A phase III trial conducted by Lebwohl et al of ingenol mebutate evaluated application-site AEs and LSRs following once daily application of 0.015% ingenol mebutate for 3 consecutive days for multiple AKs on the face or scalp or 0.05% ingenol mebutate for 2 consecutive days for multiple AKs on the trunk or extremities.29 19% of patients who applied 0.015% ingenol mebutate and 12% of patients who applied 0.05% ingenol mebutate reported any application-site AE (pruritus, pain, irritation, skin/subcutaneous tissue disorder). 6 LSRs (erythema, flaking/scaling, crusting, swelling, vesiculation/ pustulation, and erosion/ulceration) were assessed on a scale of 0-4 (0 representing absence of LSR, 4 representing severe LSR); the scores were subsequently summed to calculate a local skin response score (0-24) for each patient. Mean composite local skin response score (±SD) was 9.1±4.1 in patients applying 0.015% ingenol mebutate to the face/ scalp on day 4 of treatment and 6.8 3.5 in patients applying 0.05% ingenol mebutate to the trunk/extremities on day 3 of treatment. On day 57, mean composite local skin response scores had fallen to levels indistinguishable from vehicle.29
A phase III trial evaluating the safety and efficacy of ingenol mebutate 0.027% gel applied for 3 days to lesions on the face, scalp, or chest found that treatment area could be increased (from 25cm2 in the Lebwohl et al trials evaluating 0.015% and 0.05% ingenol mebutate) to 250cm2 without an increase in systemic side effects.30 79.8% of patients reported any treatment-related AE; the mean composite LSR was 11.7 for the face and 8.8 for the scalp. Treatment withdrawal due to AEs or LSRs was less than 1 percent in each of the aforementioned treatment arms (0.015%, 0.027%, or 0.05%).29,30
Ingenol mebutate has been withdrawn from European Union and Canadian markets due to concerns for an increase in the risk of non-melanoma skin cancer (NMSC).31 In October of 2020, LEO Pharma announced that Picato would cease to be manufactured in the US as well; patients may continue using Picato currently available for the treatment of AK, but alternative treatments will need to be used in the US after supply is depleted.32
Diclofenac Sodium
Diclofenac sodium 3% in hyaluronic acid gel (diclofenac HA; Solaraze) is a cyclooxygenase-2 (COX-2) inhibitor believed to treat AK through inhibiting tumor angiogenesis and inducing tumor apoptosis.33 It is applied twice-daily for 60 to 90 days.34 Application-site AEs and LSRs are similar to the other topical agents available for the treatment of AK and include irritation, inflammation, pruritus, burning, dryness, edema, and pain.34–36
Application-site AEs and LSRs were assessed at 30 days after treatment in a pivotal phase III trial for diclofenac HA (Solaraze) applied twice-daily for either 60 or 90 days. Application-site reactions (total) occurred in 75% of patients in the 60-day treatment arm vs 84% of patients in the 90-day treatment arm; a similar trend was observed for applicationsite contact dermatitis (19% vs 33%), exfoliation (6% vs 24%), pruritus (31% vs 52%), and rash (35% vs 46%). 18% of patients (77 of 470) discontinued diclofenac HA for any reason.34
A phase III clinical trial comparing the safety and efficacy of 0.5% 5-FU/10% salicylic acid (0.5% 5-FU/10% SA; Actikerall) to diclofenac HA or vehicle applied twice-daily until lesion clearance up to 12 weeks found that application-site AEs in the diclofenac HA treatment arm occurred at lower rates compared to Actikerall for total application-site reactions (62.7% vs 75.5%), irritation (38.4% vs 61.2%), and pruritus (38.9% vs 44.9%); application-site irritation was slightly higher in the diclofenac HA treatment arm (38.4% vs 35.7%).35 Treatment discontinuation was similar between both treatment arms at 4.9% (9 of 185) in the diclofenac HA arm and 3.7% (7 of 189) in the Actikerall arm.35
Tirbanibulin
Tirbanibulin (Klisyri) is a tubulin polymerization and Src kinase signaling inhibitor. As an anti-mitotic agent, tirbanibulin reversibly binds tubulin, arresting the cell cycle in G2/M phase in rapidly dividing cells.37 Tirbanibulin also inhibits Src kinase signaling known to be upregulated in AK and invasive SCC and increase p53 expression with subsequent induction of apoptosis.38 Tirbanibulin 1% ointment is currently available for treatment of AK of the face or scalp for once daily application over a 5-day treatment course. The reversible tubulin-binding effects of tirbanibulin may contribute to its favorable tolerability compared to other topical agents for treatment of AK; nevertheless, application-site AEs and LSRs are experienced with its use. Application-site AEs and LSRs assessed in phase III clinical trials included application-site pruritus, pain, erythema, flaking, scaling, crusting, swelling, vesiculation, pustulation, erosion, and ulceration.
Two simultaneous phase III clinical trials involving 702 patients were conducted to determine the safety and efficacy of tirbanibulin 1% ointment for treatment of AK on the face and scalp.10 Application-site pruritus and pain were experienced by 9% and 10% of participants, respectively. Most LSRs were mild-to moderate, and severe LSRs were reported in less than 10% of patients. Total and severe LSR rates observed included erythema (90.9%; 6% severe), flaking/scaling (81.9%, 9%), crusting (46.5%, 2%), swelling (38.5%, 1%), vesiculation/ pustulation (8.2%, 1%), and erosion/ulceration (11.6%, 0%). All LSRs resolved spontaneously without treatment or intervention. No patients discontinued the use of tirbanibulin due to treatment-related AEs.10
A phase III trial evaluating the safety and efficacy of ingenol mebutate 0.027% gel applied for 3 days to lesions on the face, scalp, or chest found that treatment area could be increased (from 25cm2 in the Lebwohl et al trials evaluating 0.015% and 0.05% ingenol mebutate) to 250cm2 without an increase in systemic side effects.30 79.8% of patients reported any treatment-related AE; the mean composite LSR was 11.7 for the face and 8.8 for the scalp. Treatment withdrawal due to AEs or LSRs was less than 1 percent in each of the aforementioned treatment arms (0.015%, 0.027%, or 0.05%).29,30
Ingenol mebutate has been withdrawn from European Union and Canadian markets due to concerns for an increase in the risk of non-melanoma skin cancer (NMSC).31 In October of 2020, LEO Pharma announced that Picato would cease to be manufactured in the US as well; patients may continue using Picato currently available for the treatment of AK, but alternative treatments will need to be used in the US after supply is depleted.32
Diclofenac Sodium
Diclofenac sodium 3% in hyaluronic acid gel (diclofenac HA; Solaraze) is a cyclooxygenase-2 (COX-2) inhibitor believed to treat AK through inhibiting tumor angiogenesis and inducing tumor apoptosis.33 It is applied twice-daily for 60 to 90 days.34 Application-site AEs and LSRs are similar to the other topical agents available for the treatment of AK and include irritation, inflammation, pruritus, burning, dryness, edema, and pain.34–36
Application-site AEs and LSRs were assessed at 30 days after treatment in a pivotal phase III trial for diclofenac HA (Solaraze) applied twice-daily for either 60 or 90 days. Application-site reactions (total) occurred in 75% of patients in the 60-day treatment arm vs 84% of patients in the 90-day treatment arm; a similar trend was observed for applicationsite contact dermatitis (19% vs 33%), exfoliation (6% vs 24%), pruritus (31% vs 52%), and rash (35% vs 46%). 18% of patients (77 of 470) discontinued diclofenac HA for any reason.34
A phase III clinical trial comparing the safety and efficacy of 0.5% 5-FU/10% salicylic acid (0.5% 5-FU/10% SA; Actikerall) to diclofenac HA or vehicle applied twice-daily until lesion clearance up to 12 weeks found that application-site AEs in the diclofenac HA treatment arm occurred at lower rates compared to Actikerall for total application-site reactions (62.7% vs 75.5%), irritation (38.4% vs 61.2%), and pruritus (38.9% vs 44.9%); application-site irritation was slightly higher in the diclofenac HA treatment arm (38.4% vs 35.7%).35 Treatment discontinuation was similar between both treatment arms at 4.9% (9 of 185) in the diclofenac HA arm and 3.7% (7 of 189) in the Actikerall arm.35
Tirbanibulin
Tirbanibulin (Klisyri) is a tubulin polymerization and Src kinase signaling inhibitor. As an anti-mitotic agent, tirbanibulin reversibly binds tubulin, arresting the cell cycle in G2/M phase in rapidly dividing cells.37 Tirbanibulin also inhibits Src kinase signaling known to be upregulated in AK and invasive SCC and increase p53 expression with subsequent induction of apoptosis.38 Tirbanibulin 1% ointment is currently available for treatment of AK of the face or scalp for once daily application over a 5-day treatment course. The reversible tubulin-binding effects of tirbanibulin may contribute to its favorable tolerability compared to other topical agents for treatment of AK; nevertheless, application-site AEs and LSRs are experienced with its use. Application-site AEs and LSRs assessed in phase III clinical trials included application-site pruritus, pain, erythema, flaking, scaling, crusting, swelling, vesiculation, pustulation, erosion, and ulceration.
Two simultaneous phase III clinical trials involving 702 patients were conducted to determine the safety and efficacy of tirbanibulin 1% ointment for treatment of AK on the face and scalp.10 Application-site pruritus and pain were experienced by 9% and 10% of participants, respectively. Most LSRs were mild-to moderate, and severe LSRs were reported in less than 10% of patients. Total and severe LSR rates observed included erythema (90.9%; 6% severe), flaking/scaling (81.9%, 9%), crusting (46.5%, 2%), swelling (38.5%, 1%), vesiculation/ pustulation (8.2%, 1%), and erosion/ulceration (11.6%, 0%). All LSRs resolved spontaneously without treatment or intervention. No patients discontinued the use of tirbanibulin due to treatment-related AEs.10
