A review of the safety, efficacy, and administration of hedgehog inhibitors for the treatment of advanced basal cell carcinoma: an expert consensus panel.

Hedgehog inhibitors (HHIs) can be used to treat patients with locally advanced basal cell carcinoma (laBCC) who are not candidates for surgery or radiation or whose tumors have recurred following radiation or surgery. The purpose of this expert consensus panel is to guide HHI usage, thereby informing clinical decision-making and optimizing patient care. A comprehensive literature search was completed on May 1, 2024, using the keywords "basal cell carcinoma," "hedgehog inhibitor," "sonidegib," and "vismodegib". A panel of eight dermatologists with significant expertise in the treatment of BCC gathered to review the articles and create consensus statements. A modified Delphi process was used to approve each statement and a strength of recommendation was assigned. The literature search produced 200 articles. A screening of the studies resulted in 19 articles that met the criteria. The panel unanimously voted to adopt 8 consensus statements and recommendations, two were given a strength of "A", three were given a strength of "B", and three were given a strength of "C". Sonidegib and vismodegib are FDA-approved HHIs that can decrease the size of laBCC tumors prior to surgical intervention or be used as primary therapy in certain circumstances. The most common adverse events include muscle spasms, alopecia, and taste alterations. Burshtein J, Shah M, Zakria D, et al. Efficacy and safety of hedgehog inhibitors for advanced basal cell carcinoma: an expert consensus panel. J Drugs Dermatol. 2025;24(5):465-471. doi:10.36849/JDD.8827.

e19349 Background: HHIs are oral targeted therapies approved for the treatment of advanced BCC but treatment-related adverse events may result in treatment interruptions or discontinuation. The objective of this study was to describe HHI treatment patterns among patients with BCC in real-world clinical practice. Methods: We conducted an observational cohort study using MarketScan Commercial/Medicare databases (01/01/2013–09/30/2018). We identified new users of HHIs (index date = date of the first dispensation), ≥18 years of age who were continuously enrolled for ≥6 months prior to the index date (i.e. baseline) with ≥1 baseline BCC diagnosis. Treatment interruptions (TI) were defined as a lack of dispensation following the exhaustion of days’ supply and allotted grace period (GP). Re-initiation (RI) was defined as ≥1 HHI dispensation after TI. The Kaplan–Meier method was used to estimate risk and time to TI and, among patients with a TI, incidence of RI. HHIs are generally dispensed in 30-days’ supply and indicated as long as a patient derives a clinical benefit; however, since TIs are commonly employed during HHI therapy, sensitivity analyses were conducted using GPs of 14, 30, 60, 90, and 120 days. Results: We identified 469 patients with a BCC diagnosis initiating HHIs. The mean (SD) age was 67.6 (15.8) years, 64.2% were men, 51.2% were covered by commercial insurance, and 99.2% initiated vismodegib. Using a GP of 14, 30, 60, 90, and 120 days, the risk of TI was 79.2%, 68.8%, 60.0%, 55.4%, and 51.4% at 6 months and 94.8%, 91.3%, 88.2%, 83.2%, and 80.2% at 1 year, respectively. Median HHI treatment duration ranged from 94 days (95% CI: 90–109) using a GP of 14 days to 173 days (95% CI: 156–194) using a GP of 120 days. At 6 months following TI, incidence of RI was 35.8%, 19.8%, 11.3%, 6.9%, and 4.9% using a GP of 14, 30, 60, 90, and 120 days, respectively. The incidence of HHI RI at 1-year following TI ranged from 40.8% using a 14-day GP to 13.4% using a 120-day GP. Conclusions: Median HHI treatment duration was approximately 6 months, even after allowing for a 120-day GP. Median treatment duration was considerably shorter than what has been reported in clinical trials. Our results suggest that long-term HHI therapy may be difficult in a real-world setting.

Globally, basal cell carcinoma is the most commonly diagnosed cancer. While most cases are amenable to surgery, treatment options for advanced basal cell carcinoma, including locally advanced basal cell carcinoma and metastatic basal cell carcinoma, have proved more difficult. Recent advances regarding the role of hedgehog signaling in the pathogenesis of basal cell carcinoma and the identification of hedgehog pathway inhibitors have facilitated the development of treatment options with improved clinical outcomes. The hedgehog signaling pathway regulates development, cell proliferation, and tissue repair. The pathway is tightly regulated under normal physiological conditions. However, dysregulated hedgehog signaling in human cancers was first described in patients with basal cell carcinoma nevus syndrome and sporadic basal cell carcinoma, in which germline or somatic mutations in pathway components (e.g., smoothened [Smo] and patched-1) lead to constant activation. Subsequently, inhibitors blocking hedgehog signaling either at the level of Smo (i.e., vismodegib, sonidegib, patidegib, and itraconazole) or via an unknown mode of action (arsenic trioxide) were identified. The hedgehog inhibitor vismodegib is approved for the treatment of locally advanced basal cell carcinoma and metastatic basal cell carcinoma while sonidegib is approved for the treatment of locally advanced basal cell carcinoma in the USA and Europe; and for locally advanced basal cell carcinoma and metastatic basal cell carcinoma in Switzerland and Australia. The most common treatment-emergent adverse events associated with approved hedgehog inhibitors include muscle spasms, dysgeusia, and alopecia. This review addresses the challenges associated with appropriately diagnosing locally advanced basal cell carcinoma, provides an overview of hedgehog signaling in basal cell carcinoma, and discusses the pharmacology of hedgehog inhibitors and their efficacy, and adverse events associated with hedgehog inhibitor use, and their management.

388 Natural history and management of basal cell nevus syndrome: Updates from the gorlin syndrome registry

Diagnosis and treatment of basal cell carcinoma: European consensus–based interdisciplinary guidelines

It has become routine practice in many centers to use two successive freeze-thaw cycles in the treatment of the common types of basal cell carcinoma. Because of the potential morbidity caused by this, we have investigated the cure rate achieved with one freeze-thaw cycle compared with that achieved with two freeze-thaw cycles in the treatment of facial basal cell carcinomas of a uniform type and clinically in the best prognostic group. Superficial truncal basal cell carcinomas are reported to respond to less aggressive cryosurgery, and we have investigated the cure rate achieved with one freeze-thaw cycle.To compare the efficacy of one freeze-thaw cycle versus two freeze-thaw cycles in the treatment of facial basal cell carcinomas. Second, to investigate the efficacy of one freeze-thaw cycle in the treatment of superficial truncal basal cell carcinomas. This was investigated in a prospective randomized post-treatment follow-up study.Over the past 7 years, we have treated 84 facial basal cell carcinomas with either a single 30-second freeze-thaw cycle or a double 30-second freeze-thaw cycle. Patients were allocated randomly into one of the two treatment schedules, and the cure rates achieved were compared. Second, 29 superficial truncal basal cell carcinomas were treated with a single 30-second freeze-thaw cycle. Patients were followed up to assess response to therapy.A 95.3% cure rate was achieved in the treatment of facial basal cell carcinomas with a double freeze-thaw cycle. This compared with a cure rate of only 79.4% when facial lesions were treated with a single freeze-thaw cycle. Treatment of superficial truncal basal cell carcinomas with a single freeze-thaw cycle achieved a cure rate of 95.5%.We recommend that, in order to achieve high cure rates that are equivalent to many reports of formal excision or radiotherapy, facial basal cell carcinomas require a double freeze-thaw cycle with liquid nitrogen. One freeze-thaw cycle to truncal basal cell carcinomas achieves high cure rates, equal to that achieved with a double freeze-thaw cycle to facial basal cell carcinomas.

Noninvasive monitoring of basal cell carcinomas treated with systemic hedgehog inhibitors: Pseudocysts as a sign of tumor regression

European consensus-based interdisciplinary guideline for diagnosis and treatment of basal cell carcinoma—update 2023

Vismodegib and sonidegib are sonic hedgehog inhibitors (SHHIs) available for the treatment of advanced basal cell carcinoma (BCC). Cases of sarcomatoid differentiation during treatment of BCC with SHHIs have not been previously reported. We present a unique case of a locally advanced BCC that underwent sarcomatoid transformation, manifesting as a large mass complicated by local invasion and lung metastases, following treatment with sonidegib.

Background. Basal cell cancer is the most common type of skin cancer in fair-skinned adults older than 50 years. The incidence rate of this disease is growing around the world. Basal cell carcinomas (BCC) are heterogeneous: from superficial or nodular lesions with benign prognosis to large lesions which are very difficult to cure. The prognosis of treatment is connected with the risk of recurrence of basal cell cancer or its local destructive ability. Hedgehog pathway activation is a distinctive molecular event in these tumors, which has allowed Hedgehog inhibitors for lesions that are difficult to cure to be developed, and which are also beyond the reach of surgical treatment or radiation therapy. Immunotherapy may be offered for the treatment of tumors with a high mutational load which leads to tumor resistance to Hedgehog inhibitors. Surgical intervention is a standard treatment method for most BCCs because it allows excision margins to be controlled and it shows a low risk of recurrence. The issue of removal of locally advanced forms with simultaneous reparative stage in elderly patients remains challenging. Purpose – to prove the high effectiveness of the surgical approach with simultaneous plastic surgery in locally advanced forms of BCC of the scalp in elderly patients. Materials and methods. Clinical observation of female patient A., 87 years old, who was receiving treatment in the Department of Surgical Oncology regarding multiple advanced BCC of facial skin, and patient V., 91 years old, who was undergoing treatment in the Department of Surgical Oncology regarding advanced basal cell skin carcinoma of the left pinna. Observation and treatment were performed in the State Organization «Grigoriev Institute for Medical Radiology and Oncology of the National Academy of Medical Sciences of Ukraine». Results. Clinical cases of locally advanced basal cell skin cancer in 2 elderly patients (87 and 91 years old) are presented. The effectiveness of the surgical approach with broad excision of the tumor and simultaneous reparative stage has been proven: in one case – a free split-skin autoplastic graft, in the other one – a full-thickness musculo-subcutaneous flap with axial blood circulation. In both cases there was no rejection of transplants; the scalp defects were completely covered, and a good cosmetic appearance was successfully achieved. In both cases, there were no significant complications observed. These examples have proven that the patients’ age of more than 90 years is not a counterindication to broad resections with simultaneous reparative stage in locally advanced BCC of the scalp. Conclusions. Thus, modern methods of diagnostics and treatment of BCC allow the disease to be controlled in most cases. It is also possible to cure locally advanced BCCs in patients older than 85 years surgically with a simultaneous reconstructive stage, given the reasonable selection of the patients.

Introduction Basal cell carcinoma (BCC) is the most common malignant tumor in adult white populations. If BCCs are not treated for years, if they cause massive destruction of the surrounding tissues, if they are considered unresectable or not eligible for radiotherapy they become progressively ‘locally advanced’ (laBCC) or metastatic (mBCC). These tumors are defined as ‘difficult-to-treat BCC.’ Areas covered A comprehensive search on PubMed was conducted to identify relevant literature about the several approved and recommended treatment options for the management of difficult-to-treat BCC published from January 2012 to July 2022. Surgical options, radiotherapy, hedgehog inhibitors, immunotherapy, and combined treatments are discussed. The keywords used were basal cell carcinoma; difficult-to-treat BCC; management of difficult-to-treat BCC; surgical therapy; radiotherapy; hedgehog inhibitors; immunotherapy. Expert opinion Identifying the best approach to DTT BCCs is one of the main challenges for the dermato-oncologist. The introduction of HHI for the treatment of advanced BCCs has revolutionized the clinical management of DTT BCCs. The immune checkpoint inhibitor cemiplimab has been approved for the treatment of locally advanced or metastatic BCC refractory to HHI therapy or in patients intolerant to HHI therapy. Multidisciplinary teams (MDTs) play a key role in managing these complex patients.

The need for effective treatment of patients with locally advanced or metastatic basal cell carcinoma (BCC), in conjunction with major advances in the elucidation of the molecular basis of this tumor has led to the advent of new targeted therapies - namely, hedgehog inhibitors. The rationale for their use in patients with advanced BCC is based on their inhibitory effect on the hedgehog pathway, which is aberrantly activated in BCCs due to mutations of its primary components, PTCH1 and SMO genes. Vismodegib (GDC-0449) is an orally bioavailable hedgehog pathway inhibitor that selectively inhibits SMO. The ERIVANCE BCC study is a Phase II, international, multicenter clinical trial evaluating the efficacy and safety of vismodegib 150 mg once daily in patients with locally advanced or metastatic BCC. Vismodegib has been approved for the treatment of adult patients with metastatic BCC, or with locally advanced BCC that has recurred following surgery or who are not candidates for surgery or radiation therapy. This article will outline the rationale, design and available results from the ERIVANCE BCC study and discuss the clinical implications of vismodegib in the management of patients with BCC. Challenges regarding vismodegib use include the recurrence of BCC after drug discontinuation, the development of acquired resistance, the dramatic efficacy in patients with Gorlin syndrome, and class-related drug toxicity. Ongoing clinical trials aim to explore the role of vismodegib in the neoadjuvant setting prior to surgery, the potential use of alternate dosing regimens in order to limit chronic adverse events, as well as the identification of patients with BCC that are more likely to respond to this targeted therapy based on genotypic and/or phenotypic characteristics.

Basal cell carcinoma (BCC) is the most commonly diagnosed cutaneous cancer globally. Chronic exposure to environmental triggers and genetic predisposition are risk factors that contribute to the incidence of BCC. While most cases of BCC are treated surgically with curettage or simple excision, treatment options for advanced BCC, including metastatic BCC and locally advanced BCC, are limited as some may be considered unresectable. Advancements in the role of hedgehog signaling in the pathogenesis of BCC have resulted in the development of hedgehog pathway inhibitors as the best treatment for BCC. Germline or somatic mutations in hedgehog pathway signaling components (Smoothened, Patched-1, etc.) result in constant activation of this pathway. Sonidegib and vismodegib are synthetic mimetics of hedgehog pathway inhibitors that are indicated for many subtypes of advanced BCC. We report an unusual case of locally advanced BCC in a 61-year-old male who suffered from a growing BCC for at least six years. After eight months of hedgehog pathway inhibitor (HHI) therapy, the patient reported dramatic improvements in his BCC and complete regression of smaller BCCs previously noted on his upper extremities. The patient reported only minor adverse events including hair thinning, weight loss, and rapidly growing nails.

e18830 Background: A small proportion of patients (pts) with BCC develop advanced disease (locally advanced [la] and metastatic [m] BCC). Until recently, there was no standard treatment regimen for advanced BCC following progression on or intolerance to HHIs. Some pts received systemic therapy (ST), but most received best supportive care (BSC). Cemiplimab-rwlc is the first immunotherapy indicated in the US, fully for pts with laBCC and accelerated for mBCC, post HHIs or for whom HHIs are not appropriate. This study estimated the BI of introducing cemiplimab-rwlc in the US from a healthcare payer’s perspective. Methods: A decision analytic model was developed to estimate the BI of introducing cemiplimab-rwlc to a US healthcare system over 3 years for advanced BCC treatment following HHIs. Published data were used to estimate eligible patient population size. Reference case market shares for platinum chemotherapy (CT; 4%), nivolumab (3%), pembrolizumab (2%), vismodegib (1%), sonidegib (1%), and BSC (89%) were based on market research, as were predicted uptake of cemiplimab-rwlc and changes in market distribution of STs and BSC post-cemiplimab-rwlc launch, with most pts moving from BSC. Treatment costs were sourced from the ProspectoRx drug pricing database. Total costs (2020 US dollars [$]) to the healthcare system included costs related to treatment, disease monitoring, and mitigation of Grade 3–4 adverse events. Results: In a hypothetical US healthcare plan of 1,000,000 members, ̃32 pts per year with advanced BCC would be eligible for cemiplimab-rwlc, resulting in an average additional cost of cemiplimab-rwlc introduction of $0.12 per member per month (PMPM) over 3 years. The proportion of pts receiving ST rather than BSC was estimated to increase from 11% in 2020, prior to cemiplimab-rwlc approval, to 50% in 2023. Cemiplimab-rwlc market share is projected to increase by 41% by year 3 taking shares from BSC (–39%), HHIs (–1%), and CT (–1%). Given the large proportion of pts who currently receive BSC, the availability of cemiplimab-rwlc is expected to increase payers’ 3-year budget from $978,955 to $5,487,507 post-launch. A one-way sensitivity analysis showed that BI estimates were most sensitive to estimation of the size of the eligible population (health plan population [±20%], proportion of pts with advanced BCC [±20%], and those eligible for treatment post-HHI [±19%]), cemiplimab-rwlc treatment duration (±17%), and the cost of cemiplimab-rwlc (±17%). Changes to all other inputs had a < 5% impact. Conclusions: The introduction of cemiplimab-rwlc had a minimal BI on the average PMPM cost. Modest incremental BI is directly attributable to the projected uptake of cemiplimab-rwlc in a market where pts previously received no ST. These analyses provide new insights in the management of advanced BCC noting limited available evidence for post-HHI treatment.

Topical photodynamic therapy has been used for the treatment of superficial and nodular basal cell carcinomas, with varying cure rates. This study aims to evaluate the effectiveness of topical photodynamic therapy in the treatment of superficial and nodular basal cell carcinomas in Asian patients treated at the National Skin Centre, Singapore. A retrospective analysis of Asian patients with histologically confirmed basal cell carcinomas and treated with photodynamic therapy was performed. Eight Chinese patients, with an equal gender distribution and mean age of 83.4 years were included. Five of eight basal cell carcinomas were superficial while the remaining three were nodular. The basal cell carcinomas were located in the head and neck in seven patients. The overall clearance rate at 3 months was 87.5% while the clearance rate for superficial and nodular basal cell carcinomas was 100% and 66.6% respectively at 3 months. At 12 months, the overall clearance rate was 85. 7%. This is a retrospective analysis with small patient numbers. In this small series of eight Asian patients, topical photodynamic therapy has been shown to be effective and generally well-tolerated in the treatment of basal cell carcinomas, particularly of the superficial subtype. However, larger studies are needed to evaluate its overall efficacy in Asian patients.