AK, SCC Treatments Focus on Efficacy, Tolerability, Durability

The latest additions to the armamentarium for actinic keratosis (AK) and nonmelanoma skin cancers (NMSC) combine efficacy with a reduction in adverse effects (AEs) from irritation to cosmetic concerns, according to George Martin, MD, program chairman of Maui Derm for Dermatologists 2022and a dermatologist at Dr George Martin Dermatology Associates in Kihei, Hawaii. He delved into new therapeutic and management options for cutaneous oncology in a presentation at Maui Derm for Dermatologists 2022 held in Maui, Hawaii.¹

New Drugs, New Guidelines.

The ever-increasing number of treatment options for AKs can be challenging to navigate. Recognizing that, the American Academy of Dermatology (AAD) recently published its recommendations for the treatment and management of AKs to help clinicians choose optimal treatment plans for their patients.²

Although helpful, Martin pointed out some omissions.

“There were no real surprises with the AAD’s guidelines for the treatment of AKs. Imiquimod and 5-FU have withstood the test of time and they are very good therapeutic agents. However, the guidelines did not address basic compliance, which is abysmal for local therapies,” Martin said.

He also cited a need for guidance in other important including actinic cheilitis, a significant problem in this patient population, a novel combination therapy with 5-fluorouracil (5-FU) and calcipotriene, 1% tirbanibulin (Klisyri, Almirall), as well as how to best manage immunocompromised patients in respect to field therapy to manage their actinic damage.

The combination of 5-FU cream with the synthetic vitamin D analogue calcipotriene used in equal parts twice daily for 4 days can achieve a very good clearance of lesions, according to Martin. Last year’s FDA approval of 1% tirbanibulin applied daily for 5 days for the treatment of AKs is another milestone he would like to see the guidelines address.

“Treatment for 5 days with the 1 percent tirbanibulin is a game changer for our AK patients, effectively clearing lesions with minimal cosmetic concerns, allowing them to further participate in daily social activities,” Martin said. “We are getting good efficacy with the medication on the face but less so on the scalp. What we are not seeing is a tremendous amount of irritation, which increases tolerability and patient adherence to the therapy.”

He added that milder irritation also means patients are more willing to repeat therapy as needed because they are not experiencing significant downtime with ulcerations and erosions seen with other standards of treatment.

However, he recommended reminding patients that the treatment is designed to treat a 25-cm² skin surface, and that there is no data available yet on how to treat larger surface areas such as those involved in field cancerization.

The cost for tirbanibulin presents an issue and as such, Medicare patients have little access to the medication. Martin often uses tirbanibulin as a first-line treatment for AKs but for those patients who cannot afford the medication, he will treat with the 5-FU as monotherapy for 1 to 2 weeks and repeat in a month. For more resistant field cancerization, he prescribes a 5-FU and calcipotriene combination twice a day for 4 days. This combination therapy affords a more aggressive short-term treatment option when compared to a week 1 or 2 of other therapies in Martin’s experience.

Developments in Photodynamic Therapy (PDT)

One of the most impactful recent changes in the entire field of AKs and field cancerization is the development of an improved PDT treatment protocol. A 2020 study found that applying topical 20% aminolevulinic acid (ALA) solution to patients’ face and/or scalp immediately before 30, 45, or 60 minutes of blue light treatment (rather than applying the ALA topical with a 1-hour preincubation before PDT), showed “nearly identical lesion clearance” with the conventional regimen at 3 months (as determined by statistical testing of noninferiority plus or minus 15% margin) with “significantly less paid during simultaneous illumination”, wrote the authors.³

“This optimization of PDT changed our world and the way we treat our AK patients,” Martin said. “It defined the parameters to make it painless and highly efficacious. The data proved that this regimen is equal to the standard 1-hour incubation and 1000 seconds of blue light. That’s a milestone since patients can get treated in a half hour and go home and have an effective therapy. Most importantly, PDT is covered by Medicare so Medicare patients can now have a field therapy that is both effective and painless.”

Game Changers for NMSC

Disseminated superficial actinic porokeratosis (DSAP) is an inherited keratinization disorder characterized by small, discrete, and slightly pruritic pink-to-brown circular macules with slightly raised borders on the arms and legs. The skin condition is associated with gene mutations of the mevalonate pathway involved in cholesterol synthesis. According to Martin, the more effective treatments currently available often scar the skin. In his view, other modalities have proven ineffective for clearing these that also have an increased association with cutaneous squamous cell carcinoma (cSCC).

Possible causes of DSAP include the skin’s lack of cholesterol because of the cholesterol metabolism defect or a build-up of a toxic intermediates that is triggering the disease process. Recent studiesevaluating the treatment of DSAP with a topical application of a cream containing both cholesterol to supplement the skin, and a statin to block the synthesis pathway, could achieved very dramatic clearance outcomes in small cohorts of patients.^4,5

“This novel approach to treat DSAP blocks at the very beginning of the cholesterol pathway so you do not get the build-up of the toxic intermediates,” Martin said.

According to Martin, one of the most important developments of late in the treatment of NMSC is the advent of the PD1 inhibitor cemiplimab (Libtayo; Regeneron Pharmaceuticals, Inc, and Sanofi-Aventis). This relatively new treatment option is FDA approved for cSCC in patients who have locally advanced (laCSCC) or metastatic (mCSCC) cutaneous squamous cell carcinoma. These are patients who have usually failed excision and/or radiation therapy. Most recently, it is also approved for use in patients with advanced basal cell carcinoma (BCC) who previously were treated with a hedgehog pathway inhibitor (HHI) or for whom a HHI is not appropriate.

“Cemiplimab offers our NMSC patients an effective systemic treatment option to help them control or regress their lesions, and offers a lot of hope, particularly where other therapies failed. The medication can help increase the longevity and quality of life, which is really huge for these patients suffering from this very challenging to treat chronic disease,” Martin said.

References

1. Martin G, Rosen T, Stockfleth E, Schmults C. Cutaneous Oncology. Presented at: Maui Derm for Dermatologists 2022. Held January 24 to 28, 2022, in Maui, Hawaii and virtual.
2. 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.
3. Kaw U, Ilyas M, Bullock T, Rittwage L, Riha M, et al. A regimen to minimize pain during blue light photodynamic therapy of actinic keratoses: Bilaterally controlled, randomized trial of simultaneous versus conventional illumination. J Acad Dermatol.2020 Apr;82(4):862-868. doi: 10.1016/j.jaad.2019.09.010. Epub 2019 Sep 13.
4. Byth LA, Byth J. Topical simvastatin-cholesterol for disseminated superficial actinic porokeratosis: An open-label, split-body clinical trial. Australas J Dermatol.2021 Aug;62(3):310-313. doi: 10.1111/ajd.13601.Epub 2021 May 24.
5. Atzmony L, Lim YH, Hamilton C, Leventhal JS, Wagner A, Paller AS, Choate KA. Topical cholesterol/lovastatin for the treatment of porokeratosis: A pathogenesis-directed therapy. J Am Acad Dermatol.2020 Jan;82(1):123-131. doi: 10.1016/j.jaad.2019.08.043.Epub 2019 Aug 23.