Dermatology: Practical and Conceptual Review | Dermatol Pract Concept. 2024;14(3)S1:e2024145S 1 Topical Pharmacological Treatment of Actinic Keratoses: Focus on Tirbanibulin 1% Ointment Mario Valenti1,2, Matteo Bianco1,2, Alessandra Narcisi1,2, Antonio Costanzo1,2, Riccardo Borroni1,2, Marco Ardigò1,2 1 Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy 2 Dermatology Unit, IRCCS Humanitas Research Hospital, Rozzano, Italy Key words: tirbanibulin, actinic keratoses, field of cancerization, local adverse events Citation: Valenti M, Bianco M, Narcisi A, Costanzo A, Borroni RG, Ardigò M. Topical Pharmacological Treatment of Actinic Keratoses: Focus on Tirbanibulin 1% Ointment. Dermatol Pract Concept. 2024;14(3)S1:e2024145S. DOI: https://doi.org/10.5826/dpc.1403S1a145S Accepted: April 22, 2024; Published: July 2024 Copyright: ©2024 Valenti 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: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Mario Valenti, MD, Department of Biomedical Sciences, Humanitas University, Pieve Emanuele; Dermatology Unit, IRCCS Humanitas Research Hospital, Rozzano, Italy. Email: mario.valenti@hunimed.eu 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 hyper- keratotic 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. ABSTRACT 2 Review | Dermatol Pract Concept. 2024;14(3)S1:e2024145S Introduction Actinic keratoses (or solar keratoses) are the clinical mani- festation of a common, chronic disease of the skin of adults [1], which develops in areas exposed to sunlight [2]. Risk factors for the development of actinic keratoses and SCC are I-II phototypes according to Fitzpatrick’s scale, male sex, age, and immunodepression [3-5]. The incidence of AKs is likely underestimated, as they are not recorded routinely in cancer registries. Unsurprisingly, the prevalence of AKs shows an increase in its trend [3]. AKs represent one of the most common conditions diagnosed and treated by derma- tologists in the United States (US), where currently up to 12% of individuals have AKs [6]. A Rotterdam prevalence study of >2,000 Dutch men and women, with a mean age of 72 years, found AK in 49% of men and 28% of women [7]. In Galway, South Wales and Merseyside (UK), 19-24% of individuals aged >60 had at least one AK. Over 30% of those attending a dermatology clinic (mean age of attendance 61 years) in Austria had AK. Up to 60% of Australians over the age of 40 have AKs [8,9]. Histologically, AKS are characterized by epidermal hyper- plasia and by variable degrees of keratinocyte atypia, which can involve all layers of the epidermis, as in the in-situ forms of squamous cell carcinoma [10]. Indeed, AKs are considered by some to be a precursor of SCC [11,12] by others an initial and superficial form [13,14]. The histopathological similar- ities between AKs and squamous cell carcinoma reflect their same pathogenesis, a multi-stage process caused by somatic mutations induced by the carcinogenic action of ultraviolet (UV) radiation. These critically affect the tumor suppres- sor TP53 gene, which has mutations with UV signature (e.g., pyrimidine dimers) in almost 90% of AK specimens. [7,15-19] Although on histological examination up to 90% of invasive cutaneous squamous cell carcinomas arise con- tiguously or in continuity with AKs [17,20,21], prospective evaluation of AKs over time demonstrates a low rate of trans- formation to invasive squamous cell carcinoma, with less than one invasive squamous cell carcinoma for every 1000 AKs in a year [22]. In a US study, 0.6% of patients developed invasive squamous cell carcinoma in the same anatomical site as the actinic keratosis within the first year, rising to 2.57% at 4 years [21]. Rather than referring to the anatomical re- gions affected by the keratoses actinic keratoses, the risk of developing squamous cell carcinoma can be attributed more correctly to the subject suffering from actinic keratoses, with a risk of invasive squamous cell carcinoma which increases proportionally to the number of actinic keratoses [23] and which is estimated at 10% in 10 years for an average patient with 7-8 actinic keratoses [1,21,24]. A clinical categorization method for AK grading based on the total thickness of different lesions was proposed by Olsen et al [25]. Grade 1 lesions are hardly tangible, Grade 2 lesions are rather thick, and Grade 3 lesions are very thick and hyperkeratotic according to this system. This clinical classifying system is often used to set patient inclusion crite- ria in randomized clinical trials of AK treatments. The concept of the field of cancerization was proposed by Slaugther in 1953 [28] and was applied to squamous cell carcinomas of the oral cavity, although Willis in his seminal article in 1944 first hypothesized that the proliferation of keratinocytes can occur multifocally in the epidermis [28]. From a pathological point of view, field of cancerization could currently be defined as one or more areas of epithe- lial and stromal tissue characterized by genetic and epigen- etic abnormalities, some of which are also present in cancer, even in the absence of histopathological alterations. In this perspective, the concept of field cancerization has diagnos- tic and prognostic implications, especially when consider- ing that “healthy” perilesional skin surrounding clinically evident, multiple AKs could indeed be treated treatment of AKs, since therapy of AKs should be directed not only to visible lesions but also to the field of cancerization from which they originate. For practical purposes, however, a uni- vocal consensus on the criteria required to clinically identify and treat the cutaneous field of cancerization is still lacking and it was defined in a recent review [26-29] as multifocal clinical atypia, characterized by AKs and/or squamous cell carcinoma in situ (SCCis) with or without invasive cSCC, occurring in a field exposed to chronic UVR. Sunscreens and protective clothing, together with ade- quate sun-exposure education, are crucial in managing pa- tients with AKs; however, they are often insufficient to treat existing lesions [30,31]. Currently, available therapies for AKs are divided into field-directed treatments and lesion-directed treatments [31,32]. The latter mostly include physical treat- ments, of which cryotherapy is probably the most widely used technique [33]. Lesion-directed therapies, however, do not impact the field of cancerization, leaving invisible AKs that might arise in the future. Moreover, they are usually painful and can lead to melanocyte necrosis with consequent hypo- or hyperpigmentation and cosmetic concerns [34]. A summary of the characteristics, efficacy, and mechanism of action of topical treatments are shown in Table 1. Tirbanibulin In 2020 and 2021 respectively, tirbanibulin 1% ointment has been approved by Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of Ol- sen grade 1 AKs of the scalp and the face [35]. Tirbanibulin has a short course of application, just 5 consecutive days on an area of a maximum of 25 cm2. Furthermore, the rate of skin adverse events is very low, with a vast majority of just Review | Dermatol Pract Concept. 2024;14(3)S1:e2024145S 3 mild irritative reactions. For these characteristics, tirbani- bulin represents a new effective, safe, and practical option for addressing the problem of patient compliance in AKs management. This article reviews what is currently known about tir- banibulin, from its mechanism of action to clinical trial outcomes and preliminary real-life reports regarding safety, effectiveness, and patient adherence to the treatment. Mechanism of Action Tirbanibulin is a new synthetic drug that targets α and β tu- bulin, like other antitumoral drugs including vinca alkaloids, taxanes, colchicine, and docetaxel. In immunofluorescence, studies mechanism is concentration dependent on both in in-vitro tumoral lines and murine tumor tissues [36-38]. Immortalized keratinocytes incubation with tirbanibulin has proven to cause the arrest of the end of the interphase of phase growth 2 and mitosis when the assembly of microtu- bules allows for the migration of genetic material to oppo- site poles of the cell [36-38]. Of note, the good tolerability of this drug could be attributable to the reversibility of its effect [38]. Alongside the above, preclinical studies have proven tirbanibulin to have a pro-apoptotic effect in both in-vitro and murine models by activating both intrinsic and ex- trinsic pathways such as Bcl-2 hyperphosphorylation, and caspase-mediated mechanisms [36,37,39]. Not only does tirbanibulin show an antiproliferative and pro-apoptotic effect [38], but some evidence also [39,40] suggests that it plays a role in the rapid decrease of phosphorated Scr tyrosine kinase, which plays a role in the alterations of Table 1. Comparative Treatment Efficacy and Safety of Face-Scalp Typical Actinic Keratosis Approved in Europe [24] Medication Mechanism of Action Duration of Treatment Complete Clearance Rates at the end of the standard duration treatment Or (95% Ci) Rate of Discontinuation Due to Adverse Events Cryosurgery Physical destruction of the affected tissue Once 13.4 (6.2-30.3) Not applicable Tirbanibulin 1% ointment Inhibits microtubule assembly and inhibits Scr kinase 5 consecutive days 11.1 (6.2-20.9) 0% 5-fluorouracil (FU) 0.5% + salicylate 10% 5-FU acts as a pyrimidine analogue, while salicylate has a keratolytic effect Up to 12 consecutive weeks 7.6 (4.6-13.5) 1.9%-9.1% Diclofenac 3% gel Inhibits cyclooxygenases, and thus prostaglandin E2 production Up to 12 consecutive weeks 2.9 (1.9-4.3) 2.1%-12.3% Imiquimod 3.75% cream Activates innate immune system 2 weeks, followed by a 2-week stop, followed by another 2 weeks cycle 8.5 (3.5-22.4) 0-1.6% PDT with aminolevulinate (ALA) The combined activity of a photosensitizer (ALA) and a specific wavelength cause the formation of free radicals 2 outpatient accesses 24.1 (10.9-52.8) 0.6% PDT with methyl aminolevulinate (MAL) The combined activity of a photosensitizer (MLA) and a specific wavelength cause the formation of free radicals 2 outpatient accesses 11.7 (6.0-21.9) 1.1% 5-Fluorouracil (FU) 4% 5-FU acts as a pyrimidine analogue Up to 4 weeks 30.3 (9.1-144.7) Not applicable 5-Fluorouracil (FU) 5% 5-FU acts as a pyrimidine analogue Up to 4 weeks 35.0 (10.2-164.4) 0% 4 Review | Dermatol Pract Concept. 2024;14(3)S1:e2024145S consent, while the rest (n=29) completed the treatment and the follow-up. Complete clearance was achieved in participants by rates of 25% in Cohort 1, 0% in Cohort 2, 50% in Cohort 3, and 12.5% in Cohort 4, while partial clearance was respectively 50%, 30%, 63%, and 50%. Data regarding effectiveness are summarized in Table 2. Regarding safety, the only adverse effects reported were mild local skin reactions, mostly in cohorts 3 and 4 including itching, erythema, and stinging or burning sensation, which did not lead to the discontinuation of the treatment and that self-resolved. No contact sensitization, phototoxic, or pho- toallergic effects were reported (Table 3). Phase 2 Trials The phase 2 trial [44] was aimed at open-label, uncontrolled dose regimen-finding multicentric (16 centers) in which pa- tients (n=168) aged at least 18 years were sequentially en- rolled in 2 cohorts, each consisting of 84 patients. In both cohorts, the treated area was 25 cm2, with 4-8 clinically typical AKs on the scalp, face, and/or neck area. The daily dose of tirbanibulin, applied as a 1% ointment once a day, was around 50 mg/day, however, group 1 under- went the treatment for 3 consecutive days, while group 2 was for 5 consecutive days. The results were evaluated in terms of lesion count reduction, which was classified as complete if 100% and partial if ≥75%. Each cohort was evaluated on days 8, 15, 29, and 57. Both cohorts showed a significant reduction in the lesion count by day 57, however, it was superior in those patients who used tirbanibulin for 5 days. Complete clearance was achieved by 43% (95% confidence interval [CI]: 32%, 0,54%) hemidesmosomes necessary to the progression to a cSCC [41,42]. Certain medications used to treat AK, such as 5-fluorouracil, can produce localized skin responses by caus- ing the release of proinflammatory cytokines such as tumor necrosis factor TNF α and interleukin IL 8. A preclinical in- vestigation described the potential effects of tirbanibulin on the release of pro-inflammatory cytokines during a 24-hour incubation period of CCD-1106 KERTr keratinocytes. The findings demonstrated that whereas 5-fluorouracil generated a substantial rise in TNF α and IL-8, tirbanibulin incuba- tion only slightly increased IL-8 at the highest dosage. Fur- thermore, IL-1, an indicator of cell death, was significantly higher in tirbanibulin-treated cells than in control (DMSO) and 5-fluorouracil. These findings imply that 5-fluorouracil is more likely to trigger a robust proinflammatory cytokine response than tirbanibulin, which could minimize the sever- ity of local skin responses [41]. Phase 1 Trials The Phase 1 trial [44] was an open-label single-center study. The enrolled patients had clinically typical AKs, and their age had to be ≥18. Thirty participants were enrolled in 4 suc- cessive cohorts. Cohort 1 was treated in a 25 cm2 area with 4-8 AKs with tirbanibulin ointment 1% applied once a day for 3 consecutive days. Cohort 2 was 1 treated in a 100 cm2 area with 8-16 AKs with tirbanibulin 200 mg once a day for 3 consecutive days. Cohorts 3 and 4 resembled cohorts 1 and 2 at baseline, except the treatment was carried on for 5 con- secutive days. The results were evaluated in terms of lesion count reduction, which was classified as complete if 100% and partial if ≥75%. Each cohort was followed on days 10, 17, 31, and through day 45. Only 1 patient withdrew his Table 2. Actinic Keratosis Clearance Rates* Through Phase 1,2 and 3 [44,45] 100% clearance % (n) ≥75% clearance % (n) Phase 1 Trial* Cohort 1: 50 mg once daily for 3 days >25 cm2 (n=4) 1 (25%) 2 (50%) Cohort 2: 200 mg once daily for 3 days >100 cm2 (n=10) 0 (0%) 3 (30%) Cohort 3: 200 mg once daily for 5 days >25 cm2 (n=8) 4 (50%) 5 (50%) Cohort 4: 200 mg once daily for 5 days >25 cm2 (n=8) 1 (12.5%) 4 (63%) Phase 2 study# 5-day cohort: 50 mg once-daily for 5 days over 25 cm2 (n=84) 36 (43%) 47 (56%) 5-day cohort: 50 mg once-daily for 3 days over 25 cm2 (n=84) 27 (32%) 44 (52%) Phase 3 study° Tirbanibulin group (n=353) 174 (49%) 255 (72%) Vehicle (n=349) 30 (9%) 63 (18%) *Clearance rates were either classified as complete (100%) or partial (≥75%) at day 45. Data of cohorts 1-4 are summarized above. #Clearance rates were either classified as complete (100%) or partial (≥75%) at day 57. Data from 3- and 5-day cohorts are s umma- rized above. °Clearance rates were either classified as complete (100%) or partial (≥75%) at day 57. Clearance was assessed for both tirbanibulin and vehicle (placebo) cohorts. The percentage difference between the 2 groups is shown. Data are from intention-to-treat analysis. Review | Dermatol Pract Concept. 2024;14(3)S1:e2024145S 5 complete clearance or incomplete lesion count reduction at day 57. These patients were re-evaluated after 12 months to assess the recurrence rate. In trial 1 complete clearance occurred in 44% of pa- tients (n=77) treated with tirbanibulin vs the placebo group 5% (n=8). Similar results were reported in trial 2 with 54% (n=97) vs 13% (n=22). Overall, a complete clearance was achieved by 49% (n=174) of the tirbanibulin group vs 9% (n=30) of the controls, with a difference of 41% (95% CI: 35%, 47%). Results were consistent with regards to the par- tial clearance outcome: across the 2 trials, a ≥75% clearance was obtained by 72% (n=255) of the tirbanibulin group vs 18% (n=63) of the vehicle, with a difference of 54% (95% CI: 48%, 60%) (Table 2). No SAEs or discontinuation due to AEs occurred. The only AEs that occurred at a significantly higher rate in the tirbanibulin group vs placebo were LRSs, the most common of which were erythema (91%) and flaking or scaling (82%). Pain in the application site and pruritus were much less com- mon. All the adverse effects were mild to moderate and re- solved without the need for further treatment. Real-World Studies A real-world study that showed the real effectiveness of tir- banibulin in a real clinical contest was published by Kirch- berger et al [46]. It was a single-center study of adult patients with AK of face and scalp treated with tirbanibulin ointment 1% applied daily for 5 consecutive days on the same lesion or field. The results of treatment were assessed 4 weeks after the beginning of administration of tirbanibulin plus optional assessments later in time. The effectiveness of tirbanibulin over the AKs was measured before and after the treatment with a specific score, the actinic keratosis area and severity in the 5-day group vs 32% (95% CI: 22%, 43%) in the 3-day group while a ≥75% clearance was achieved by 56% (95% CI: 45%, 67%) and 52% (41%, 63%) respectively. Data regarding effectiveness is summarized in Table 1. Furthermore, all the patients who achieved complete clearance (n=63) were included in a further 12-month follow-up to evaluate the rate of recurrence. Consistent with the data above, the recurrence rate was lower in the 5-day cohort (57% [95% CI: 41%, 73%]) when compared to the 3-day cohort (70% [95% CI: 51%, 87%]). One hundred percent of patients completed the treat- ment and the follow-up. No severe adverse effects (SAEs) or discontinuation of the therapy due to adverse effects were reported, and 7% (n=12) of the patients reported adverse effects, with a slightly higher occurrence in the 5-day cohort (11%, n=9) vs the 3-day cohort (4%, n=3). However, these effects were mostly mild lysosomal stress responses (LSRs), which never required discontinuation of the treatment or further interventions, and that were self-resolved (Table 3). Phase 3 Trials Phase 3 trials [45], conducted in the United States, were multicentric (62 centers), randomized, double-blind, parallel-group, vehicle-controlled (placebo trials). Patients were eligible for enrollment if they had 4-8 clinically typical AKs within a contiguous area of 25 cm2 in the face-scalp area and were aged ≥18 years. The patients (n=702) were divided into 2 identical-sized groups (n=301, each) and were randomly assigned to receive a vehicle ointment or tirbanibu- lin 1% ointment with a 1:1 ratio. Enrollment, however, was controlled to achieve, within each trial, a 2:1 facial: scalp treated area ratio. Patients were evaluated at baseline and day 57. Primary and secondary outcomes were respectively Table 3. Treatment-Related Adverse Effects* Through Phases 1, 2, and 3. [44,45] Phase 1 study Mild n (%) Severe n (%) Cohort 1: 50 mg once daily for 3 days >25 cm2 (n=4) 0 0 Cohort 2: 200 mg once daily for 3 days >100 cm2 (n=4) 0 0 Cohort 3: 200 mg once daily for 5 days >25 cm2 (n=4) 0 0 Cohort 4: 200 mg once daily for 5 days >25 cm2 (n=4) 0 0 Phase 2 study 5-day cohort: 50 mg once daily for 5 days >25 cm2 (n=84) 9 (11) 0 5-day cohort: once daily for 3 days >25 cm2 (n=84) 3 (4) 0 Phase 3 study, intention-to-treat Tirbanibulin 124 (35) 0 Vehicle 124 (36) 0 *Adverse events are classified as mild (no need to discontinue the treatment) and severe (need to discontinue the treatment). Of note, most adverse events were treatment-related mild. 6 Review | Dermatol Pract Concept. 2024;14(3)S1:e2024145S cost-effectiveness compared to other approved treatments are still lacking. A recent systematic review [24] of several phases 2 and 3 randomized controlled trials (RCTs) showed how tirbani- bulin proved comparable effectiveness in lesion count reduc- tion and complete clearance of the lesions when compared to both physical and topical FC-directed treatments. Odds ra- tio (OR), for complete clearance, with their respective 95% confidence interval, assessed at 8 weeks after baseline were: cryosurgery 13.4 (6.2-30.3); diclofenac 3% 2.9 (1.9-4.3); fluorouracil 0.5% + salicylic acid 7.6 (4.6-13.5); fluoroura- cil 4% 30.3 (9.1-144.7); fluorouracil 5% 35.0 (10.2-164.4); imiquimod 3.75% 8.5 (3.5-22.4); imiquimod 5% 17.9 (9.1- 36.6); ingenol mebutate 0.015% 12.5 (8.1-19.9); photody- namic therapy with aminolevulinic acid 24.1 (10.9-52.8); photodynamic therapy with methyl aminolevulinate 11.7 (6.0-21.9); tirbanibulin 1% 11.1 (6.2-20.9). Longer duration of topical therapy has repeatedly been shown to lower patient adherence to the therapy, leading to worse outcomes in real life [2,51]. This data is coherent with a recent systematic encompassing 14 studies and over 4,000 patients of patient-reported outcomes evaluating topic therapies for treating AKs, which improved significantly in both shorter-duration treatments [51]. Even though tirban- ibulin was not directly evaluated in that systematic review, it is suggested that its 5-day course treatment would lead to high compliance and adherence to the treatment, in line with findings of Phases 1, 2, and 3 of the random controlled trials. The safety of the drug is supported by the lack of signif- icant changes in the clinical examination as well as in blood chemistry, urine, physical examination, and instrumental tests (ECG, blood pressure) in phase 1 and 2 trials [44] and by phase 3 trials [45]. This new drug, thus, not only seems to bring higher compliance but is very well tolerated. It has been proposed that the safety of tirbanibulin might be due to the reversibility of its mechanism of action [50]. Another review [35] investigated the most common application-site side effects, noting that they were mild LSRs: erythema (91%) scaling or flaking (82%), and much more rarely pain or itching at the application site. Consistently to the previous review, no severe AEs were reported, all AEs were resolved, and did not affect the adherence to therapy. All of these data from different trials are comparable with the local adverse events reported in real-life studies demon- strating the real safety of this treatment [59]. Moreover, a recent group of phase 1 studies in healthy volunteers [54] demonstrated that tirbanibulin ointment 1% had no sensi- tization or phototoxic or photoallergic potential connected with the treatment and supported the safety of this topical medication. Unsurprisingly, compliance to topical treatments seems to be related to both the length of the treatments and their tolerability profile [52,53]. One crucial point was that index (AKASI), and with digital dermoscopy. A group of 33 patients was eligible for the study design and treated but only 30 were analyzed because 3 were lost to follow-up. The results of this study showed that before treatment, the median AKASI score was 5.6 (1.4–11), after treatment it was 1.2 (0–7.4) (p < 0.0001), and at a second follow-up af- ter a mean of 3.7 months was 0.6 (0-1.4). At the first and second follow-ups, 47 percent of patients (n = 14) and 57 percent of patients (n = 13) had complete clearance, as in- dicated by AKASI scores less than 1. Local adverse events occur between 2 and 10 days from the beginning of the treat- ment, with a median onset at the seventh day and a mean resolution time of 5 days. The most common local reaction reported is erythema (80%, n=26) followed by scaling and flaking (43%, n= 13%) and by pustulation ad pruritus (7%, n = 2). Six patients (20%) did not report any local adverse event. Every local reaction ended on its own, without any aftereffects. Another real-world experience involved 30 pa- tients with AKs on their faces or scalps in a single-center, prospective, observational trial in which tirbanibulin oint- ment was applied to a 25 cm2 area for five days in a row. To evaluate the drug’s safety profile, effectiveness, and patient satisfaction, they were monitored for a minimum of 57 days. Six local skin response (LSR) symptoms were assessed and their intensity was rated as mild, moderate, or severe. These signs were erythema, scaling, crusting, swelling, blisters/ pustules, and erosions/ulcerations. Dermatoscopically and clinically, the efficacy was assessed. The Medication Treat- ment Satisfaction Questionnaire (TSQM 1.4) was used to measure treatment satisfaction. The majority of LSRs, which included swelling (3.3%), scaling (30%), and erythema (83.3%), appeared on day 8 but went away on their own. moscopic response was observed in 70% of the patients on day 57.[47]. To evaluate the efficacy and safety of tirbani- bulin 1% ointment, a spontaneous open-label, prospective non-randomized study focused on the treatment of 228 AKs in 38 consecutive patients—28 males (73%) and 10 fe- males (26%), aged between 52 and 92 years (mean age: 72 ± 8.92 years). Of the lesions that were reported, 51% had total clearance and 73% had partial clearance. There was no treatment termination owing to the occurrence of adverse events, and an outstanding tolerability profile and high com- pliance rate were noted.[48] Discussion Tirbanibulin is approved by the FDA and EMA in the formu- lation of 1% ointment for treating grade I AKs (according to Olsen’s grading) of the head and the neck in a contiguous area of no more than 25 cm2. The application cycle must be of 5 consecutive days [35,49]. Since this drug has been marketed very recently, studies on compliance, efficacy, and Review | Dermatol Pract Concept. 2024;14(3)S1:e2024145S 7 3. 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 4. 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. 5. Woodhead AD, Setlow RB, Tanaka M. Environmental factors in nonmelanoma and melanoma skin cancer. J Epidemiol. 1999;9 (6 Suppl): S102-114. 6. 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. 7. 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. 8. Memon AA, Tomenson JA, Bothwell J, Friedmann PS. Prevalence of solar damage and actinic keratosis in a Merseyside popula- tion. Br J Dermatol. 2000;142(6):1154-1159. 9. Eder J, Prillinger K, Korn A, Geroldinger A, Trautinger F. Prev- alence of actinic keratosis among dermatology outpatients in Austria. Br J Dermatol. 2014;171(6):1415-1421. 10. Peris K, Calzavara-Pinton PG, Neri L, et al. Italian expert consen- sus for the management of actinic keratosis in immunocompetent patients. J Eur Acad Dermatol Venereol. 2016;30(7):1077-1084. 11. Marks R. Who benefits from calling a solar keratosis a squamous cell carcinoma?. Br J Dermatol. 2006;155(1):23-26. 12. 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. 13. 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. 14. 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 ver- sion. J Eur Acad Dermatol Venereol. 2015;29(11):2069-2079. 15. Lai V, Cranwell W, Sinclair R. Epidemiology of skin cancer in the mature patient. Clin Dermatol. 2018 Mar-Apr;36(2):167-176. Epub 2017 Oct 13. PMID: 29566921. 16. Brash DE, Rudolph JA, Simon JA, et al. A role for sunlight in skin cancer: UV-induced 512 p53 mutations in squamous cell carci- noma. Proc Natl Acad Sci USA. 513 1991;88(22):10124-10128. 17. Anwar J, Wrone DA, Kimyai-Asadi A, Alam M. The develop- ment of actinic keratosis into invasive squamous cell carcinoma: evidence and evolving classification schemes.  Clin Dermatol. 2004;22(3):189-196. 18. Ashton KJ, Weinstein SR, Maguire DJ, Griffiths LR. Chromo- somal aberrations in squamous cell carcinoma and solar ker- atoses revealed by comparative genomic hybridization.  Arch Dermatol. 2003;139(7):876-882. 19. 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. 20. Mittelbronn MA, Mullins DL, Ramos-Caro FA, Flowers FP. Frequency of pre-existing actinic keratosis in cutaneous squa- mous cell carcinoma. Int J Dermatol. 1998;37(9):677-681. 21. Criscione VD, Weinstock MA, Naylor MF, et al. Actinic kerato- ses: Natural history and risk of malignant transformation in the in the reviews [44,45,49,50] tirbanibulin showed the lowest discontinuation rate with a compliance percentage of up to 100%. This is likely due to the well-tolerated profile of the drug and its easy administration regimen. Incidentally, anecdotal experience from these two studies proves that the antitumoral effects above make tirbanibulin a potential candidate for future treatment of skin carcinomas, especially basocellular and squamocellular carcinomas even though it is not approved yet for these indications [55,56]. In patients with AK, a new Phase 1 trial assessed the safety and systemic exposure of tirbanibulin ointment 1% when applied under maximal usage settings, i.e., 350 mg once day for five days in a row to 100 cm2 of the face or balding scalp having eight or more AK lesions. The majority of TEAEs were mild, with application site reactions being the most common treatment-related TEAEs, similar to other topical AK treatments [57]. Finally, given the great effectiveness and safety of this medication, new sites for possible application over the ap- proved face and scalp start to be reported. As shown in this case review study [58] tirbanibulin 1 % ointment demon- strated efficacy for the treatment of grade I and II AKs of upper arms with approximately 45% of complete clear- ance after a single cycle of therapy. Following the profile of safeness described for the face and scalp also for the upper extremities, tirbanibulin showed a significative level of toler- ability and adherence to treatment thanks to its proapoptotic effect which reduces the inflammatory necrosis typical of the other medications prescribed for AKs. Conclusions Considering the short-term course of application, the low rate of local cutaneous side effects, and the efficacy profile, tirbanibulin represents a safe, effective, and practical option for managing grade I face and scalp AKs. In particular, tir- banibulin seems to raise patient adherence rates to topical AKs therapies. Furthermore, tirbanibulin shows potential benefits also on more advanced AKs or AKs located in other anatomical areas. 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