker rats with glomerulosclerosis. Kidney Int Suppl. 2005;67(S93):S10-4.

66.

Agabiti-Rosei E. Structural and functional changes of the microcirculation in hypertension: influence of pharmacological therapy. Drugs. 2003;63(Spec No 1):19–29.

67.

Rosen AC, Wu S, Damse A, et al. Risk of rash in cancer patients treated with vandetanib: systematic review and meta-analysis. J Clin Endocrinol Metab. 2012;97(4):1125–33.PubMedCrossRef

68.

Lacouture ME, Laabs SM, Koehler M, et al. Analysis of dermatologic events in patients with cancer treated with lapatinib. Breast Cancer Res Treat. 2009;114(3):485–93.PubMedCrossRef

69.

Choi NM. Chemotherapy-induced iatrogenic injury of skin: new drugs and new concepts Clin Dermatol. 2011;29(6):587–601.

70.

Hirsh V. Managing treatment-related adverse events associated with EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer. Curr Oncol. 2011;18(3):126–38.PubMedCrossRef

71.

Suzumura T, Kimura T, Kudoh S, et al. Reduced CYP2D6 function is associated with gefitinib-induced rash in patients with non-small cell lung cancer. BMC Cancer. 2012;4(12):568.CrossRef

72.

Li J, Karlsson MO, Brahmer J, et al. CYP3A phenotyping approach to predict systemic exposure to EGFR tyrosine kinase inhibitors. J Natl Cancer Inst. 2006;98(23):1714–23.PubMedCrossRef

73.

Pérez-Soler R, Zou Y, Li T, et al. The phosphatase inhibitor menadione (vitamin K3) protects cells from EGFR inhibition by erlotinib and cetuximab. Clin Cancer Res. 2011;17(21):6766–77.PubMedCrossRef

74.

Mitra SS, Simcock R. Erlotinib induced skin rash spares skin in previous radiotherapy field. J Clin Oncol. 2006;24(16):e28–9.PubMedCrossRef

75.

Pérez-Soler R. Can rash associated with HER1/EGFR inhibition be used as a marker of treatment outcome? Oncology (Williston Park). 2003;17(11 Suppl. 12):23–8.

76.

Pérez-Soler R. Rash as a surrogate marker for efficacy of epidermal growth factor receptor inhibitors in lung cancer. Clin Lung Cancer. 2006;8(Suppl. 1):S7–14.PubMedCrossRef

77.

Wacker B, Nagrani T, Weinberg J, et al. Correlation between development of rash and efficacy in patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies. Clin Cancer Res. 2007;13(13):3913–21.PubMedCrossRef

78.

Liu G, Gurubhagavatula S, Zhou W, et al. Epidermal growth factor receptor polymorphisms and clinical outcomes in non-small-cell lung cancer patients treated with gefitinib. Pharmacogenomics J. 2008;8(2):129–38.PubMedCrossRef

79.

Vincenzi B, Santini D, Russo A, et al. Early skin toxicity as a predictive factor for tumor control in hepatocellular carcinoma patients treated with sorafenib. Oncologist. 2010;15(1):85–92.PubMedCrossRef

80.

Petrelli F, Borgonovo K, Cabiddu M, et al. Relationship between skin rash and outcome in non-small-cell lung cancer patients treated with anti-EGFR tyrosine kinase inhibitors: a literature-based meta-analysis of 24 trials. Lung Cancer. 2012;78(1):8–15.PubMedCrossRef

81.

Stepanski EJ, Reyes C, Walker MS, et al. The association of rash severity with overall survival: findings from patients receiving erlotinib for pancreatic cancer in the community setting. Pancreas. 2013;42(1):32–6.PubMedCrossRef

82.

Fiala O, Pesek M, Finek J, et al. Skin rash as useful marker of erlotinib efficacy in NSCLC and its impact on clinical practice. Neoplasma. 2013;60(1):26–32.PubMedCrossRef

83.

Mita AC, Papadopoulos K, de Jonge MJA, et al. Erlotinib ‘dosing-to-rash’: a phase II intrapatient dose escalation and pharmacologic study of erlotinib in previously treated advanced non-small cell lung cancer. Br J Cancer. 2011;105(7):938–44.

84.

Liu HB, Wu Y, Lv TF, et al. Skin rash could predict the response to EGFR tyrosine kinase inhibitor and the prognosis for patients with non-small cell lung cancer: a systematic review and meta-analysis. PLoS One. 2013;8(1):e55128.PubMedCrossRef

85.

Jonker DJ, O’Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357(20):2040–8.PubMedCrossRef

86.

Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359(17):1757–65.PubMedCrossRef

87.

Van Cutsem E, Tejpar S, Vanbeckevoort D, et al. Intrapatient cetuximab dose escalation in metastatic colorectal cancer according to the grade of early skin reactions: the randomized EVEREST study. J Clin Oncol. 2012;30(23):2861–8.PubMedCrossRef

88.

Lièvre A, Bachet JB, Boige V, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 2008;26(3):374–9.PubMedCrossRef

89.

FDA. Oncologic Drugs Advisory Committee meeting (24 September 2002). Clinical review: IRESSA NDA 21-399. Available from URL: http://www.fda.gov/ohrms/dockets/ac/02/briefing/3894B1_03_FDA-Medical%20Officer%20Review.pdf. Accessed 22 Oct 2012.

90.

European Medicines Agency. NEXAVAR public assessment report (4 March 2007). Available from URL: http://www.emea.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000690/WC500027707.pdf. Accessed 22 Oct 2012.

91.

European Medicines Agency. VOTRIENT public assessment report (EMA/CHMP/248579/2010) [14 June 2010]. Available from URL: http://www.emea.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001141/WC500094275.pdf. Accessed 22 Oct 2012.

92.

Marshall JL. Maximum-tolerated dose, optimum biologic dose, or optimum clinical value: dosing determination of cancer therapies. J Clin Oncol. 2012;30(23):2815–6.PubMedCrossRef

93.

Mukohara T, Nakajima H, Mukai H, et al. Effect of axitinib (AG-013736) on fatigue, thyroid-stimulating hormone, and biomarkers: a phase I study in Japanese patients. Cancer Sci. 2010;101(4):963–8.PubMedCrossRef

94.

Fujiwara Y, Kiyota N, Chayahara N, et al. Management of axitinib (AG-013736)-induced fatigue and thyroid dysfunction, and predictive biomarkers of axitinib exposure: results from phase I studies in Japanese patients. Invest New Drugs. 2012;30(3):1055–64.PubMedCrossRef

95.

European Medicines Agency. IRESSA public assessment report (EMEA/CHMP/563746/2008) [22 July 2009]. Available from URL:0 http://www.emea.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001016/WC500036361.pdf. Accessed 22 Oct 2012.

96.

FDA. Clinical pharmacology and biopharmaceutics review(s) – INLYTA NDA. Application number 203324Orig1s000. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202324Orig1s000ClinPharmR.pdf. Accessed 22 Oct 2012.

97.

Girardi F, Franceschi E, Brandes AA. Cardiovascular safety of VEGF-targeting therapies: current evidence and handling strategies. Oncologist. 2010;15(7):683–94.PubMedCrossRef

98.

Franklin PH, Banfor PN, Tapang P, et al. Effect of the multitargeted receptor tyrosine kinase inhibitor, ABT-869 [N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N’-(2-fluoro-5-methylphenyl)urea], on blood pressure in conscious rats and mice: reversal with antihypertensive agents and effect on tumor growth inhibition. J Pharmacol Exp Ther. 2009;329(3):928–37.PubMedCrossRef

99.

Izzedine H, Ederhy S, Goldwasser F, et al. Management of hypertension in angiogenesis inhibitor-treated patients. Ann Oncol. 2009;20(5):807–15.PubMedCrossRef

100.

Molteni A, Heffelfinger S, Moulder JE, et al. Potential deployment of angiotensin I converting enzyme inhibitors and of angiotensin II type 1 and type 2 receptor blockers in cancer chemotherapy. Anticancer Agents Med Chem. 2006;6(5):451–60.PubMedCrossRef

101.

Wolter P, Stefan C, Decallonne B, et al. The clinical implications of sunitinib-induced hypothyroidism: a prospective evaluation. Br J Cancer. 2008;99(3):448–54.PubMedCrossRef

102.

Garfield DH, Wolter P, Schöffski P, et al. Documentation of thyroid function in clinical studies with sunitinib: why does it matter? J Clin Oncol. 2008;26(31):5131–2.PubMedCrossRef

103.

Lynch TJ Jr, Kim ES, Eaby B, et al. Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007;12(5):610–21.PubMedCrossRef

104.

Thatcher N, Nicolson M, Groves RW, for the UK Erlotinib Skin Toxicity Management Consensus Group, et al. Expert consensus on the management of erlotinib-associated cutaneous toxicity in the UK. Oncologist. 2009;14(8):840–7.

105.

Potthoff K, Hofheinz R, Hassel JC, et al. Interdisciplinary management of EGFR-inhibitor-induced skin reactions: a German expert opinion. Ann Oncol. 2011;22(3):524–35.PubMedCrossRef

106.

Abdullah SE, Haigentz M Jr, Piperdi B. Dermatologic toxicities from monoclonal antibodies and tyrosine kinase inhibitors against EGFR: pathophysiology and management. Chemother Res Pract. 2012;2012:351210.PubMed

107.

Robert C, Sibaud V, Mateus C, et al. Advances in the management of cutaneous toxicities of targeted therapies. Semin Oncol. 2012;39(2):227–40.PubMedCrossRef

108.

Hassel JC, Kripp M, Al-Batran S, et al. Treatment of epidermal growth factor receptor antagonist-induced skin rash: results of a survey among German oncologists. Onkologie. 2010;33(3):94–8.PubMedCrossRef

109.

Bidoli P, Cortinovis DL, Colombo I, et al. Isotretinoin plus clindamycin seem highly effective against severe erlotinib-induced skin rash in advanced non-small cell lung cancer. J Thorac Oncol. 2010;5(10):1662–3.PubMedCrossRef

110.

Requena C, Llombart B, Sanmartín O. Acneiform eruptions induced by epidermal growth factor receptor inhibitors: treatment with oral isotretinoin. Cutis. 2012;90(2):77–80.PubMed

111.

Blanchetot C, Tertoolen LG, den Hertog J. Regulation of receptor protein-tyrosine phosphatase alpha by oxidative stress. EMBO J. 2002;21(4):493–503.PubMedCrossRef

112.

Talon Therapeutics, Inc. Safety, tolerability and systemic absorption of menadione topical lotion for epidermal-growth-factor-receptor (EGFR) inhibitor-associated rash [ClinicalTrials.gov identifier NCT00656786]. US National Institutes of Health, ClinicalTrials.gov. Available from URL: http://www.clinicaltrials.gov. Accessed 29 Oct 2012.

113.

Mayo Clinic. Menadione topical lotion in treating skin discomfort and psychological distress in patients with cancer receiving panitumumab, erlotinib hydrochloride, or cetuximab [ClinicalTrials.gov identifier NCT01393821]. Available from URL: http://www.clinicaltrials.gov. Accessed 29 Oct 2012.

Title: Tyrosine Kinase Inhibitors: Their On-Target Toxicities as Potential Indicators of Efficacy
Authors: Devron R. Shah
Rashmi R. Shah
Joel Morganroth
Publication date: 01-06-2013
Publisher: Springer International Publishing AG
Published in: Drug Safety / Issue 6/2013
Print ISSN: 0114-5916
Electronic ISSN: 1179-1942
DOI: https://doi.org/10.1007/s40264-013-0050-x

At a glance: The STEP trials

Springer Medicine

Tyrosine Kinase Inhibitors: Their On-Target Toxicities as Potential Indicators of Efficacy

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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