Commentary: Impact of Prior Treatment in the Efficacy and Tolerability of Tirbanibulin Ointment 1% for Actinic Keratosis: Pooled Results from Two Phase III Studies

In 2021, two Phase III, randomized, double-blind, vehicle-controlled studies were completed evaluating tirbanibulin ointment 1% as a field treatment for actinic keratosis (AK).1 A post-hoc analysis of pooled results from the two Phase III trials was conducted to determine if there would be differences in efficacy and tolerability among groups stratified by prior AK treatment.2

The Phase III trials accounted for patients showing 4 to 8 clinically visible AK lesions within a 25cm² area. The patients were randomized with a 1:1 ratio into two groups. Both groups consisted of a double-blind treatment labeled either tirbanibulin ointment 1% or vehicle.1 For the post-hoc analysis, the complete (100%) clearance (CC) rate, defined as the proportion of patients with no clinically visible lesions, and the partial (≥ 75%) clearance (PC) rate, defined as the proportion of patients with at least a 75-percent reduction in lesions, were used when quantifying the pooled data. The post-hoc analysis showed CC and PC rates of 49 percent and 72 percent, respectively, for tirbanibulin-treated participants versus nine percent and 18 percent, respectively, for vehicle-treated participants. Both treatments were self-applied by the participants once daily for five consecutive days. Alongside the self-applied treatment, the clinically visible lesions were counted at different time points on all patients throughout the study. A distinction was made for patients previously treated for AK either through cryosurgery or topicals—these patients were defined as “pretreated.” The patients’ conditions within the areas of interest were rated on a severity scale ranging from 0 to 3 (0=absent, 3=severe) for observation of local skin responses (LSR) displaying erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, or erosions/ulceration. A sum of these scores was calculated for each patient (scores ranged from 0–18) with an averaged maximum composite score for each study period.2

Results of the post-hoc study indicated that the proportion of pretreated patients in the tirbanibulin and vehicle groups were 37 percent and 40 percent, respectively. Of those pretreated patients, 70 percent received cryosurgery and 35 percent received topicals in the treatment area. Tirbanibulin treatment resulted in CC of 45.1 percent for patients pretreated with cryosurgery and 33.3 percent for patients pretreated with topicals. Moreover, tirbanibulin treatment achieved PC in 71.4 percent of patients pretreated with cryosurgery and 60.0 percent of patients pretreated with topicals. The LSR composite scores showed similarities between test groups and pretreatment groups. The LSR scores of overall pretreated, cryosurgery, topical, and non-pretreated groups from the tirbanibulin and vehicle populations were compared to one another. The conclusion reached is that there was no significant difference between mean LSR composite scores between the two populations.2

Similar studies have been conducted to test tirbanibulin as a treatment for AK. A pharmacokinetic (PK) and safety study was conducted in which tirbanibulin ointment was administered to a 25cm² area for five consecutive days.3 Eighteen participants with at least 4 to 8 clinically visible AK lesions were divided into two nonrandom, uncontrolled treatment groups. Most subjects (15 out of 18) had previous AK treatment histories, which included liquid nitrogen, 5-fluorouracil/Efudex, cryosurgery, investigational products, and local excision/curettage. Results of this study indicate that tirbanibulin ointment 1%, administered once daily for five days, for treatment of AK lesions on the face or scalp was well tolerated.3

Comparatively, treatments including 5% fluorouracil cream, 5% imiquimod cream, methyl aminolevulinate photodynamic therapy (MAL-PDT), and 0.015% ingenol mebutate gel have been implemented into studies evaluating treatments for AK.4 A specific study testing each treatment and comparing the results included 624 patients who were divided into four treatment groups in a 1:1:1:1 ratio. The study was a single-blind, multicentered design in which observations of AK lesions over a 12-month period were noted. Results indicated that 5% fluorouracil cream was the superior treatment, with a 75.3-percent success rate (≥75% clearance) in patients in that treatment group. The other treatments of imiquimod, PDT, and ingenol mebutate resulted in success rates of 52.6 percent, 38.7 percent, and 30.2 percent, respectively.4

Fluorouracil cream 5% was also compared to 0.5% fluorouracil cream to determine which formula was more effective as a treatment for AK lesions.5 Complete clearance rates of 0.5% 5-fluorouracil cream ranged from 14.9 percent (1 week treatment) to 57.8 percent (4 weeks treatment). Complete clearance rates of the 5% formulation ranged from 43 percent (4 weeks treatment) to 100 percent (2 weeks treatment). While results suggest that 5% fluorouracil is superior to the 0.5% formulation, further investigation is required.5

This post-hoc analysis2 of two Phase III trials concluded that while the safety and efficacy of tirbanibulin ointment 1% allow it to be considered as a first-line treatment for AK, further research and clinical trials are needed to determine the most suitable treatment for AK. The comparison of LSR composite scores of two populations—tirbanibulin-treated patients and vehicle-treated patients—showed no significant difference in the tolerability of the treatments. The tirbanibulin treatment group also displayed higher levels of CC and PC in pretreated patients, compared to the vehicle-treated group. The difference in CC and PC rates support the conclusion that tirbanibulin ointment 1% is superior to vehicle at the time point of data collection (57 days).2