Klisyri superior to placebo for treatment of actinic keratoses in randomized studies

Robert T. Brodell, MD, FAAD

In my 36 years of clinical dermatology practice, 5-fluorouricil (5-FU) twice daily for 2 to 3 weeks has always been the gold-standard “field” treatment for actinic keratoses. 5-FU was released in 1957 as a novel compound for systemic chemotherapy for solid tumors in rats. It “attacks” rapidly proliferating cells in cancer by inhibiting DNA in the cell blocking production of vital proteins that result in death of the cell. 5-FU was subsequently used as systemic chemotherapy in humans for breast and colon cancer and then some patients were noted to develop a “rash” when on their systemic chemotherapy. Biopsies showed the rash was caused by inflamed pre-cancers — actinic keratoses — and patients treated for their internal cancer were demonstrated to have clearing of their pre-cancers and resolution of the inflammation with continued treatment. It was then a simple step to apply 5-FU topically with a similar response.

Recognizing that any individual actinic keratoses may have only a small chance of becoming a skin cancer, resolving hundreds of pre-cancers at a time with this treatment has been shown to lead to a decrease in the development of nonmelanoma — keratinocytic — skin cancers in treated areas. In addition, the skin no longer has a sandpapery feel caused by scores of actinic keratoses that bleed when bumped. Of course, if a patient has a small, solitary actinic keratoses, it is likely to be treated with liquid nitrogen freezing at a dermatologist’s office. Many lesions over a large area are too much to handle with this painful cryotherapy.

Field therapy has also been accomplished with imiquimod 5% cream, but this treatment is dispensed in small packets that make it difficult to treat broad areas of the body like the arms. Ingenol mebutate 0.015% cream was then released and subsequently withdrawn from the market after more skin cancers were noted in a group treated with this agent when compared with imiquimod.

Now we have tirbanibulin 1% ointment, an Src Kinase signaling inhibitor that has been shown to be a highly effective treatment for these pre-cancerous actinic keratoses. After applying just twice daily for 5 days to areas with multiple lesions, patients were evaluated at 1 month, and almost half had 100% clearance of their actinic keratoses. Patients have redness and scaling in response to the treatment, but severe reactions with moist, crusting, edema, erosion and blistering were rare.

A large trial comparing 5-FU and tirbanibulin ointment is needed to confirm that clearance of actinic keratoses is as good or better with this new approach. Although the length of treatment is shorter, perhaps it will be shown that there is less local reaction during the treatment. Time will tell, but this could be a significant advance that will be appreciated by our patients as we try to prevent nonmelanoma skin cancer rather than wait for it to develop, which requires surgical approaches.

Whitney A. High, MD, JD, MEng

Actinic keratoses are routinely treated by dermatologists every day in America, using methods such as liquid nitrogen destruction or using topical medicaments, such as 5‐FU, imiquimod, diclofenac sodium and ingenol mebutate. It has been estimated that nearly 36 million actinic keratoses were treated by dermatologists in 2015, and it is likely higher each year, as the American population ages.

The current study describes treatment of actinic keratoses with a new medication, tirbanibulin 1% cream. Appealing to me, as a clinician who deals with this issue daily, the cream need only be applied once daily for 5 days. The medication achieved clearance rates that were superior to placebo and entirely comparable to other recent trials of the medications I already mentioned.

Moreover, although it is disappointing that no photos were included in the publication, the text reports minimal side effects of erythema and scaling, with a very low incidence of pain and pruritus. This is important to practicing clinicians and patients alike, for many of our oft‐prescribed topical therapies result in considerable discomfort with use, and the treatment course for these irritating topical therapies can last days, weeks, months or more.

I will be intrigued to hear of more developments.