Dermatology: Practical and Conceptual Review | Dermatol Pract Concept. 2025;15(3):5921 1 Real-World Efficacy of Tirbanibulin in Actinic Keratosis Treatment: Expert Consensus and Clinical Insights Marco Ardigò1,2, Giuseppe Argenziano3, Elena Campione4, Stefania Guida5, Caterina Longo6,7, Giuseppe Micali8, Gianluca Nazzaro9,10, Ketty Peris11,12, Federico Venturi13,14, Alessia Villani15, Iris Zalaudek16 1 Dermatology Unit, IRCCS Humanitas Research Hospital, Rozzano, Italy 2 Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milano, Italy 3 Dermatology Unit, University of Campania, Naples, Italy 4 Dermatology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy 5 Dermatology Clinic, IRCCS San Raffaele Hospital, Milan, Italy 6 Skin Cancer Center, Azienda Unità Sanitaria Locale, IRCCS Reggio Emilia, Reggio Emilia, Italy 7 Dermatology Department, University of Modena and Reggio Emilia, Italy 8 Dermatology Clinic, University of Catania, Catania, Italy 9 Dermatology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy 10 Department of Physiopathology and Transplantation, University of Milan, Italy 11 Dermatology, Department of Medical Science and Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy 12 Department of Dermatology, Catholic University of the Sacred Heart, Rome, Italy 13 Oncologic Dermatology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy 14 Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy 15 Dermatology Section, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy 16 Department of Dermatology and Venereology, University of Trieste, Trieste, Italy Key words: Actinic keratosis, Tirbanibulin, Topical treatment, Expert opinion Key Message: Tirbanibulin use in the treatment of actinic keratosis is expanding owing to its proven efficacy, tolerability, and short treatment regimen. This expert consensus provides guidance on optimal use of tirbanibulin in real-life clinical practice. Citation: Ardigò M, Argenziano G, Campione E, et al. Optimal Use of Tirbanibulin in the Real-Life Treatment of Actinic Keratosis: Expert Consensus. Dermatol Pract Concept. 2025;15(3):5921. DOI: https://doi.org/10.5826/dpc.1503a5921 Accepted: May 19, 2025; Published: July 2025 Copyright: ©2025 Ardigò et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: This article was sponsored by Almirall S.p.A. Assistance with coordination of the consensus process and medical writing was provided by Editamed and funded by Almirall S.p.A. Competing Interests: MA reports speaker fees from Almirall, La Roche-Posay, and Cantabria and advisory boards for Almirall. EC reports speaker fees from Almirall, Amgen, BMS, and UCB and advisory boards for Almirall, Amgen, BMS, Cantabria, and UCB. CL reports speaker fees from Almirall Hermal and advisory boards for Regeneron. GN reports speaker fees from Giuliani, Ideka, and Novartis and advisory boards for Almirall, L’Oreal, and Novartis. KP reports grants from Abbvie, Almirall, Lilly, Novartis, and Sanofi, consulting fees from Galderma, Leo Pharma, Lilly, and Sanofi, and participation in advisory boards for Abbvie, Almirall, Biogen, Galderma, Leo Pharma, Lilly, MSD, Pierre Fabre, Regeneron, Sun Pharma, Janssen, and Sanofi. AV reports speaker fees from Almirall. IZ reports speaker fees from Almirall Hermal, Sanofi, La Roche-Posay, Bioderma, Canova, MSD, Sanofi Genzyme, and FotoFinder and advisory boards for Philogen and Regeneron. SG reports speaker fees from L’Oreal and Almirall and consultation fees from Istituto Ganassini, Merz Aesthetics. GA, GM, and FV report no conflicts of interest. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Marco Ardigò, MD, Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy. E-mail: marco.ardigo@hunimed.eu 2 Review | Dermatol Pract Concept. 2025;15(3):5921 Introduction Actinic keratosis (AK) is a chronic skin disease character- ized by the abnormal proliferation of epidermal keratino- cytes that typically presents as scaly erythematous papules or hyperkeratotic plaques in chronically sun-exposed areas [1,2]. AK lesions are considered either a precursor or an initial and superficial form of cutaneous squamous cell car- cinoma (cSCC), although low rates of progression to inva- sive cSCC have been reported, ranging from 0% to 0.075% per lesion-year [1,3]. Mutations in oncogenic and tumor- suppressing genes (e.g., p53, CDKN2A and PTEN) induced by cumulative ultraviolet B (UVB) radiation are believed to be the main factor in the pathogenesis of both AK and cSCC [1]. Important risk factors for the development of AK include male sex, age >45 years, light Fitzpatrick phototypes, and the use of photosensitizing drugs [1,4]. The concept of field cancerization (FC), generally referred to as an area of subclinical changes surrounding AK lesions that displays ge- netic changes similar to those found in AK, has diagnostic and prognostic implications and is an important aspect in the management of AK [1,3,5]. A vast array of treatments for AK, either lesion- or field-directed, is currently available, including topical drugs, surgical procedures, cryotherapy, laser ablation, and photodynamic therapy. However, many therapies are associated with important local or systemic ad- verse reactions, and they often require a long duration of treatment, resulting in poor patient adherence and subop- timal outcomes [1,4]. The recently introduced tirbanibulin ointment, a promising topical treatment option that targets both AK lesions and surrounding FC, has rapidly gained fa- vor among dermatologists mainly due to its good tolerability and ease of use, with a short-term course of therapy (once daily application for five days) [1,3,6,7]. A first-in-class mi- crotubule inhibitor, tirbanibulin targets tubulin polymeriza- tion and Src tyrosine kinase signaling, two pathways that are upregulated in AK and cSCC [6,7]. Tirbanibulin has demonstrated efficacy in clearing AK lesions, with a good tolerability profile, in large randomized clinical trials as well as in real-world studies and is listed among recommended options for the treatment of AK in all major international guidelines [1,7-11]. Given the chronic, relapsing nature of AK, the grow- ing body of knowledge about its pathophysiology, and the increasing availability of treatment options, clini- cians face many challenges in the long-term management of this disease. The aim of this consensus document was to deliver real-world guidance on the optimal use of tir- banibulin in the treatment of AK throughout the patient journey. Methods Eleven dermatologists with extensive clinical experience in the treatment of AK convened to discuss best-practice pa- tient management and optimal use of tirbanibulin based on the presentation of exemplary clinical cases and the review of relevant literature data. The panel then developed expert recommendations in the form of statements, subsequently voted on, related to two areas: 1) clinical assessment of pa- tients and real-life diagnostic procedures; 2) key aspects of tirbanibulin therapy, including patient selection, treatment modalities, and patient education. Only statements with a consensus of 100% were included. Introduction: Tirbanibulin, a topical treatment for actinic keratosis (AK) with a novel antiprolifer- ative mechanism of action, has demonstrated efficacy and a favorable tolerability profile in clinical trials and real-life studies. An insight into best-practice use of tirbanibulin in different clinical presen- tations of AK would be useful. Objectives: The aim of this article was to deliver advice, via expert consensus, on the optimal use of tirbanibulin in the real-life management of AK. Methods: A panel of 11 dermatologists with expertise in the treatment of AK convened to develop consensus statements about key aspects of tirbanibulin treatment in AK patients based on selected literature data and on their own clinical experience. Results: Two areas were examined and discussed: clinical assessment/diagnostic procedures and key aspects of tirbanibulin therapy. A total of 19 statements concerning clinical evaluation of AK patients, routine and advanced diagnostic instruments, patient selection, treatment modalities, and key mes- sages for patient communication were drafted and voted on. Conclusion: Tirbanibulin should be considered as a first-line option for most patients with AK ow- ing to its proven efficacy, good local and systemic tolerability, and a short treatment regimen of five days. All these factors encourage patient acceptability and treatment compliance. The favorable safety profile and tolerability of tirbanibulin also enable flexible therapeutic schedules, including repeated treatment cycles, if needed. ABSTRACT Review | Dermatol Pract Concept. 2025;15(3):5921 3 Clinical Assessment and Diagnostic Procedures Initial Patient Evaluation AK can have multiform clinical presentations (including distinct clinical variants such as pigmented, bowenoid, or lichenoid AK), with lesions of variable thickness and size [1,12-14]. Hyperkeratotic lesions are best examined after applying an ointment containing keratolytic agents, since the thick layer of scaly tissue may mask the real aspect of the lesion. AK lesions are most visible on the face and scalp but can also be found on the limbs and trunk. AK lesions located on the lower lip or ears are considered high-risk lesions that are often resistant to treatment [1,9]. In addition to assessing the number, aspect, and location of the lesions, it is important to accurately evaluate the photodamaged skin surrounding the lesions, since severe FC identifies a patient population at high risk for recurrence of AK and the development of mul- tiple cSCCs that requires a prompt and aggressive therapeu- tic approach [4,15,16]. There is evidence from the literature that several UVB-induced mutations and gene expression al- terations that are frequently observed in photodamaged skin (e.g., deregulation of tumor suppressor genes p53, CDKN2A and PTEN, disruption of the RAF-1/MER/ERK cell survival pathway) become increasingly more severe in AK and SCC, suggesting that photodamaged skin, AK, and SCC may be part of a disease continuum that is manifested as FC [17,18]. Despite the lack of a clear and consistent definition of FC, an expert consensus based on an extensive review proposed a clinical definition of FC as “the anatomical area with or adjacent to AK and visibly sun-damaged skin identified by at least two of the following signs: telangiectasia, atrophy, pigmentation disorders and sand paper-like texture” [17]. Even without diagnostic instruments, therefore, perilesional skin should be assessed for visible signs of inflammation and UV damage. The initial clinical evaluation should also al- ways consider patient-specific factors such as demographics, Fitzpatrick type, comorbidities, current medications, past clinical history (especially regarding skin cancer), previous AK treatments, and sun-protection behavior. Particular at- tention should be paid to immunosuppression, as immuno- compromised patients, mainly organ transplant recipients, have a greatly increased risk of developing more severe AK and SCC, with worse treatment outcomes compared to im- munocompetent AK patients. In fact, immunocompromised patients represent a distinct population requiring a dedicated treatment algorithm [1,19]. The complexity of AK features cannot be captured by rigid classification systems. In the Olsen clinical classifica- tion scale, one of the most commonly used parameters for assessing AK severity, single lesions are graded based on their thickness [20]. The Olsen scale has been used in most clinical trials of AK treatments and is a valuable tool for the assessment of individual lesions, but it does not consider the severity of FC. For a more complete assessment of AK se- verity that includes FC, the Actinic Keratosis Field Assess- ment Scale (AK-FAS) is preferable [15]. This validated tool, a 4-grade scale which evaluates AK area, hyperkeratosis, and sun damage, provides objective and clinically relevant infor- mation and is easy to use in routine practice. Instrumental Diagnostic Techniques and Histopathology Dermatoscopy is an easy-to-use, readily available, non- invasive technique that should always be part of the clinical assessment of AK. Dermatoscopy enables clinicians to visu- alize typical clinical aspects of AK (e.g., erythematous pseu- donetwork, ‘strawberry pattern’, large white follicles, and yellow or whitish scales), and thus it helps in the differential diagnosis of AK and superficial basal cell carcinoma, lentigo melanoma, irritated seborrheic keratosis, or other inflamma- tory skin diseases [1,14,21]. Dermatoscopy also plays an im- portant role in monitoring treatment response and identifying early signs of invasive SCC such the presence of peripheral ra- dial lines or vessels in the context of typical AK signs [14,21]. Histopathological examination of biopsy specimens should be carried out when atypical lesions are present, especially if they show features that may suggest a diagnosis of cSCC or other types of skin cancer [1]. Although more advanced imaging techniques, such as reflectance confocal microscopy (RCM), optical coherence tomography (OCT), and line-field confocal OCT (LC-OCT), are not part of the routine clinical assessment, when available, they can provide useful informa- tion in specific cases. Overall, these non-invasive techniques help increase diagnostic accuracy and provide additional in- formation on the microenvironment of AK lesions, enabling detection of subclinical changes [1,14,22,23]. They also play an important role in monitoring treatment response, thus op- timizing patient management [1,14,24,25] (Figure 1). Expert consensus statements with recommendations on clinical assessment and diagnosis of AK are reported in Table 1(A). Treatment of AK with Tirbanibulin AK is a chronic disease that requires regular surveillance and long-term, personalized management based on prevention (i.e., photoprotection) and therapy of both visible lesions and FC; compliance is crucial to treatment success. In the natural history of the disease, the evolution of AK lesions (e.g., persistence, resolution, or progression to cSCC) is un- predictable, and disease recurrence is the norm owing to the continuous presence of mutagenic disease drivers induced by UV radiation [2,4,13,26]. The main objective of AK therapy 4 Review | Dermatol Pract Concept. 2025;15(3):5921 a topical ointment approved in the US (2020) and Europe (2021) for the treatment of AK on the face or scalp, has demonstrated significant clinical potential owing to its effi- cacy and good tolerability, supported by a novel mechanism of action, as well as to its short treatment course [1,3,6]. Evidence of Tirbanibulin Efficacy and Tolerability from Clinical Studies In the phase III registration trials (two identical multicenter randomized double-blind placebo-controlled clinical studies enrolling a total of 702 patients with AK on the face or scalp), the percentage of patients with complete clearance (100% reduction in the number of lesions, as assessed at day 57 after completion of a 5-day regimen) was significantly higher for patients treated with tirbanibulin than for those who received control ointment (44% and 54% in trial 1 and 2, respectively, vs 5% and 13%, P<0.001 for both trails), while the percentages of patients with partial clearance (≥75% re- duction in the number of lesions) were 68% and 76% vs 16% and 20%, respectively; P<0.001) [8]. At 1-year follow-up, the estimated percentage of tirbanibulin recipients with re- current lesions, among those who had experienced complete clearance, was 47%. Tirbanibulin was well tolerated. Local reactions, including erythema, flaking/ scaling, pruritus, and pain at the application site, were mostly graded as mild or moderate and resolved spontaneously. Unlike with most top- ical therapies, severe local reactions (e.g.,  vesicles /pustules, erosion/ulceration) were infrequent. As expected from the negligible absorption rate of tirbanibulin, systemic adverse is still a matter of debate. Although prevention of progres- sion to invasive cSCC is still generally considered the key reason for treatment, there is no actual evidence that treat- ing of AK and FC decreases the risk of developing cSCC in immunocompetent patients without a previous skin cancer history [13,27]. Few studies have specifically investigated the incidence of cSCC over time in patients treated for AK. A secondary analysis of a randomized clinical trial found that the 4-year risk of developing cSCC in a previously treated AK area was 3.7%, increasing to 20.9% in patients with Olsen grade III lesions and to 33.5% in those with se- vere AK needing retreatment, while a retrospective cohort study that followed 5700 patients for five years after treat- ment with 5-fluorouracil or imiquimod found no significant difference between the two treatments in the 2- or 5-year cumulative risk for a subsequent keratinocyte carcinoma [28,29]. However, since these studies did not include a con- trol arm of untreated patients, the impact of AK treatment per se on the risk of developing cSCC remains unclear. Aside from the potential reduction in the risk of progression, the treatment goals of AK therapy are sustained total or partial clearance of visible lesions and improvement in FC. Field- directed therapies are currently the preferred option for most clinical cases of AK since, unlike lesion-directed treatments, they can target the subclinical changes underlying FC. How- ever, many field therapies with proven efficacy (e.g., pho- todynamic therapy or 5-fluorouracil) are associated with adverse events such as intense local reactions or pain, which restrict their use and impact adherence [1,3-5]. Tirbanibulin, Figure 1. Reflectance confocal microscopy image of a small area of field cancerization on the right temporal area of a 63-year-old male with multiple AK lesions on the face and scalp and a history of chronic myelofibrosis and resected melanomas: (A) before treatment, show- ing atypical honeycomb pattern together with small bright round inflammatory cells; (B) at 29 days after starting treatment with tirban- ibulin 1% ointment, showing partial restoration of the typical honeycomb pattern with no atypical features. (Courtesy of Dr. F. Venturi) Review | Dermatol Pract Concept. 2025;15(3):5921 5 Table 1. Expert Consensus Statements on Optimal Use of Tirbanibulin in the Treatment of Actinic Keratosis. A) Clinical assessment/ diagnostic procedures • Assessment of patient characteristics (e.g., Fitzpatrick skin type, comorbidities, previous therapies, risk factors for AK, immunosuppression, history of NMSC) should always be part of the clinical examination • The Olsen severity classification system can be useful for evaluating single lesions, but FC should also be assessed, preferably by using the Actinic Keratosis Field Assessment Scale (AK-FAS) • Both AK lesions and the surrounding skin should be carefully examined • The use of a keratolytic ointment allows a better evaluation of hyperkeratotic lesions by reducing the masking effect of the scaly tissue • Dermatoscopy should always be carried out, both at baseline for diagnosis and for monitoring treatment response • Advanced instrumental techniques (e.g. RCM, OCT, LC-OCT) or histopathological examination are not routinely necessary, but may be useful in specific cases B) Treatment • Due to the chronic nature of AK, repeated treatment over time is part of the long-term management of AK • Compliance is crucial to treatment success • It is still a matter of debate whether treatment of both AK lesions and FC can prevent progression to SCC • Tirbanibulin can be considered as a first-line treatment for most patients (both treatment- naïve and previously treated) because of its efficacy, short regimen, and favorable tolerability profile • The area of skin to be covered by tirbanibulin 1% ointment depends on the distribution of AK lesions and FC • The area of application of tirbanibulin is limited to 25 cm2 for each anatomical area (scalp, forehead, left/right cheek with ear, nose, and chin) • More than 25 cm2 can be treated by one sachet of tirbanibulin 1% ointment • When treating large fields (>25 cm2), sequential or simultaneous schedules can be considered • The standard tirbanibulin treatment period is five days. Up to four consecutive treatment cycles 1–2 months apart can be planned if needed • Multiple treatment cycles can be performed in immunocompromised patients, those with a history of skin cancer, or advanced photodamage • Patients should be informed about the chronic nature of AK and the need for repeated treatments over time • Although tirbanibulin-related local reactions are usually mild and transient, severe reactions may occur, and patients should be reassured • Patients should be given detailed instructions about tirbanibulin application at home AK: actinic keratosis; FC: field cancerization; LC-OCT: line-field confocal optical coherence tomography; NMSC: non-melanoma skin cancer; OCT: optical coherence tomography; RCM: reflectance confocal microscopy; SCC: squamous cell carcinoma. events were uncommon. Notably, none of the patients dis- continued treatment for tirbanibulin-related adverse events [8]. Post-hoc analyses of these phase 3 trials suggested that comorbidities and concomitant treatments (which were common in the elderly population enrolled in the studies) do not affect the efficacy and tolerability of tirbanibulin. Also, no correlation was found between the number of AK lesions at baseline and the severity of local reactions in tirbanibulin-treated patients [30]. The efficacy and favorable tolerability profile of tirbanibulin as well as the high rates of treatment compliance have been confirmed in several real-life studies, including case series and prospective or ret- rospective observational studies [9-11,30,31]. Despite their limitations (e.g., lack of a control group, small number of cases in some reports), the findings of real-life studies offer an insight into the effects of tirbanibulin in a much wider spectrum of patients and clinical presentations compared with the populations enrolled in randomized clinical tri- als. Although the European indication of tirbanibulin is for treatment of non-hyperkeratotic, non-hypertrophic AK (Ol- sen grade I) of the face or scalp, its use has been successfully extended to a range of clinical conditions, including AK pa- tients with Olsen grade II or III lesions, AK lesions located on the trunk or limbs, or AK in organ transplant recipients [9,30,31]. High rates of patient satisfaction with tirbanibulin (as assessed by the Treatment Satisfaction Questionnaire for Medication) have also been reported, especially in domains related to treatment tolerability and convenience [10]. 6 Review | Dermatol Pract Concept. 2025;15(3):5921 skin reactions, and patient confusion regarding treatment regimens [37]. Consistently with the data reported in clinical trials and real-life studies, this expert panel suggests that tir- banibulin should be considered as a first-line treatment for most AK patients, both naïve and previously treated, because of its efficacy, short treatment regimen, and favorable toler- ability profile. As widely acknowledged, appropriate man- agement of AK should consider patient preferences, clinical presentation (including localization, extension and severity of lesions and FC, duration and severity of symptoms) and patient characteristics (e.g., general health, comorbidities, risk factors for skin cancer) [4,12,27]. In the expert pan- el’s experience, tirbanibulin has been successfully used in a wide range of clinical scenarios, including isolated or mul- tiple AK lesions of varying severity (Olsen grade I and II) located in different areas of the face and scalp, extensive FC, patients who had received multiple AK therapies, and those with a history of chronic sun damage. In particular, tirbanibulin therapy has been selected as the treatment of choice in subjects with comorbidities and those with a his- tory of skin cancer owing to its tolerability and lack of sys- temic adverse events. The efficacy of tirbanibulin appears to be maintained in difficult-to-treat sites, including ears, lips, and limbs, and in areas with adnexa or pigmented lesions. Examples of tirbanibulin-treated clinical cases with vari- ous AK presentations are illustrated in Figures 2–5. Even in cases where total clearance of AK lesions was not achieved, a substantial clinical improvement in both lesions and FC was observed. According to the authors’ clinical experience, tirbanibulin therapy is readily accepted by patients, with a high degree of satisfaction and treatment compliance. Local reactions (mostly erythema and flaking/scaling) are gener- ally mild, peak at approximately day 8 after treatment ini- tiation (consistently with clinical study reports), and resolve spontaneously over an average of 10 days, without sequelae. Some patients experience a burning or itching sensation at the application site. The intensity of local reactions seems to be correlated to the extent of inflammation and photodam- age in the treated field (Figure 3). However, severe local reactions such as swelling or erosion/ulceration are rarely observed. In addition to clearing or reducing AK signs, tir- banibulin treatment was also found to be associated with cosmetic benefits, such as improvement in skin quality and texture and a more uniform complexion (Figures 4 and 5). These emerging potential effects of tirbanibulin in target- ing signs of skin aging, especially hyperpigmentation, have been investigated in recent preliminary studies [38,39]. In particular, tirbanibulin, unlike other AK therapies, appears to exert a skin-lightening effect on solar lentigines, hyperpig- mented areas that are frequently observed in the context of AK and FC [39]. Although the mechanisms of action under- lying these effects need to be further elucidated, the potential The efficacy and favorable tolerability profile of tirban- ibulin are believed to be related to the novel mechanism of action of this molecule. Preclinical studies show that tirban- ibulin, a potent antiproliferative agent, induces cell cycle arrest at G2/M phase and triggers programmed cell death of keratinocytes (via activation of intrinsic and extrinsic apoptotic pathways) by reversibly binding to tubulin, thus inhibiting tubulin polymerization, and by disrupting Src in- tracellular trafficking and Src-mediated signaling. Another possible antiproliferative mechanism is the induction of tu- mor suppressor p53 expression. Tirbanibulin antiprolifer- ative effects have been demonstrated in several tumor cell lines, including SCC, suggesting that keratinocytes with an aberrant cell growth rate may be selectively targeted by tir- banibulin [32,33]. As for the mechanisms accounting for tol- erability, tirbanibulin displayed an apoptotic effect without inducing overt toxicity in vitro owing to its fully reversible binding to tubulin [34]. The induction of apoptosis has also been demonstrated in a study using line-field confocal op- tical coherence tomography and confirmed by histopathol- ogy [35]. The severe adverse local reactions caused by many AK treatments are known to be triggered by the release of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-8 (IL-8). Notably, pro- inflammatory response assays show that tirbanibulin induces only a small increase in IL-8, unlike the significant increase in both TNF-α and IL-8 caused by 5-fluorouracil [32]. These data suggest a milder pro-inflammatory effect of this molecule compared with 5-fluorouracil, which could explain the favorable tol- erability and safety profile observed in tirbanibulin-treated patients. Patient Selection and Clinical Scenarios As demonstrated in clinical trials and real-life studies, tir- banibulin is effective in achieving high clearance rates of AK lesions, with fewer severe local skin reactions compared with other commonly used topical treatments for AK. Importantly, tirbanibulin’s mechanism of action targets oncogenic path- ways that are believed to be key factors in the progression from AK to SCC. The short duration of treatment is another aspect of tirbanibulin therapy which is relevant to real-life practice since, together with its favorable tolerability profile, it facilitates patient compliance, thus enhancing the chance of a successful outcome. Acceptance of therapy and treat- ment adherence are important considerations in real-world practice and are often underestimated when selecting AK therapies based on evidence derived solely from clinical tri- als [36]. In a systematic review investigating adherence and persistence associated with topical AK therapies, combined non-adherence and non-persistence rates were found to be as high as 88%, and key contributing factors were identified as duration of treatment, severity and persistence of local Review | Dermatol Pract Concept. 2025;15(3):5921 7 Figure 2. Images of AK lesions (Olsen grade I-II) in two small fields of cancerization on the scalp of a 75-year-old male with a long-standing history (>5 years) of AK on the scalp, previously treated with cryotherapy, topical diclofenac gel, and daylight photodynamic therapy: (A) before tirbanibulin treatment; (B) at the 2-month follow-up after treatment with tirbanibulin 1% ointment, showing complete clearance of occipital area and residual AK lesions (Olsen grade I) in the parietal field. The total area covered by tirbanibulin measured 26 cm2 (2x3 cm=6 cm2 for the occipital area and 4x5 cm=20 cm2 for the parietal area). (Courtesy of Dr. G. Nazzaro) Figure 3. Images of AK lesions (Olsen grade I-II) in a large field of cancerization on the left cheek of a 76-year-old male with a history of basal cell carcinomas on the trunk and limbs and with AK of the face and scalp (previously treated with physical therapies and topical drugs, with partial results): (A) before tirbanibulin treatment; (B) at 10 days after the end of treatment with tirbanibulin 1% ointment, showing erythema and scaling/flaking (the patient reported a burning sensation in the application area, but no intervention was required); (C) at 60 days after the end of treatment, showing complete clearance of the AK lesions (both Olsen grade I and II) and resolution of the local adverse reactions. (Courtesy of Dr. A. Villani) benefit of cosmetic improvement induced by tirbanibulin therapy should be mentioned to patients, as it may represent an additional motivation for treatment, further enhancing compliance. Treatment Modalities and Patient Education The area of skin to be treated with tirbanibulin ointment depends on the distribution of AK lesions and FC on the face and scalp. In line with current indications, a thin layer of tir- banibulin 1% ointment should be applied to cover a 25 cm2 treatment field in each of four anatomical areas (scalp, fore- head, left/right cheek with ear, nose, and chin). When treat- ment fields are not in close proximity, the total area to be covered by tirbanibulin can be divided into smaller sections, as shown in Figure 2. Addressing the needs of patients with large AK fields to be treated, recent studies have evaluated 8 Review | Dermatol Pract Concept. 2025;15(3):5921 Figure 4. Images of multiple AK lesions (Olsen grade I-II), field of cancerization, and actinic cheilitis on the face of a 70-year-old treat- ment-naïve woman: A) before treatment, in the foreground square close-up; B) at four months after completion of 4 cycles of tirbanibulin 1% ointment (standard treatment of five days per cycle), showing efficacy on AK lesions, FC, and actinic cheilitis (with a close-up in the foreground square) as well as improvement in skin quality, with reduction in dyspigmentation and a more uniform complexion. A sequential treatment scheduled was adopted, with four cycles 10 to 30 days apart, as follows: cycle 1→right forehead and nose, cycle 2→left forehead and nose, cycle 3→right cheek, cycle 4→left cheek. (Courtesy of Dr. S. Guida) Figure 5. Images (with dermatoscopic view) of AK lesions (Olsen grade I-II) in the right frontotemporal region of an 83-year-old male, Fitzpatrick skin type I, with a history of chronic sun exposure and an extensive field of cancerization involving the head and neck which was treated with cycles of oral nicotinamide 250 mg four times daily. AK lesions had previously been treated with imiquimod 5% and piroxicam and sun filters for local use. The patient also had comorbid ischemic heart disease and depression (treated with calcium antagonists, clopidogrel, and sertraline) and had undergone surgery for a pigmented basal cell carcinoma on the forehead. (A) Before tirbanibulin treatment; (B) at 12 days after starting treatment with tirbanibulin 1% ointment, showing mild, well-tolerated local reactions (erythema and flaking); (C) at 58 days after treatment, showing complete clearance of the AK lesion. (Courtesy of Prof. E. Campione) Review | Dermatol Pract Concept. 2025;15(3):5921 9 favorable tolerability profile of this topical drug. In clinical studies as well as in routine clinical practice, tirbanibulin therapy is associated with high rates of patient acceptability and treatment compliance, thus increasing the chance of a successful outcome. References 1. Kandolf L, Peris K, Malvehy J, et al. European Association of Dermato-Oncology, European Dermatology Forum, European Academy of Dermatology and Venereology and Union of Med- ical Specialists (Union Européenne des Médecins Spécialistes). European consensus-based interdisciplinary guideline for diag- nosis, treatment and prevention of actinic keratoses, epithelial UV-induced dysplasia and field cancerization on behalf of Euro- pean Association of Dermato-Oncology, European Dermatology Forum, European Academy of Dermatology and Venereology and Union of Medical Specialists (Union Européenne des Mé- decins Spécialistes). J Eur Acad Dermatol Venereol. 2024;38(6): 1024-1047. DOI: 10.1111/jdv.19897. 2. Malvehy J, Stratigos AJ, Bagot M, Stockfleth E, Ezzedine K, Delarue A. Actinic keratosis: Current challenges and unanswered questions. J Eur Acad Dermatol Venereol. 2024;38 Suppl 5:3-11. DOI: 10.1111/jdv.19559. PMID: 38923589. 3. Valenti M, Bianco M, Narcisi A, Costanzo A, Borroni R, Ardigò M. Topical Pharmacological Treatment of Actinic Keratoses: Focus on Tirbanibulin 1% Ointment. Dermatol Pract Concept. 2024;14(3 S1). DOI: 10.5826/dpc.1403S1a145S. PMID: 3913 3636. 4. Arcuri D, Ramchatesingh B, Lagacé F, et al. Pharmacological Agents Used in the Prevention and Treatment of Actinic Keratosis: A Review. Int J Mol Sci. 2023;24(5):4989. DOI: 10.3390 /ijms24054989. PMID: 36902419. 5. Aggarwal I, Puyana C, Chandan N, Jetter N, Tsoukas M. Field Cancerization Therapies for the Management of Actinic Keratosis: An Updated Review. Am J Clin Dermatol. 2024;25(3):391-405. DOI: 10.1007/s40257-023-00839-8. PMID: 38351246. 6. Dao DD, Sahni VN, Sahni DR, Balogh EA, Grada A, Feldman SR. 1% Tirbanibulin Ointment for the Treatment of Actinic Keratoses. Ann Pharmacother. 2022;56(4):494-500. DOI: 10.1177/10600280211031329. PMID: 34301153. 7. Eisen DB, Dellavalle RP, Frazer-Green L, Schlesinger TE, Shive M, Wu PA. Focused update: Guidelines of care for the manage- ment of actinic keratosis. J Am Acad Dermatol. 2022;87(2): 373-374.e5. DOI: 10.1016/j.jaad.2022.04.013. PMID: 35439607. 8. Blauvelt A, Kempers S, Lain E, et al., Phase 3 Tirbanibulin for Actinic Keratosis Group. Phase 3 Trials of Tirbanibulin Oint- ment for Actinic Keratosis. N Engl J Med. 2021;384(6):512-520. DOI: 10.1056/NEJMoa2024040. PMID: 33567191. 9. Nazzaro G, Carugno A, Bortoluzzi P, et al. Efficacy and toler- ability of tirbanibulin 1% ointment in the treatment of can- cerization field: a real-life Italian multicenter observational study of 250 patients. Int J Dermatol. 2024;63(11):1566-1574. DOI: 10.1111/ijd.17168. PMID: 38605473. 10. Campione E, Rivieccio A, Gaeta Shumak R, et al. Preliminary Evidence of Efficacy, Safety, and Treatment Satisfaction with Tirbanibulin 1% Ointment: A Clinical Perspective on Actinic Keratoses. Pharmaceuticals (Basel). 2023;16(12):1686. DOI: 10.3390/ph16121686. PMID: 38139813. the pharmacokinetics and tolerability of tirbanibulin oint- ment when applied to fields larger than 25 cm2, supporting its use (as one 350 mg sachet applied daily) in fields measur- ing up to 100 cm2 [40,41]. The safety and tolerability pro- files of tirbanibulin when used at approximately 100 cm2 fields were found to be consistent with those reported for smaller fields, and exploratory efficacy data also suggest similar benefits to those observed with the application of tir- banibulin over a more restricted area [41]. According to this expert panel’s experience, more than 25 cm2 can be treated by one sachet of tirbanibulin 1% ointment. The standard period of treatment with tirbanibulin is five days. However, owing to the favorable tolerability profile of the drug, various protocols are possible. Forward planning of the treatment regimen (including repeated treatment of severely affected areas) is always advisable. When treating large fields (>25 cm2), sequential or simultaneous thera- peutic schedules can be considered. Up to four consecutive treatment cycles one to two months apart can be planned if needed, based on disease and patient characteristics. Multi- ple treatment cycles can be performed in immunocompro- mised patients, those with a history of skin cancer, and those with advanced photodamage. Good communication with the patient is essential in the long-term management of AK. Clinicians should under- stand the patient’s priorities and concerns, setting realistic treatment expectations [26]. Patient should be informed about the chronic nature of AK, the unpredictable evolution of AK lesions, and the high rates of recurrence, hence the need for repeated treatment courses over time. It is partic- ularly important to inform patients about the occurrence and transient nature of local skin reactions associated with tirbanibulin treatment. Although skin reactions are usually mild, severe local adverse events may occur, and patients need reassurance that these will eventually resolve without sequelae. Correct treatment modalities are another import- ant aspect of care that can affect the outcome of therapy. Patients should be given detailed instructions about tirbani- bulin application at home. Expert consensus statements with recommendations on tirbanibulin treatment are reported in Table 1(B). Conclusion With its novel mechanism of action, proven efficacy, good tolerability, and short duration of therapy, tirbanibulin is an important treatment for the management of AK and should be considered as a first-line option for most patients, in- cluding treatment-naïve and pre-treated subjects as well as those with difficult-to-treat lesions, comorbid conditions, or a history of previous skin cancer. Flexible therapeutic proto- cols with repeated treatment cycles are made possible by the 10 Review | Dermatol Pract Concept. 2025;15(3):5921 24. Lacarrubba F, Verzì AE, Polita M, Aleo A, Micali G. Line-field confocal optical coherence tomography in the treatment mon- itoring of actinic keratosis with tirbanibulin: A pilot study. J Eur Acad Dermatol Venereol. 2023;37(9):e1131-e1133. DOI: 10.1111/jdv.19147. PMID: 37102431. 25. Venturi F, Veronesi G, Baraldi C, Dika E. Reflectance confocal microscopy as noninvasive tool for monitoring tirbanibulin efficacy in actinic keratosis. 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