Topical Pharmacological Treatment of Actinic Keratoses: Focus on Tirbanibulin 1% Ointment
Keywords:
tirbanibulin, actinic keratoses, field of cancerization, local adverse eventsAbstract
Actinic keratosis (AK) is a frequent precancerous skin lesion that mostly affects chronically sun-exposed areas. Chronic sun damage leads to various mutations in onco-suppressor and oncogenic genes which cause an uncontrolled proliferation of atypical keratinocytes. Untreated AKs may evolve in cutaneous squamous cell carcinoma (cSCC), with the consequent need for dermato-surgical excision or even for systemic immunotherapy in case of invasive/metastatic cSCCs. Epidemiology data on AK prevalence are various, however, the literature unanimously reports an increasing prevalence due to the aging of the population. Clinically AKs appear as a scaly, erythematous macule or papule or hyperkeratotic plaque. Management of AKs and the field of cancerization is important to avoid the natural evolution into squamous cell carcinomas (SCCs). Both physical and topical treatments are approved for managing AKs. Patient compliance with topical regimens is usually low due to the length of the posology and frequent skin adverse events. A recently approved tirbanibulin-based ointment, showed potential for inhibiting cell proliferation and blocking SRC-kinases, implicated in the progression of AKs in SCCs. The advantage of this new treatment is the practical posology, with a daily application for 5 consecutive days on AKs of the face-scalp area. Local skin reactions are usually mild and do not require treatment discontinuation. The short course of this new therapy and its excellent tolerance massively increased patient compliance. This article reviews what is currently known about this new therapy from its mechanism of action to clinical trial outcomes regarding safety, effectiveness, and patient adherence to the treatment.
References
Werner RN, Sammain A, Erdmann R, Hartmann V, Stockfleth E, Nast A. The natural history of actinic keratosis: a systematic review. Br J Dermatol. 2013;169(3):502-518. doi:10.1111/bjd.12420
de Berker D, McGregor JM, Mohd Mustapa MF, Exton LS, Hughes BR. British Association of Dermatologists' guidelines for the care of patients with actinic keratosis 2017. Br J Dermatol. 2017;176(1):20-43. doi:10.1111/bjd.15107
Memon AA, Tomenson JA, Bothwell J, et al. Prevalence of solar damage and 394 actinic keratosis in a Merseyside population. Br J Dermatol. 2000;142(6):1154-1159. 395 17
Hensen P, Müller ML, Haschemi R, et al. Predisposing factors of actinic keratosis in a 396 North-West German population. Eur J Dermatol. 2009;19(4):345-354.
Woodhead AD, Setlow RB, Tanaka M. Environmental factors in nonmelanoma and melanoma skin cancer. J Epidemiol. 1999;9(6 Suppl): S102-114.
Frost C, Williams G, Green A. High incidence and regression rates of solar keratoses in a queensland community. J Invest Dermatol. 2000;115(2):273-277. doi:10.1046/j.1523-1747.2000.00048.x
Flohil SC, van der Leest RJ, Dowlatshahi EA, Hofman A, de Vries E, Nijsten T. Prevalence of actinic keratosis and its risk factors in the general population: the Rotterdam Study. J Invest Dermatol. 2013;133(8):1971-1978. doi:10.1038/jid.2013.134
Memon AA, Tomenson JA, Bothwell J, Friedmann PS. Prevalence of solar damage and actinic keratosis in a Merseyside population. Br J Dermatol. 2000;142(6):1154-1159. doi:10.1046/j.1365-2133.2000.03541.
Eder J, Prillinger K, Korn A, Geroldinger A, Trautinger F. Prevalence of actinic keratosis among dermatology outpatients in Austria. Br J Dermatol. 2014;171(6):1415-1421. doi:10.1111/bjd.13132
Peris K, Calzavara-Pinton PG, Neri L, et al. Italian expert consensus for the management of actinic keratosis in immunocompetent patients. J Eur Acad Dermatol Venereol. 2016;30(7):1077-1084. doi:10.1111/jdv.13648
Marks R. Who benefits from calling a solar keratosis a squamous cell carcinoma?. Br J Dermatol. 2006;155(1):23-26. doi:10.1111/j.1365-2133.2005.07122.
Peris K, Neri L, Calzavara Pinton P, et al. Physicians' opinions and clinical practice patterns for actinic keratosis management in Italy. G Ital Dermatol Venereol. 2014;149(2):185-192.
Heaphy MR Jr, Ackerman AB. The nature of solar keratosis: a critical review in historical perspective. J Am Acad Dermatol. 2000;43(1 Pt 1):138-150. doi:10.1067/mjd.2000.107497
Werner RN, Stockfleth E, Connolly SM, et al. Evidence- and consensus-based (S3) Guidelines for the Treatment of Actinic Keratosis - International League of Dermatological Societies in cooperation with the European Dermatology Forum - Short version. J Eur Acad Dermatol Venereol. 2015;29(11):2069-2079. doi:10.1111/jdv.13180
Lai V, Cranwell W, Sinclair R. Epidemiology of skin cancer in the mature patient. Clin Dermatol. 2018 Mar-Apr;36(2):167-176. doi: 10.1016/j.clindermatol.2017.10.008. Epub 2017 Oct 13. PMID: 29566921.
Brash DE, Rudolph JA, Simon JA, et al. A role for sunlight in skin cancer: UV-induced 512 p53 mutations in squamous cell carcinoma. Proc Natl Acad Sci USA. 513 1991;88(22):10124-10128.
Anwar J, Wrone DA, Kimyai-Asadi A, Alam M. The development of actinic keratosis into invasive squamous cell carcinoma: evidence and evolving classification schemes. Clin Dermatol. 2004;22(3):189-196. doi:10.1016/j.clindermatol.2003.12.006
Ashton KJ, Weinstein SR, Maguire DJ, Griffiths LR. Chromosomal aberrations in squamous cell carcinoma and solar keratoses revealed by comparative genomic hybridization. Arch Dermatol. 2003;139(7):876-882. doi:10.1001/archderm.139.7.876
Eisen DB, Asgari MM, Bennett DD, et al. Guidelines of care for the management of actinic keratosis. J Am Acad Dermatol. 2021;85(4):e209-e233. doi:10.1016/j.jaad.2021.02.082
Mittelbronn MA, Mullins DL, Ramos-Caro FA, Flowers FP. Frequency of pre-existing actinic keratosis in cutaneous squamous cell carcinoma. Int J Dermatol. 1998;37(9):677-681. doi:10.1046/j.1365-4362.1998.00467.x
Criscione VD, Weinstock MA, Naylor MF, et al. Actinic keratoses: Natural history and risk of malignant transformation in the Veterans Affairs Topical Tretinoin Chemoprevention Trial. Cancer. 2009;115(11):2523-2530. doi:10.1002/cncr.24284
Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet. 1988;1(8589):795-797. doi:10.1016/s0140-6736(88)91658-3
Dodson JM, DeSpain J, Hewett JE, Clark DP. Malignant potential of actinic keratoses and the controversy over treatment. A patient-oriented perspective. Arch Dermatol. 1991;127(7):1029-1031.
Heppt MV, Dykukha I, Graziadio S, Salido-Vallejo R, et al. Comparative Efficacy and Safety of Tirbanibulin for Actinic Keratosis of the Face and Scalp in Europe: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials. J Clin Med. 2022 Mar 16;11(6):1654.
Rowert-Huber J., Patel M.J., Forschner T., et al. Actinic keratosis is an early in situ squamous cell carcinoma: A proposal for reclassification. Br. J. Dermatol. 2007;156(Suppl. S3):8–12
Casari A, Chester J, Pellacani G. Actinic Keratosis and Non-Invasive Diagnostic Techniques: An Update. Biomedicines. 2018 Jan 8;6(1):8.
SLAUGHTER DP, SOUTHWICK HW, SMEJKAL W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer. 1953;6(5):963-968. doi:10.1002/1097-0142(195309)6:5<963::aid-cncr2820060515>3.0.co;2-q
Willenbrink TJ, Ruiz ES, Cornejo CM, et al. Field cancerization: Definition, epidemiology, risk factors, and outcomes. J Am Acad Dermatol. 2020 Sep;83(3):709-717. doi: 10.1016/j.jaad.2020.03.126. Epub 2020 May 7. PMID: 32387665.
Dianzani C, Conforti C, Giuffrida R, et al. Current therapies for actinic keratosis. Int J Dermatol. 2020 Jun;59(6):677-684
Dirschka T, Gupta G, Micali G, et al. Real-world approach to actinic keratosis management: practical treatment algorithm for office-based dermatology. J Dermatolog Treat. 2017;28(5):431–442. doi: 10.1080/09546634.2016.1254328
Miller AC, Adjei S, Temiz LA, et al. Tirbanibulin for the Treatment of Actinic Keratosis: A Review. Skin Therapy Lett. 2022 Jul;27(4):4-7.
Ranpariya VK, Muddasani S, Mahon AB, et al. Frequency of procedural and medical treatments of actinic keratosis. J Am Acad Dermatol. 2022;86(4):916–918.
Krawtchenko N, Roewert-Huber J, Ulrich M et al. A randomised study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: a comparison of clinical and histological outcomes including 1-year follow-up. Br J Dermatol. 2007;157:34–40
European Medicines Agency .Summary of Product Characteristics: Klisyri 10 mg/g ointment [Webpage] European Medicines Agency; Amsterdam, The Netherlands: 2021. [(accessed on 20 January 2022)]. Last updated August 2021
S. Kim, A. Min, K.-H. Lee, et al. Antitumor Effect of KX-01 through Inhibiting Src Family Kinases and Mitosis. Cancer Res Treat Off J Korean Cancer Assoc., 49 (2017), pp. 643-655
M.P. Smolinski, Y. Bu, J. Clements, I.H. Gelman, et al. Discovery of Novel Dual Mechanism of Action Src Signaling and Tubulin Polymerization Inhibitors (KX2-391 and KX2-361). J Med Chem., 61 (2018), pp. 4704-47190
T. Liu, W. Hu, H.J. Dalton, et al. Targeting Src and tubulin in mucinous ovarian carcinoma. Clin Cancer Res Off J Am Assoc Cancer Res., 19 (2013) S. Kim, A. Min, K.-H. Lee, et al. Antitumor Effect of KX-01 through Inhibiting Src Family Kinases and Mitosis. Cancer Res Treat Off J Korean Cancer Assoc., 49 (2017), pp. 643-655
M. Anbalagan, A. Ali, R.K. Jones, C.G. Marsden, et al. Peptidomimetic Src/pretubulin inhibitor KX-01 alone and in combination with paclitaxel suppresses growth, metastasis in human ER/PR/HER2-negative tumor xenografts. Mol Cancer Ther., 11 (2012), pp. 1936-1947
M. Anbalagan, L. Carrier, S. Glodowski, D. Hangauer, et al. KX-01, a novel Src kinase inhibitor directed toward the peptide substrate site, synergizes with tamoxifen in estrogen receptor α positive breast cancer. Breast Cancer Res Treat., 132 (2012), pp. 391-409
Schlesinger T, Stockfleth E, Grada A, et al. Tirbanibulin for Actinic Keratosis: Insights into the Mechanism of Action. Clin Cosmet Investig Dermatol. 2022 Nov 16;15:2495-2506.
S.A. Ainger, R.A. Sturm. Src and SCC: getting to the FAKs. Exp Dermatol., 24 (2015), pp. 487-488
Kempers S, DuBois J, Forman S., et al. Tirbanibulin Ointment 1% as a Novel Treatment for Actinic Keratosis: Phase 1 and 2 Results. J Drugs Dermatol. 2020 Nov 1;19(11):1093-1100.
Blauvelt A, Kempers S, Lain E, et al. Phase 3 Tirbanibulin for Actinic Keratosis Group. Phase 3 Trials of Tirbanibulin Ointment for Actinic Keratosis. N Engl J Med. 2021 Feb 11;384(6):512-520. doi: 10.1056/NEJMoa2024040. PMID: 33567191.
Kirchberger MC, Gfesser M, Erdmann M, Schliep S, Berking C, Heppt MV. Tirbanibulin 1% Ointment Significantly Reduces the Actinic Keratosis Area and Severity Index in Patients with Actinic Keratosis: Results from a Real-World Study. J Clin Med. 2023;12(14):4837. Published 2023 Jul 22. doi:10.3390/jcm12144837
Markham A, Duggan S. Tirbanibulin: first approval. Drugs. 2021 Mar;81(4): 509-13.
Goldenberg G. Treatment considerations in actinic keratosis. J Eur Acad Dermatol Venereol. 2017;31(Suppl2):12–16.
Grada A, Feldman SR, Bragazzi NL, et al. Patient-reported outcomes of topical therapies in actinic keratosis: A systematic review. Dermatol Ther. 2021 Mar;34(2):e14833
L. Niu, J. Yang, W. Yan, et al. Reversible binding of the anticancer drug KXO1 (tirbanibulin) to the colchicine-binding site of β-tubulin explains KXO1’s low clinical toxicity. J Biol Chem., 294 (2019), pp. 18099-18108
Dosik J, Cutler DL, Fang J, Padullés L. Contact Sensitization and Phototoxic and Photoallergic Potential of Tirbanibulin 1% Ointment in Healthy Volunteers. JID Innov. 2022;3(2):100170. Published 2022 Nov 17. doi:10.1016/j.xjidi.2022.100170
Moore AY, Moore S. Topical tirbanibulin eradication of periungual squamous cell carcinoma. JAAD Case Rep. 2021 Jun 26;14:101-103. doi: 10.1016/j.jdcr.2021.06.013. PMID: 34307817; PMCID: PMC8283266
Moore A, Hurley K, Moore SA. Rapid resolution of recalcitrant basal cell carcinoma of the ear with topical tirbanibulin. JAAD Case Rep. 2022 Aug 10;28:11-13.
Iglesias-Puzas Á, Conde-Taboada A, Campos-Muñoz L, Sirgado-Martínez A, López-Bran E. 1% Tirbanibulin Ointment for Actinic Keratoses on Upper Extremities: A Retrospective Case Review Study. Acta Derm Venereol. 2023;103:adv15296. Published 2023 Oct 24. doi:10.2340/actadv.v103.15296
Published
Issue
Section
License
Copyright (c) 2024 Mario Valenti, Matteo Bianco, Alessandra Narcisi, Antonio Costanzo, Riccardo Borroni, Marco Ardigò
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Dermatology Practical & Conceptual applies a Creative Commons Attribution License (CCAL) to all works we publish (http://creativecommons.org/licenses/by-nc/4.0/). Authors retain the copyright for their published work.
How to Cite
Share
