lde225 and Skin-Neoplasms

Basal cell carcinoma (BCC) of the skin is the most common form of skin cancer in the United States. In life-threatening, advanced BCC, sonic hedgehog inhibitors (SSHis) remain a pre-eminent treatment option for locally advanced BCC and metastatic BCC.. In this updated systematic review and meta-analysis, we aimed to better characterize the efficacy and safety of SSHis by including final updates from pivotal clinical trials and additional new recent studies.. An electronic database search was performed for articles including clinical trials, prospective case series, and retrospective medical record reviews on human subjects. Overall response rates (ORRs) and complete response rates (CRRs) were the primary outcomes. For safety assessment, the prevalence of the following adverse effects was analyzed: muscle spasms, dysgeusia, alopecia, weight loss, fatigue, nausea, myalgias, vomiting, skin squamous cell carcinoma, increased creatine kinase, diarrhea, decreased appetite, and amenorrhea. Analyses were performed using R statistical software. Data were pooled using linear models with fixed effects meta-analysis for primary analyses, along with 95% confidence intervals (CIs) and p-values. Intermolecular differences were calculated using Fisher's exact test.. A total of 22 studies (N = 2384 patients) were included in the meta-analysis: 19 studies assessing both efficacy and safety, 2 studies assessing safety only, and 1 study assessing efficacy only. Overall, the pooled ORR for all patients was 64.9% (95% CI 48.2-81.6%), implicating there is at least a partial response (z = 7.60, p < 0.0001) in most patients receiving SSHis. The ORR for vismodegib was 68.5% and 50.1% for sonidegib. The most common adverse effects for vismodegib and sonidegib were muscle spasms (70.5% and 61.0%, respectively), dysgeusia (58.4% and 48.6%, respectively), and alopecia (59.9% and 51.1%, respectively). Patients were likely to experience weight loss (35.1%, p < 0.0001) from vismodegib. Alternatively, patients taking sonidegib experienced more nausea, diarrhea, increased creatine kinase levels, and decreased appetite compared with those receiving vismodegib.. SSHis are an effective treatment for advanced BCC disease. Given the high discontinuation rates, management of patient expectations is warranted for compliance and achieving long-term efficacy. It is essential to stay updated with the latest discoveries on the efficacy and safety of SSHis.

Topics: Alopecia; Anilides; Antineoplastic Agents; Carcinoma, Basal Cell; Creatine Kinase; Diarrhea; Drug-Related Side Effects and Adverse Reactions; Dysgeusia; Female; Hedgehog Proteins; Humans; Nausea; Retrospective Studies; Skin Neoplasms; Spasm; Weight Loss

As one of the most common malignancies, basal cell carcinoma (BCC) has evolved as a global burden with incidence annually rising, especially in the older population. Even though the condition is mostly localized, the nature of the disease is destructive and can evolve as either locally advanced BCC (laBCC) or even more rarely as metastatic BCC (mBCC). There are well-established conventional treatment options for these cases, including surgeries and radiotherapy. However, not all cases are eligible for conventional treatments. Recently, biologic treatment has gained a lot of attention and research. This has led to the development of targeted treatment involving the hedgehog pathway inhibitor (HPI), a key pathogenesis in laBCC and mBCC. There are currently two approved HPIs, vismodegib and sonidegib to treat inoperable laBCC and mBCC. This review seeks to explore the pathophysiology of hedgehog pathway behind the development of BCC, and the current update of the efficacy as well as pharmacokinetics properties of HPIs that led to the ideal treatment for laBCC or mBCC, either as monotherapy or in combination with other conventional therapies.

Topics: Anilides; Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Hedgehog Proteins; Humans; Pyridines; Skin Neoplasms

Basal cell carcinoma (BCC) is one of the most common neoplasms in the population. A good prognosis and mainly non-aggressive development have made it underdiagnosed and excluded from the statistics. Due to the availability of efficient surgical therapy, BCC is sometimes overlooked in the search for novel therapies. Most clinicians are unaware of its complicated pathogenesis or the availability of effective targeted therapy based on Hedgehog inhibitors (HHI) used in advanced or metastatic cases. Nevertheless, the concomitance and esthetic burden of this neoplasm are severe. As with other cancers, its pathogenesis is multifactorial and complicated with a network of dependencies. Although the tumour microenvironment (TME), genetic aberrations, and risk factors seem crucial in all skin cancers, in BCC they all have become accessible as therapeutic or prevention targets. The results of this review indicate that a central role in the development of BCC is played by the Hedgehog (Hh) signalling pathway. Two signalling molecules have been identified as the main culprits, namely Patched homologue 1 (PTCH1) and, less often, Smoothened homologue (SMO). Considering effective immunotherapy for other neoplastic growths being introduced, implementing immunotherapy in advanced BCC is pivotal and beneficial. Up to now, the US Food and Drug Administration (FDA) has approved two inhibitors of SMO for the treatment of advanced BCC. Sonidegib and vismodegib are registered based on their efficacy in clinical trials. However, despite this success, limitations might occur during the therapy, as some patients show resistance to these molecules. This review aims to summarize novel options of targeted therapies in BCC and debate the mechanisms and clinical implications of tumor resistance.

Topics: Antineoplastic Agents; Carcinoma, Basal Cell; Hedgehog Proteins; Humans; Patched-1 Receptor; Signal Transduction; Skin Neoplasms; Smoothened Receptor; Tumor Microenvironment; United States

Systemic treatment with hedgehog inhibitors (HHis) is available to treat basal cell carcinomas but their utility is limited by adverse effects. Topical delivery methods may reduce adverse effects, but successful topical treatment depends on sufficient skin uptake, biological response, and time in tumor tissue. The aim of this review was to evaluate the current status of topical HHi delivery for BCCs and discuss barriers for translating systemic HHis into topical treatments. A literature search identified 16 preclinical studies and 7 clinical trials on the topical delivery of 12 HHis that have been clinically tested on BCCs. Preclinical studies on drug uptake demonstrated that novel formulations, and delivery- and pre-treatment techniques enhanced topical HHi delivery. Murine studies showed that the topical delivery of sonidegib, itraconazole, vitamin D₃ and CUR-61414 led to biological responses and tumor remission. In clinical trials, only topical patidegib and sonidegib led to at least a partial response in 26/86 BCCs and 30/34 patients, respectively. However, histological clearance was not observed in the samples analyzed. In conclusion, the incomplete clinical response could be due to poor HHi uptake, biodistribution or biological response over time. Novel topical delivery techniques may improve HHi delivery, but additional research on cutaneous pharmacokinetics and biological response is needed.

Topics: Administration, Cutaneous; Animals; Carcinoma, Basal Cell; Hedgehog Proteins; Humans; Itraconazole; Mice; Skin Neoplasms; Tissue Distribution

Basal cell carcinoma is one of the most common types of non-melanoma skin cancers, which can be locally destructive despite low-rate metastasis. Surgery is the treatment of choice, but it lacks of efficacy on advanced cases. Hedgehog pathway inhibitors are a class of drugs providing a new therapeutic option for patients affected by advanced disease. Besides systemic therapy, such as vismodegib and sonidegib, also topical inhibitors have been developed. Patidegib is able to decrease tumor burden, reducing the adverse effects induced by systemic targeted therapies.. We performed comprehensive research to summarize the use of patidegib in advanced and recurrent aggressive basal cell carcinomas. Only English language human studies were included in the search.. Seven trials reported the application of patidegib. Both topical and systemic patidegib demonstrated safety, tolerability, and efficacy in naïve patients with stage II and III basal cell carcinomas, while stage IV disease and not-naïve patients did not show any benefit.. Unlike systemic Hedgehog pathway inhibitors, patidegib 2% gel is not associated with systemic adverse effects and allows a better patient management. Considering the multidisciplinary management of neoplasia, in the era of precision medicine, it is mandatory to confide in pharmacogenomics to obtain personalized combined or sequential therapies.

Topics: Antineoplastic Agents; Biphenyl Compounds; Clinical Trials as Topic; Dermatology; Hedgehog Proteins; Humans; Molecular Targeted Therapy; Prognosis; Pyridines; Signal Transduction; Skin Neoplasms; Treatment Outcome; Veratrum Alkaloids

Sonidegib is an antagonist of the transmembrane protein Smoothened in the Hedgehog signaling pathway. It is indicated for the treatment of locally advanced basal cell carcinoma (BCC) that is not amenable to curative surgery or radiotherapy. Sonidegib's efficacy and safety were demonstrated in the phase 2 BOLT trial, where 61% (95% CI, 48-72%) of patients with locally advanced BCC treated with sonidegib 200 mg achieved an objective response to treatment with a mean time to response of 4 months. The median duration of response was 26.1 months and the median progression-free survival was 22.1 months. The most common adverse events were muscle spasms (54.4%), hair loss (49.4%), and loss of taste (44.3%); most events were grade 1 or 2. In this review, we summarize the main findings on the efficacy, safety, and tolerability of sonidegib and discuss the management of locally advanced BCC with this drug.

Topics: Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Hedgehog Proteins; Humans; Pyridines; Skin Neoplasms

Basal cell carcinoma (BCC) is the most common malignancy in fair-skinned populations. Most cases are successfully treated with surgery, but in advanced BCC—including locally advanced BCC and metastatic BCC—surgery is likely to result in substantial morbidity or unlikely to be effective. In those patients, the systemic Hedgehog inhibitors (HHIs) sonidegib and vismodegib are the only approved pharmacologic treatment option. Although a number of clinical studies highlight the similarities and differences between the two HHIs, no head-to-head clinical comparison is available. Results from the pivotal BOLT and ERIVANCE clinical studies for sonidegib and vismodegib, respectively, demonstrate similar efficacy measured by objective response rate, complete response rate, and histologic tumor subtype. Safety results for both studies are comparable with similar common adverse events reported for muscle spasms, alopecia, and dysgeusia. A notable difference between sonidegib and vismodegib is their respective pharmacokinetic profiles with sonidegib reaching peak concentration in plasma within 2–4 hours of dosing and steady state in plasma achieved by week 17 of treatment, while vismodegib reaches peak plasma concentration approximately 2 days after a single dose and steady state within 21 days of repeated dosing. This review compares efficacy, safety, and pharmacokinetics of sonidegib and vismodegib based on published literature to date. J Drugs Dermatol. 2021;20(2):156-165. doi:10.36849/JDD.5657\ \ THIS ARTICLE HAD BEEN MADE AVAILABLE FREE OF CHARGE. PLEASE SCROLL DOWN TO ACCESS THE FULL TEXT OF THIS ARTICLE WITHOUT LOGGING IN. NO PURCHASE NECESSARY. PLEASE CONTACT THE PUBLISHER WITH ANY QUESTIONS.

Topics: Alopecia; Anilides; Biphenyl Compounds; Carcinoma, Basal Cell; Clinical Trials, Phase II as Topic; Dysgeusia; Hedgehog Proteins; Humans; Multicenter Studies as Topic; Progression-Free Survival; Pyridines; Randomized Controlled Trials as Topic; Signal Transduction; Skin Neoplasms; Spasm

Topics: Anilides; Animals; Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Hedgehog Proteins; Humans; Pyridines; Randomized Controlled Trials as Topic; Skin Neoplasms; Smoothened Receptor

Sonidegib and vismodegib are hedgehog pathway inhibitors (HhIs) approved for the treatment of advanced basal cell carcinoma (BCC). Until recently, vismodegib was the only targeted treatment available for patients with locally advanced BCC (laBCC) in cases where surgery and radiotherapy are inappropriate. Sonidegib has recently been approved and now presents an alternative treatment option. The clinical differences between the two HhIs in patients with laBCC are unclear, as no head-to-head randomized controlled trials are or will be initiated. Moreover, there were important differences in the designs of their pivotal studies, BOLT (sonidegib) and ERIVANCE (vismodegib), and these differences complicate evidence-based analysis of their relative efficacy and safety profiles. In this paper, a group of clinical experts in the management of laBCC summarizes the clinical and pharmacological profiles of sonidegib and vismodegib based on published data and their own clinical experience. One key difference between the two pivotal studies was the criteria used to assess BCC severity. ERIVANCE (a single-arm phase II trial) used the conventional Response Evaluation Criteria in Solid Tumors (RECIST), while the more recent double-blind randomized BOLT trial used the stringent modified RECIST. A preplanned analysis adjusted the outcomes from BOLT with RECIST-like criteria, and this enabled the experts to discuss relative efficacy outcomes for the two treatments. Centrally reviewed objective response rate (ORR) for vismodegib was 47.6% (95% CI: 35.5-60.6) at 21-month follow-up using RECIST. After adjusting with RECIST-like criteria, the ORR for sonidegib according to central review at 18-month follow-up was 60.6% (95% CI: 47.8-72.4). Both treatments were associated with similar patterns of adverse events. Sonidegib and vismodegib share the same efficacy and tolerability profiles, but their pharmacokinetic profiles show several differences, such as volume of distribution and half-life. Further studies are needed to understand how these differences may impact clinical practice.

Topics: Anilides; Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Expert Testimony; Hedgehog Proteins; Humans; Pyridines; Skin Neoplasms

Basal cell carcinoma is the most common skin tumour, with the majority of the cases occurring on the head and neck district, where cosmetic and functional results are crucial. It can be locally destructive if not diagnosed early and treated appropriately. Surgery is the treatment of choice for most lesions, but aggressive, recurrent, or unresectable tumours can be challenging to manage. Advanced basal cell carcinoma includes high recurrence risk subtypes, in which standard therapies demonstrate lack of efficacy. This led to a need for investigating more deeply the pathogenesis of the disease and to the discovery of the implication of the hedgehog pathway. The development of systemic inhibitors of this pathway provides new treatment options for patients with advanced disease, resulting in survival improvement. Food and Drug Administration, before, and European Medicines Agency later approved 2 Hedgehog pathway inhibitors for the treatment of advanced basal cell carcinomas, vismodegib and sonidegib. Here, we present a review of the current English language literature trying to analyze differences in the 2 drugs as a head-to-head comparison between them has not already been documented in a randomized controlled clinical trial. Although vismodegib and sonidegib showed similar efficacy and safety profiles, in an indirect comparison scenario, sonidegib has shown slightly better outcomes in locally advanced basal cell carcinoma than vismodegib. They present different molecular structures, as they bind different residues on their targets and develop resistance for different mutations. In a future scenario, clinical trials comparing the 2 drugs are needed, as well as expanding data on discontinuation of therapy and/or consequential administration of them, with the aim to improve our clinical practise.

Topics: Anilides; Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Drug Resistance, Neoplasm; Hedgehog Proteins; Humans; Neoplasm Recurrence, Local; Pyridines; Signal Transduction; Skin Neoplasms

Basal cell carcinoma (BCC) is the most common non-melanoma skin cancer (NMSC). Although surgery is the first-line therapy for BCC, some cases can progress to an advanced or, rarely, a metastatic state and targeted therapy are required. The main pathway involved in BCC tumorigenesis is the Hedgehog (Hh) signaling pathway and its inhibition is among the few treatment options available for patients with advanced BCCs. Recent advances in targeting this pathway have led to the development of two small-molecule oral Hh inhibitors, vismodegib and sonidegib.. The aim of this article is to provide a complete overview on the use of HPI for the treatment of advanced BCCs describing the efficacy, the benefits, and risks related to these small molecules.. To date, the class of Hh inhibitors has revolutionized the management of patients with advanced BCCs, even though they are usually related to a toxicity profile that may represent the major cause of treatment discontinuation; an accurate study of the Hh signaling pathway and the development of other small molecules could be useful to enlarge the armamentarium of treatment in order to assure patients a personalized approach to the choice of treatment.

Topics: Anilides; Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Hedgehog Proteins; Humans; Pyridines; Signal Transduction; Skin Neoplasms

Although surgical intervention remains the standard of care for nonmelanoma skin cancer, other treatment modalities have been studied and used. Nonsurgical treatment methods include cryotherapy, topical medications, photodynamic therapy, radiation therapy, Hedgehog pathway inhibitors, programmed cell death protein 1 inhibitors, and active nonintervention. Despite the favorable efficacy of surgical treatment methods, many factors, including but not limited to patient age, preference, and severity of disease, must be taken into consideration when choosing the most appropriate, patient-centered treatment approach.

Topics: Administration, Cutaneous; Anilides; Antineoplastic Agents; Antineoplastic Agents, Immunological; Biphenyl Compounds; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Cryosurgery; Cyclooxygenase Inhibitors; Diclofenac; Diterpenes; Fluorouracil; Humans; Imiquimod; Photochemotherapy; Programmed Cell Death 1 Receptor; Pyridines; Radiotherapy; Skin Neoplasms; Watchful Waiting

Locally advanced and metastatic nonmelanoma skin cancer (NMSC) not amenable to surgical resection requires a different approach to therapy.. To review the efficacy and adverse effects of emerging treatment options for locally advanced and metastatic NMSC.. A comprehensive search on PubMed was conducted to identify relevant literature investigating the role of program cell death 1 (PD-1) inhibitor, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, epidermal growth factor receptor (EGFR) inhibitor, and Hedgehog pathway inhibitors in the treatment of NMSC.. PD-1 inhibitor and CTLA-4 inhibitor have shown promising efficacy with tolerable side-effect profiles in the treatment of NMSC, although the number of cases reported is limited. Currently, 3 larger-scale clinical trials are investigating PD-1 inhibitor therapy for NMSC. Similarly, EGFR inhibitor demonstrated marginal success in unresectable cutaneous squamous cell carcinomas. Hedgehog pathway inhibitors were approved by the US FDA for treatment of locally advanced and metastatic basal cell carcinomas and have shown favorable efficacy. Common adverse effects included muscle spasm, alopecia, and dysgeusia.. Systemic therapies including PD-1 inhibitors and CTLA-4 inhibitors have demonstrated early promising results for difficult-to-treat NMSC. Future studies are necessary to optimize treatment outcome.

Topics: Anilides; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Biphenyl Compounds; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Cetuximab; CTLA-4 Antigen; ErbB Receptors; Hedgehog Proteins; Humans; Ipilimumab; Nivolumab; Programmed Cell Death 1 Receptor; Pyridines; Skin Neoplasms

Basal cell carcinoma (BCC) is the most common type of skin cancer, with rising incidence rates primarily attributed to an aging population and ultraviolet radiation exposure. While the majority of BCCs are localized and respond to standard therapies, a very small minority of these tumors become locally destructive or metastasize. These advanced BCCs may not be amenable to localized treatment with surgery and/or radiation therapy. Most BCCs result from mutations in key receptors in the Hedgehog (HH) signaling pathway. As a result, identification of drugs that inhibit the receptor Smoothened (SMO) in the HH pathway has resulted in novel therapeutic approaches to treating patients with advanced BCC. These HH-pathway inhibiting medications have shown efficacy in clinical trials, and two medications, vismodegib and sonidegib, have received FDA approval. However, several limitations of these drugs have been identified, including treatment-limiting adverse events, drug resistance, and the formation of additional malignancies. This paper aims to summarize the clinical trials leading to the approval of SMO inhibitors, as well as reviewing potential mechanisms driving tumor resistance and the formation of cutaneous squamous cell carcinomas. Strategies to overcome some of these challenges, including the development of drugs that inhibit other downstream targets in the HH pathway, are the subject of ongoing clinical trials.

Topics: Anilides; Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Clinical Trials as Topic; Drug Resistance, Neoplasm; Hedgehog Proteins; Humans; Mutation; Neoadjuvant Therapy; Pyridines; Signal Transduction; Skin Neoplasms; Smoothened Receptor; Treatment Outcome

Sonic hedgehog inhibitors (SHHis) provide an additional treatment option for basal cell carcinomas (BCCs), especially for metastatic or locally advanced BCC. However, studies have been heterogeneous and lacked direct comparisons between molecules.. To determine the efficacy and safety of the class of molecules SHHi for treating BCC and to compare them individually.. We performed a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)-compliant systematic review of studies followed by a meta-analysis.. Eighteen articles were included in our meta-analysis; 16 articles were combined for efficacy and 16 for safety. In locally advanced BCC, overall response rates (ORRs) were similar for vismodegib and sonidegib (69% vs 57%, respectively) but not complete response rates (31% vs 3%, respectively). In metastatic disease, the ORR of vismodegib was 2.7-fold higher than the ORR of sonidegib (39% vs 15%, respectively). For side effects affecting a majority of patients, prevalences for muscle spasms (67.1%), dysgeusia (54.1%), and alopecia (57.7%) were in similar proportions for sonidegib and vismodegib. Patients receiving sonidegib experienced more upper gastrointestinal distress than patients receiving vismodegib.. SHHis induce a partial response to locally advanced BCC disease. Side effects are common, similar across molecules, associated with high discontinuation rates, and warrant discussion beforehand.

Topics: Alopecia; Anilides; Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Clinical Trials as Topic; Dysgeusia; Gastrointestinal Diseases; Hedgehog Proteins; Humans; Muscular Diseases; Neoplasm Proteins; Prospective Studies; Pyridines; Skin Neoplasms

Until recently, advanced BCC were only accessible to a highly morbid surgery not necessarily proving to be carcinologic, and leaving terrible dysmorphic sequelae hard to accept by the patient. Another possibility, the only one in case of metastatic BCC, was chemotherapy which efficacy has never been proven in a clinical trial. Radiotherapy is most often not accessible because of previous radiotherapy or because of the localization or the extension of the lesion. The discovery of the importance of the sonic hedgehog pathway in the physiopathology of BCC has opened a new strategy with the development of targeted anti SMO drugs inactivating the pathway. Two molecules have become available following Phase I and II studies: vismodegib (Erivedge®) the first in class indicated for locally advanced and metastatic BCC and sonidegib (Odomzo®) indicated only for locally advanced BCC. The pharmacokinetic profiles of sonidegib and vismodegib showed several differences. No head to head comparative studies are available between these two drugs. Their pivotal phase II studies had similar study designs and endpoints. The objective response rate (ORR) by central review for vismodegib was 47.6% (95% CI 35.5-60.6) at 21 months follow-up. The ORR for sonidegib according to central review at 18 months follow-up is 56.1% (95% CI 43.3-68.3). Although both treatments share a similar adverse event profile with possible numerically differences in incidence, most patients will discontinue hedgehog inhibitors treatment in the long term because of side effects. Some resistant cases to these drugs have been described but are rather rare. In case of resistance or bad tolerability to the drug future hopes rely on immunotherapy currently under investigation. © 2018. Published by Elsevier Masson SAS. All rights reserved. Cet article fait partie du numéro supplément Prise en charge des carcinomes basocellulaires difficiles à traiter réalisé avec le soutien institutionnel de Sun Pharma.

Topics: Alopecia; Anilides; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Basal Cell Nevus Syndrome; Biphenyl Compounds; Carcinoma, Basal Cell; Cisplatin; Clinical Trials as Topic; Drug Resistance, Neoplasm; Dysgeusia; Fluorouracil; Hedgehog Proteins; Humans; Molecular Targeted Therapy; Multicenter Studies as Topic; Muscle Cramp; Mutation; Neoplasm Proteins; Patched-1 Receptor; Patched-2 Receptor; Pyridines; Signal Transduction; Skin Neoplasms; Smoothened Receptor

Basal cell carcinoma (BCC) is the most prevalent malignant tumor in humans and the local destruction of tissue that can result from excision has a significant impact on well-being. Treating BCC is costly for health care systems given the high incidence of this tumor, especially in older patients. Standard treatment involves either resection with histologic assessment of margins or Mohs micrographic surgery. Surgery is sometimes contraindicated, however, due to the presence of significant comorbidity or high cosmetic expectations. For such patients, nonsurgical treatments have become available. These alternatives can offer good local control of disease, preserve function, and achieve excellent cosmetic results.

Topics: Administration, Cutaneous; Aminoquinolines; Anilides; Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Clinical Trials as Topic; Fluorouracil; Humans; Imiquimod; Interferons; Meta-Analysis as Topic; Molecular Targeted Therapy; Neoplasm Invasiveness; Photochemotherapy; Pyridines; Randomized Controlled Trials as Topic; Risk Assessment; Skin Neoplasms

Nonmelanoma skin cancer (NMSC) is the most common cancer in patients and includes basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Treatments useful for SCC and BCC include surgical, topical, and in advanced cases systemic chemo-radiation. This review of the literature aims to describe previous and current treatment options for oral therapy in locally advanced and metastatic NMSC otherwise unamenable to standard treatment. Oral Smoothened (Smo) inhibitors Vismodegib, Sonidegib, and Taladegib have shown to be effective in several trials. Oral tyrosine kinase inhibitors Erlotinib and Gefitinib, which target epidermal growth factor receptor (EGFR), have early supporting data and are currently undergoing large multicenter trials. Other less studied oral therapies which have shown at least partial efficacy include 5-Fluorouracil, capecitabine, and picropodophyllin. In vitro studies have elucidated new targets for dual combination oral therapy targeting both EGFR and insulin-like growth factor 1 receptor (IGF-1R). It is important to stratify treatment options based on patient risk of advanced disease, failure of conservative treatment, and ill-tolerated intravenous chemotherapy adverse events. Oral therapy in NMSC is useful in high risk patients with recurrent and aggressive disease who may not tolerate other systemic therapies.

Topics: Administration, Oral; Anilides; Antineoplastic Agents; Biphenyl Compounds; Capecitabine; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; ErbB Receptors; Erlotinib Hydrochloride; Fluorouracil; Gefitinib; Hedgehog Proteins; Molecular Targeted Therapy; Phthalazines; Podophyllotoxin; Pyridines; Quinazolines; Receptor, IGF Type 1; Retinoids; Skin Neoplasms; Tumor Burden

The advent of more sophisticated studies published has clarified the understating of the root cause of various skin cancers or basal cell carcinomas (BCCs). The remarkable role is played by the comprehensive work done on unraveling the mechanism controlling the function of hedgehog (Hh) pathway. The defective Hh pathway has been found as the major cause for BCCs as activated Hh signaling within primary cilia plays a key role in the pathogenesis of BCCs. The BCC accounts for up to 40% of all cancers in the US, with growing incidences in other countries as well. Thus, it is considered to be utmost important by the researchers all over the world developing drugs for the treatment of skin cancers targeting Hh pathway. Fewer drugs like vismodegib, itraconazole and sonidegib have shown promising results inhibiting the awry function of Hh pathway resulting in treatment of different forms of skin cancers. These drugs have shown positive results but failed to prove their potential as expected. Vismodegib and sonidegib are better but fail in case of resistant tumors. This review article describes the mechanism of actions of these Hh pathway inhibitors and provides the rationale for their effectiveness/non-effectiveness for the treatment of metastatic or locally advanced BCC.

Topics: Anilides; Antineoplastic Combined Chemotherapy Protocols; Biphenyl Compounds; Carcinoma, Basal Cell; Drug Resistance, Neoplasm; Hedgehog Proteins; Humans; Itraconazole; Pyridines; Signal Transduction; Skin Neoplasms

We summarize the concept of a locally advanced basal cell carcinoma (laBCC) and present the current consensus definition. We also review the key pieces of primary research undertaken in the past year and how these affect the use of smoothened inhibitors in a clinical setting.. Medium term follow-up (30 months) of patients treated with vismodegib shows an improvement in response rates for patients with laBCC. The safety profile of vismodegib demonstrated in the original ERIVANCE study has been replicated in a larger patient cohort in a repeat study. Sonidegib is a new smoothened inhibitor currently under investigation for treatment of laBCC, which demonstrates a comparable safety profile to vismodegib. The side-effects of smoothened inhibitors appear related to both dose and duration of treatment. The durability of response to vismodegib is uncertain, but has been observed to last for over a year following discontinuation of treatment.. The understanding of the efficacy and safety of vismodegib has improved since its introduction in 2012. A broadening evidence base supports its use as a valid treatment for laBCC. However, questions remain as to how to integrate its use into existing pathways for treating laBCC and its long-term efficacy.

Topics: Anilides; Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Hedgehog Proteins; Humans; Pyridines; Receptors, G-Protein-Coupled; Skin Neoplasms; Smoothened Receptor

Sonidegib (Odomzo®), an oral smoothened (SMO) antagonist, is indicated for the treatment of adults with locally advanced basal cell carcinoma (laBCC) who are not candidates for surgery or radiation therapy, or adults with recurrent laBCC following surgery or radiation therapy. In the multicentre BOLT trial, the primary endpoint (i.e., an objective tumour response rate point estimate of ≥30 % and a 95 % confidence interval lower bound of >20 % in patients with fully assessable laBCC and all patients with metastatic BCC) was met at the primary analysis cut-off date (median follow-up 13.9 months) in the sonidegib 200 mg (36 % [95 % CI 24-50]) and 800 mg (34 % [95 % CI 25-43]) once-daily groups. Sonidegib 200 mg once daily (recommended dosage) had a better benefit-risk profile than the 800 mg dosage. Central review of the patients with laBCC in this population showed that 43 % achieved an objective response with sonidegib 200 mg once daily at the primary analysis date. Clinically meaningful responses were sustained in the sonidegib 200 mg group, based on an 18-month analysis. The majority of treatment-emergent adverse events were of mild to moderate severity and manageable with dosage adjustments, concomitant medications and/or non-drug therapies (e.g., adequate hydration). The acceptable benefit-risk profile of sonidegib, along with a paucity of treatment options and the seriousness of the condition, makes sonidegib an emerging option for the treatment of adults with laBCC that has recurred following surgery or radiation therapy, or in those who are not candidates for surgery or radiation therapy.

Topics: Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Humans; Pyridines; Skin Neoplasms

Topics: Biphenyl Compounds; Carcinoma, Basal Cell; Clinical Trials as Topic; Hedgehog Proteins; Humans; Pyridines; Skin Neoplasms; Spasm

Hedgehog pathway inhibitors (HPIs) were made available by US Food and Drug Administration approval in 2012 for vismodegib and 2015 for sonidegib. Both target the Smoothened molecule and are indicated for locally advanced basal cell carcinoma (laBCC) and metastatic basal cell carcinoma (mBCC).. To evaluate clinical experience with HPIs, including efficacy and adverse effects.. We conducted a systematic review in concordance with the PRISMA guidelines of PubMed, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and EMBASE, using search terms "vismodegib," "sonidegib," "Erivedge," "Odomza," "basal cell carcinoma," and "BCC.". We included clinical trials, retrospective medical record reviews, and prospective case series that used HPIs for the treatment of laBCC or mBCC in human subjects. Individual case reports and limited, retrospective case series were excluded from our review.. Data were extracted independently by 2 reviewers on a predesigned, standardized form.. The following data were recorded: number of patients with laBCC or mBCC, dose and frequency of drug administration, median duration of treatment, clearance and recurrence rates, and adverse effects.. Eleven vismodegib articles (published between 2009 and 2015) met criteria for inclusion, and 8 articles were able to be pooled for analysis. The 8 pooled articles included 744 total patients with 704 patients clinically evaluable. Sonidegib did not yield enough publications for a formal analysis. Objective response to vismodegib for laBCC had a weighted average of 64.7% (95% CI, 63.7%-65.6%); complete response averaged 31.1% (95% CI, 30.4%-31.8%). Objective response for mBCC was 33.6% (95% CI, 33.1%-34.2%); complete response averaged 3.9% (95% CI, 3.3%-4.4%). Median duration of therapy was 35.8 weeks (95% CI, 35.1-36.5 weeks).. In a systematic review of HPIs for laBCC and mBCC, vismodegib, but not sonidegib, had enough studies to warrant a pooled analysis. Vismodegib was identified to have a significant, consistent effect on the median duration of therapy of laBCC and mBCC. While mBCC responses are superior to any traditional approach, the response rate for laBCC might be considered in the context of other standard treatment options including surgery and radiation therapy.

Topics: Anilides; Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Hedgehog Proteins; Humans; Pyridines; Skin Neoplasms; Smoothened Receptor

The Hedgehog inhibitors are promising alternative for patients with advanced basal cell carcinoma that are not amenable to radiotherapy or surgery. Sonidegib, also known as LDE225, is an orally available SMO antagonist that was recently approved by the US FDA for the treatment of patients with locally advanced basal cell carcinoma. This article will provide an overview of the pharmacology and pharmacokinetics of sonidegib and in-depth analysis of the BOLT trial with additional data from the 12-month update. The present challenges associated with Hedgehog inhibitors will also be discussed.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biphenyl Compounds; Carcinoma, Basal Cell; Clinical Trials as Topic; Follow-Up Studies; Hedgehog Proteins; Humans; Mice; Pyridines; Signal Transduction; Skin Neoplasms; Smoothened Receptor; Treatment Outcome

Advanced and metastatic basal cell carcinomas (BCCs) are rare but still present a severe medical problem. These tumors are often disfiguring and impact the quality of life by pain or bleeding. Based on discovery of the hedgehog (Hh) signaling pathway and its role in the pathogenesis of BCCs, smoothened (SMO) inhibitors have been developed with Sonidegib being the 2nd in class. It is the only Hh pathway inhibitor investigated in a randomized trial accompanied by pharmacodynamic investigations. Also, the disease assessment criteria applied were more stringent than those used in trials of 1st developed SMO inhibitor - vismodegib, and required annotated photographs, MRI as well as multiple biopsies in case of regression.. All available papers from Medline and the abstracts of the most important dermato-oncology meetings were included.. Sonidegib is a promising medication for advanced BCC and other malignancies, driven by Hh signaling. It presents favorable pharmacokinetic properties and causes class specific toxicity with dose dependent adverse events in muscular and taste bud homeostasis, gastrointestinal symptoms and hair growth. Early after treatment initiation, it impacts the immunesusceptibility of the tumor lesions. Sonidegib deserves further development in combination with other drugs or antibodies, or alternative dosing schedules.

Topics: Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Hedgehog Proteins; Humans; Pyridines; Quality of Life; Randomized Controlled Trials as Topic; Signal Transduction; Skin Neoplasms; Smoothened Receptor

Basal cell carcinomas (BCCs) are the commonest malignancy in the Western world. Locally advanced BCCs (laBCCs) represent tumours that have developed in difficult-to-treat facial sites, aggressively recurrent tumours, large neglected tumours and those in which current treatment options are excluded by clinical or patient-driven criteria. It is estimated laBCCs represent 1% of BCCs.. Sonidegib is an oral hedgehog pathway inhibitor with a novel structure. It has recently been licensed for the treatment of laBCC. This article provides a comprehensive review of the literature regarding sonidegib, detailing the pharmacology of the compound, clinical trial data, competitor compounds and a future perspective. Expert commentary: Sonidegib is a novel smoothened (SMO) inhibitor with comparable efficacy to vismodegib, with patient response rates of 44% (sonidegib) and 43% (vismodegib). The adverse effect profile of these two treatments is similar with the main effects being considered to be class effects of SMO inhibitors.

Topics: Animals; Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Hedgehog Proteins; Humans; Neoplasm Recurrence, Local; Pyridines; Skin Neoplasms; Smoothened Receptor

Sonidegib (Odomzo™) is an orally bioavailable, small molecule, Smoothened (SMO) receptor antagonist that is being developed by Novartis for the treatment of cancer. SMO is a G protein-coupled receptor-like molecule that is essential for the actions of the Hedgehog family of secreted proteins, which play a critical role in the development and homeostasis of many organs and tissues. Oral sonidegib is approved in Switzerland for the treatment of adult patients with advanced basal cell carcinoma (BCC) and in the US and EU for the treatment of adult patients with locally advanced BCC that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy. Submissions to other global authorities are being contemplated or planned. Additionally, phase I/II investigation is being conducted in other malignancies, including multiple myeloma, medulloblastoma, myelofibrosis, ovarian cancer, prostate cancer, breast cancer, chronic myeloid leukaemia, myelodysplastic syndromes, oesophageal cancer and pancreatic cancer. This article summarizes the milestones in the development of sonidegib leading to the first approvals for advanced and locally advanced BCC.

Topics: Administration, Oral; Adult; Animals; Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Drug Approval; Humans; Neoplasms; Pyridines; Receptors, G-Protein-Coupled; Skin Neoplasms; Smoothened Receptor

Basal cell carcinoma (BCC) is the most common cancer in the U.K. and its incidence is increasing. Vismodegib, a hedgehog pathway inhibitor, has recently been licensed by the U.S. Food and Drug Administration for treatment of advanced BCC. Phase 2 trials have demonstrated efficacy in cases of locally advanced and metastatic BCC, as well as cases of hereditary basal cell naevus (Gorlin) syndrome. Side-effects are frequent and considerable and include myalgia, taste disturbance, alopecia, weight loss and fatigue. Further research is needed to investigate means of circumventing these side-effects, and longitudinal data are required to assess the long-term benefits of, and the nature of resistance to, this novel class of agents. Alternative hedgehog inhibitors are currently in clinical development. We review the current data pertaining to this novel treatment modality and discuss its likely future role in the management of BCC.

Topics: Anilides; Antineoplastic Agents; Benzamides; Biphenyl Compounds; Carcinoma, Basal Cell; Clinical Trials as Topic; Hedgehog Proteins; Humans; Pyridines; Quinazolines; Skin Neoplasms

Acquired resistance to targeted therapies threatens the value of these otherwise very promising agents. The recent description of resistance to the Hedgehog pathway inhibitor vismodegib (GDC-0449) in a medulloblastoma patient who had a dramatic initial response has spurred efforts to understand potential mechanisms of drug resistance. Elucidating these mechanisms will play a significant role in informing strategies to overcome this meaningful limitation.

Topics: Anilides; Animals; Antineoplastic Agents; Basal Cell Nevus Syndrome; Biphenyl Compounds; Carcinoma, Basal Cell; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Hedgehog Proteins; Humans; Medulloblastoma; Mice; Mice, Knockout; Mice, Nude; Molecular Targeted Therapy; Mutation, Missense; Neoplasm Proteins; Patched Receptors; Phosphoinositide-3 Kinase Inhibitors; Pyridines; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Signal Transduction; Skin Neoplasms; Smoothened Receptor; Xenograft Model Antitumor Assays

Sonidegib is approved to treat locally advanced basal cell carcinoma (laBCC) in patients not amenable to surgery or radiation. The BOLT trial demonstrated durable efficacy of sonidegib in laBCC patients over 42 months. BCC is most common in the elderly, who often take chronic medications.. We evaluated the efficacy of sonidegib (200 mg daily) in laBCC patients on select concomitant medications.. In the Phase II BOLT study, laBCC patients were randomized 1:2 to sonidegib 200 mg:800 mg daily. The primary endpoint was objective response rate (ORR) per central review. Post hoc assessments included ORR and duration of response (DOR) per investigator review for patients on concomitant medications.. At 42 months, ORR for laBCC patients taking sonidegib 200 mg daily (n=66) was 71.2% and DOR was 15.7 months according to investigator review. Patients on select concomitant medications (n=37) had an ORR of 73.0%; DOR was not estimable.. Administration of sonidegib with concomitant medications, excluding strong cytochrome P450 3A4/5 inhibitors/inducers, does not appear to alter its efficacy in laBCC patients.

Topics: Aged; Biphenyl Compounds; Carcinoma, Basal Cell; Humans; Pyridines; Skin Neoplasms

The BOLT study for sonidegib, a Hedgehog pathway inhibitor (HHI) approved for patients with locally advanced basal cell carcinoma (laBCC) not amenable to curative surgery or radiotherapy, used modified Response Evaluation Criteria in Solid Tumors (mRECIST) for laBCC tumor evaluation. The ERIVANCE study for vismodegib, another HHI, used a composite RECIST endpoint of ≥30% reduction in externally visible tumor or radiographic dimension, or complete ulceration resolution. This preplanned sensitivity BOLT analysis evaluated efficacy outcomes using ERIVANCE-like criteria in patients with laBCC who received sonidegib 200 mg once daily.. This phase 2, double-blind study randomized patients 1:2 to sonidegib 200:800 mg daily, respectively. Key endpoints included objective response rate (ORR), duration of response (DOR), complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). laBCC tumors were assessed by both mRECIST and ERIVANCE-like criteria. Per mRECIST, an overall response of CR was based on negative histology; photographic assessment of CR, PR (scar/fibrosis only), SD (scar/fibrosis only), or not available (NA); and a magnetic resonance imaging response of CR or NA. An overall response of CR was primarily based on negative histology using ERIVANCE-like criteria.. Per mRECIST criteria, ORR (95% confidence interval [CI]) by central and investigator review for patients with laBCC (n = 66) was 56.1% (43.3-68.3%) and 71.2% (58.7-81.7%), respectively. CR per central review was achieved in 3 (4.5%) patients and PR, SD, and PD occurred in 34 (51.5%), 23 (34.8%), and 1 (1.5%) patient, respectively. Median (95% CI) DOR was 26.1 months (not estimable [NE]). Using ERIVANCE-like criteria, efficacy outcomes per central and investigator review were higher, with an ORR (95% CI) of 60.6% (47.8-72.4%) and 74.2% (62.0-84.2%), respectively. CR per central review was reached in 14 (21.2%) patients and PR, SD, and PD occurred in 26 (39.4%), 20 (30.3%), and 1 (1.5%) patient, respectively. DOR was unchanged with a median (95% CI) of 26.1 months (NE).. Overall, applying ERIVANCE-like criteria to patients with laBCC receiving sonidegib 200 mg daily yielded higher response rates vs mRECIST criteria.. BOLT registration: ClinicalTrials.gov ( NCT01327053 ) on March 30, 2011.

Topics: Adult; Anilides; Biphenyl Compounds; Carcinoma, Basal Cell; Confidence Intervals; Disease Progression; Double-Blind Method; Drug Administration Schedule; Humans; Pyridines; Response Evaluation Criteria in Solid Tumors; Skin Neoplasms; Treatment Outcome

Topics: Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Double-Blind Method; Humans; Pyridines; Skin Neoplasms; Treatment Outcome

Basal cell carcinomas (BCCs) exhibit aberrant activation of the hedgehog pathway. Sonidegib is a hedgehog pathway inhibitor approved for the treatment of locally advanced BCC (laBCC) and metastatic BCC (mBCC) based on primary results of the BOLT study [Basal Cell Carcinoma Outcomes with LDE225 (sonidegib) Treatment].. This is the final 42-month analysis of the BOLT study, evaluating the efficacy and safety of sonidegib.. Adults with no prior hedgehog pathway inhibitor therapy were randomized in a 1 : 2 ratio to sonidegib 200 mg or 800 mg once daily. Treatment continued for up to 42 months or until disease progression, unacceptable toxicity, death, study termination or withdrawal of consent. The primary efficacy end point was the objective response rate (ORR) by central review, assessed at baseline; weeks 5, 9 and 17; then subsequently every 8 or 12 weeks during years 1 or 2, respectively. Safety end points included adverse event monitoring and reporting.. The study enrolled 230 patients, 79 and 151 in the 200-mg and 800-mg groups, respectively, of whom 8% and 3.3% remained on treatment by the 42-month cutoff, respectively. The ORRs by central review were 56% [95% confidence interval (CI) 43-68] for laBCC and 8% (95% CI 0·2-36) for mBCC in the 200-mg group and 46·1% (95% CI 37·2-55·1) for laBCC and 17% (95% CI 5-39) for mBCC in the 800-mg group. No new safety concerns emerged.. Sonidegib demonstrated sustained efficacy and a manageable safety profile. The final BOLT results support sonidegib as a viable treatment option for laBCC and mBCC. What's already known about this topic? Basal cell carcinoma (BCC) is usually treatable with surgery or radiation therapy, but there are limited treatment options for patients with advanced BCC. Sonidegib, a hedgehog pathway inhibitor approved for the treatment of advanced BCC, demonstrated clinically relevant efficacy and manageable safety in prior analyses of the phase II randomized, double-blind BOLT study [Basal Cell Carcinoma Outcomes with LDE225 (sonidegib) Treatment]. What does this study add? This final 42-month analysis of BOLT is the longest follow-up available for a hedgehog pathway inhibitor. Clinically relevant efficacy results were sustained from prior analyses, with objective response rates by central review of the approved 200-mg daily dose of 56% in locally advanced BCC and 8% in metastatic BCC. No new safety concerns were raised. The results confirmed sonidegib as a viable long-term treatment option for patients with advanced BCC.

Topics: Adult; Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Hedgehog Proteins; Humans; Pyridines; Skin Neoplasms

Patients with locally advanced basal cell carcinoma (laBCC) or metastatic BCC (mBCC), two difficult-to-treat populations, have had limited treatment options. Sonidegib, a hedgehog pathway inhibitor (HPI), was approved in laBCC based on results from the BOLT trial.. To evaluate long-term efficacy and safety of sonidegib in laBCC and mBCC in the BOLT 18- and 30-month analyses.. BOLT (NCT01327053, ClinicalTrials.gov), a double-blind phase 2 study, enrolled patients from July 2011 until January 2013. Eligible HPI-treatment-naïve patients with laBCC not amenable to curative surgery/radiotherapy or mBCC were randomized 1 : 2 to sonidegib 200 mg (laBCC, n = 66; mBCC, n = 13) or 800 mg (laBCC, n = 128; mBCC, n = 23). Tumour response was assessed per central and investigator review.. With 30 months of follow-up, among patients treated with sonidegib 200 mg (approved dose), objective response rates were 56.1% (central) and 71.2% (investigator) in laBCC and 7.7% (central) and 23.1% (investigator) in mBCC. Tumour responses were durable as follows: median duration of response was 26.1 months (central) and 15.7 months (investigator) in laBCC and 24.0 months (central) and 18.1 months (investigator) in mBCC. Five patients with laBCC and three with mBCC in the 200-mg arm died. Median overall survival was not reached in either population; 2-year overall survival rates were 93.2% (laBCC) and 69.3% (mBCC). In laBCC, efficacy was similar regardless of aggressive or non-aggressive histology. Sonidegib 200 mg continued to have a better safety profile than 800 mg, with lower rates of grade 3/4 adverse events (43.0% vs. 64.0%) and adverse events leading to discontinuation (30.4% vs. 40.0%).. Sonidegib continued to demonstrate long-term efficacy and safety in these populations. These data support the use of sonidegib 200 mg per local treatment guidelines.

Topics: Adult; Aged; Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Double-Blind Method; Female; Follow-Up Studies; Hedgehog Proteins; Humans; Male; Middle Aged; Neoplasm Metastasis; Pyridines; Skin Neoplasms; Survival Rate; Treatment Outcome

Sonidegib, a hedgehog pathway inhibitor, was approved by the US FDA for the treatment of locally advanced basal cell carcinoma which cannot be readily treated with surgery or radiotherapy. The pharmacology and pharmacokinetics of sonidegib will be discussed in this review. Additionally, an in-depth analysis of the BOLT trial and data from the 30-month update will be included. This will serve as an update to a previously published article which reported the 12-month update of the BOLT trial.

Topics: Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Follow-Up Studies; Humans; Molecular Targeted Therapy; Pyridines; Skin Neoplasms; Treatment Outcome

To assess the tumor response to the smoothened (SMO) inhibitor, sonidegib (LDE225), in patients with an advanced basal cell carcinoma (BCC) resistant to treatment with vismodegib (GDC0449).. Nine patients with an advanced BCC that was previously resistant to treatment with vismodegib were given sonidegib in this investigational, open-label study. Tumor response was determined using the response evaluation criteria in solid tumors. SMO mutations were identified using biopsy samples from the target BCC location.. The median duration of treatment with sonidegib was 6 weeks (range, 3-58 weeks). Five patients experienced progressive disease with sonidegib. Three patients experienced stable disease and discontinued sonidegib either due to adverse events (n = 1) or due to election for surgery (n = 2). The response of one patient was not evaluable. SMO mutations with in vitro data suggesting resistance to Hh pathway inhibition were identified in 5 patients, and none of these patients experienced responses while on sonidegib.. Patients with advanced BCCs that were previously resistant to treatment with vismodegib similarly demonstrated treatment resistance with sonidegib. Patients who have developed treatment resistance to an SMO inhibitor may continue to experience tumor progression in response to other SMO inhibitors.

Topics: Adult; Aged; Aged, 80 and over; Anilides; Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Drug Resistance, Neoplasm; Female; Humans; Male; Middle Aged; Models, Molecular; Mutation; Neoplasm Staging; Protein Conformation; Pyridines; Retreatment; Skin Neoplasms; Smoothened Receptor; Treatment Outcome

The hedgehog pathway inhibitor sonidegib demonstrated meaningful tumor shrinkage in more than 90% of patients with locally advanced basal cell carcinoma (BCC) or metastatic BCC in the BCC Outcomes with LDE225 Treatment study.. This report provides long-term follow-up data collected up to 12 months after the last patient was randomized.. In this multicenter, randomized, double-blind phase II study, patients were randomized 1:2 to sonidegib 200 or 800 mg. The primary end point was objective response rate assessed by central review.. Objective response rates in the 200- and 800-mg arms were 57.6% and 43.8% in locally advanced BCC and 7.7% and 17.4% in metastatic BCC, respectively. Among the 94 patients with locally advanced BCC who responded, only 18 progressed or died and more than 50% had responses lasting longer than 6 months. In addition, 4 of 5 responders with metastatic BCC maintained an objective response. Grade 3/4 adverse events and those leading to discontinuation were less frequent with sonidegib 200 versus 800 mg (38.0% vs 59.3%; 27.8% vs 37.3%, respectively).. No placebo or comparator arms were used because sonidegib demonstrated efficacy in advanced BCC in a phase I study, and the hedgehog pathway inhibitor vismodegib was not yet approved.. With longer follow-up, sonidegib demonstrated sustained tumor responses in patients with advanced BCC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Disease Progression; Double-Blind Method; Female; Humans; Male; Middle Aged; Pyridines; Skin Neoplasms; Smoothened Receptor; Survival Rate; Young Adult

Patients with advanced basal cell carcinoma have limited treatment options. Hedgehog pathway signalling is aberrantly activated in around 95% of tumours. We assessed the antitumour activity of sonidegib, a Hedgehog signalling inhibitor, in patients with advanced basal cell carcinoma.. BOLT is an ongoing multicentre, randomised, double-blind, phase 2 trial. Eligible patients had locally advanced basal cell carcinoma not amenable to curative surgery or radiation or metastatic basal cell carcinoma. Patients were randomised via an automated system in a 1:2 ratio to receive 200 mg or 800 mg oral sonidegib daily, stratified by disease, histological subtype, and geographical region. The primary endpoint was the proportion of patients who achieved an objective response, assessed in the primary efficacy analysis population (patients with fully assessable locally advanced disease and all those with metastatic disease) with data collected up to 6 months after randomisation of the last patient. This trial is registered with ClinicalTrials.gov, number NCT01327053.. Between July 20, 2011, and Jan 10, 2013, we enrolled 230 patients, 79 in the 200 mg sonidegib group, and 151 in the 800 mg sonidegib group. Median follow-up was 13·9 months (IQR 10·1-17·3). In the primary efficacy analysis population, 20 (36%, 95% CI 24-50) of 55 patients receiving 200 mg sonidegib and 39 (34%, 25-43) of 116 receiving 800 mg sonidegib achieved an objective response. In the 200 mg sonidegib group, 18 (43%, 95% CI 28-59) patients who achieved an objective response, as assessed by central review, were noted among the 42 with locally advanced basal cell carcinoma and two (15%, 2-45) among the 13 with metastatic disease. In the 800 mg group, 35 (38%, 95% CI 28-48) of 93 patients with locally advanced disease had an objective response, as assessed by central review, as did four (17%, 5-39) of 23 with metastatic disease. Fewer adverse events leading to dose interruptions or reductions (25 [32%] of 79 patients vs 90 [60%] of 150) or treatment discontinuation (17 [22%] vs 54 [36%]) occurred in patients in the 200 mg group than in the 800 mg group. The most common grade 3-4 adverse events were raised creatine kinase (five [6%] in the 200 mg group vs 19 [13%] in the 800 mg group) and lipase concentration (four [5%] vs eight [5%]). Serious adverse events occurred in 11 (14%) of 79 patients in the 200 mg group and 45 (30%) of 150 patients in the 800 mg group.. The benefit-to-risk profile of 200 mg sonidegib might offer a new treatment option for patients with advanced basal cell carcinoma, a population that is difficult to treat.. Novartis Pharmaceuticals Corporation.

Topics: Adult; Aged; Aged, 80 and over; Biphenyl Compounds; Carcinoma, Basal Cell; Disease-Free Survival; Double-Blind Method; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Pyridines; Skin Neoplasms; Treatment Outcome

Basal cell carcinoma (BCC) is a distinctive manifestation in nevoid basal cell carcinoma syndrome (NBCCS) patients. Both inherited and acquired mutations of patched 1 (PTCH1), a tumor-suppressor gene controlling the activity of Smoothened (SMO), are the primary cause of the constitutive activation of the Hedgehog (HH) pathway, leading to the emergence of BCCs in NBCCS. LDE225, a distinct, selective antagonist of SMO, showed potent inhibition of basaloid tumor nest formation and mediated regression of preformed basaloid tumors in organ cultures of skin derived from Ptch1 heterozygous knockout mice. In a double-blind, randomized, vehicle-controlled, intraindividual study, a total of 8 NBCCS patients presenting 27 BCCs were treated twice daily with 0.75% LDE225 cream or vehicle for 4 weeks. Application of 0.75% LDE225 cream was well tolerated and showed no skin irritation. Of 13 LDE225-treated BCCs, 3 showed a complete, 9 a partial, and only 1 no clinical response. Except for one partial response, the vehicle produced no clinical response in any of the 14 treated BCCs. Treatment with 0.75% LDE225 cream in NBCCS patients was very well tolerated and caused BCC regression, thus potentially offering an attractive therapeutic alternative to currently available therapies for this indication.JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article, please go to http://www.nature.com/jid/journalclub.

Topics: Administration, Topical; Animals; Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Female; Hair; Hedgehog Proteins; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Organ Culture Techniques; Patched Receptors; Patched-1 Receptor; Pregnancy; Pyridines; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Signal Transduction; Skin Neoplasms; Smoothened Receptor

A man in his 50s presented with an ulcerative lesion within the left axillary fold that had progressively worsened over 18 months. Biopsy revealed an ulcerative basal cell carcinoma (BCC), which was surgically managed. CT chest scans done 7 months later assessed post-treatment of radiotherapy. This revealed pulmonary lesions, which were biopsy-proven metastatic BCC. Sonidegib, a hedgehog signalling inhibitor, was used for first-line treatment. Due to progressive disease, sonidegib was ceased. Cemiplimab, a checkpoint inhibitor, was used as second-line treatment based on a phase II trial demonstrating efficacy in the setting of metastatic BCC. CT reports were initially consistent with response but after 6 months of cemiplimab treatment, repeat CT chest scans revealed a decrease in size of the previously cited pulmonary lesions.This is a rare case of BCC metastases which has limited treatment options. This case provides insight of the patient experience on such treatment.

Topics: Carcinoma, Basal Cell; Hedgehog Proteins; Humans; Lung Neoplasms; Male; Pyridines; Skin Neoplasms

Topics: Carcinoma, Basal Cell; Humans; Retreatment; Skin Neoplasms

Topics: Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Humans; Liver Transplantation; Skin Neoplasms

Advanced basal cell carcinoma (aBCC) represents a complex and clinically heterogeneous group of lesions for which curative surgery and/or radiotherapy is unlikely. Systemic therapy with hedgehog pathway inhibitors (HHIs) changed the treatment landscape for this complex patient population.. The aims of the present study are to describe the clinical characteristics of a real-life Italian cohort diagnosed with aBCC and to investigate effectiveness and safety of HHI.. A multicenter observational study was performed by twelve Italian centers in the period January 1, 2016 - October 15, 2022. Patients aged ≥18 years and diagnosed with aBCC (locally advanced [laBCC] and metastatic BCC [mBCC]) were eligible for the study. Methods for investigating tumor response to HHI included clinical and dermatoscopic evaluation, radiological imaging, and histopathology. For HHI safety assessment, therapy-related adverse events (AEs) were reported and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.. We enrolled 178 patients under treatment with HHI: 126 (70.8%) and 52 patients (29.2%) received sonidegib and vismodegib, respectively. Comprehensive data on HHI effectiveness and disease outcome were available for 132 (74.1%) of 178 patients: 129 patients had a diagnosis of laBCC (n = 84, sonidegib; n = 45, vismodegib) and 3 patients of mBCC (n = 2, vismodegib; n = 1, sonidegib, off-label). Objective response rate was 76.7% (95% confidence interval [CI]: 82.3-68.7) and 33.3% (95% CI: 88.2-1.7) for laBCC (complete response [CR]: 43/129; PR: 56/129) and mBCC (CR: 0/3; PR: 1/3), respectively. High-risk aBCC histopathological subtypes and occurrence of >2 therapy-related AEs were significantly associated with nonresponse to HHI therapy ([OR: 2.61; 95% CI: 1.09-6.05; p: 0.03] and [OR: 2.74; 95% CI: 1.03-7.9; p: 0.04]), respectively. Majority of our cohort (54.5%) developed at least 1 therapy-related AE, most of which were mild-moderate in severity.. Our results demonstrate the effectiveness and safety profile of HHI and confirm the reproducibility of pivotal trial results in real-life clinical setting.

Topics: Adolescent; Adult; Anilides; Antineoplastic Agents; Carcinoma, Basal Cell; Hedgehog Proteins; Humans; Reproducibility of Results; Skin Neoplasms

Topics: Biphenyl Compounds; Carcinoma, Basal Cell; Carcinoma, Basosquamous; Humans; Neoadjuvant Therapy; Skin Neoplasms

Nevoid basal-cell carcinoma syndrome (Gorlin syndrome) is characterized by numerous cutaneous basal cell carcinomas mediated by mutations in the hedgehog pathway. Vismodegib or sonidegib represent promising treatment options. We identified 10 Gorlin patients who were treated with sonidegib (

Topics: Basal Cell Nevus Syndrome; Carcinoma, Basal Cell; Hedgehog Proteins; Humans; Skin Neoplasms

Basal cell carcinoma (BCC) is the most common cancer worldwide. While most BCC cases respond to surgical management, complex BCC often presents treatment challenges for patients unsuitable for, or refractory to, surgery and radiotherapy-limiting treatment options. Hedgehog pathway inhibitors (HHI) have emerged as an important treatment option for patients with complex BCC-providing a durable treatment modality and improved clinical outcomes. We present a case series of 10 patients with complex BCC treated with sonidegib, an oral HHI, at a dose of 200 mg once daily for a mean duration of 6 months and a mean follow-up of 7 months. Of these patients, sonidegib monotherapy was curative in eight cases. Of the remaining two patients, treatment with sonidegib arrested tumor progression and decreased tumor size to a point where surgical removal was straightforward. The positive treatment response we observed supports use of sonidegib as an effective treatment option for patients with complex BCC.

Topics: Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Hedgehog Proteins; Humans; Pyridines; Skin Neoplasms

Topics: Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Hedgehog Proteins; Humans; Pyridines; Skin Neoplasms

Topics: Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Humans; Pyridines; Skin Neoplasms

A 78-year-old woman was referred to our skin cancer centre with three previous incomplete resections in the left cavum conchae of a deep-infiltrating locally advanced, but still asymptomatic basal cell carcinoma (BCC). The patient noted furthermore two rapidly growing exophytic lesions in the left preauricular and cervical area in the last weeks. The clinical and histological distinction of locally advanced from metastatic cutaneous squamous cell carcinoma (CSCC) lesions was challenging. Imaging analysis with CT scans showed, however, an involvement of the parotid gland as well as multiple small lymph node metastases. The interdisciplinary tumour board decision at our institution recommended a systemic treatment with the PD1-antibody cemiplimab. After 13 cycles with cemiplimab at a dose of 350 mg intravenously every 3-weeks, the patient showed a complete response of the two CSCC lesions with histological confirmation. However, the BCC of the left ear appeared to be unchanged and still asymptomatic. The interdisciplinary tumour board considered this tumour to be no candidate for a curative resection or irradiation. Therefore, the patient was exposed to the hedgehog inhibitor sonidegib with a conventional dose of 200 mg orally per day. After 3 months of treatment, the tumour showed a markable regression and a complete response was confirmed by 3-punch biopsies from this preoperated lesion. Both cemiplimab and sonidegib were excellently tolerated with almost no adverse events apart from a mild fatigue (CTC grade 1) over the first 3 weeks of the cemiplimab therapy. There were no laboratory abnormalities found.

Topics: Aged; Antibodies, Monoclonal, Humanized; Biphenyl Compounds; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Epithelial Cells; Female; Hedgehog Proteins; Humans; Pyridines; Skin Neoplasms

Topics: Biphenyl Compounds; Carcinoma, Basal Cell; COVID-19; Humans; Pandemics; Pyridines; Skin Neoplasms

Topics: Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Humans; Pyridines; Skin Neoplasms

Topics: Antibodies, Monoclonal, Humanized; Biphenyl Compounds; Carcinoma, Basosquamous; Humans; Pyridines; Skin Neoplasms

Topics: Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Carcinoma, Basosquamous; Humans; Pyridines; Skin Neoplasms

In recent years, the category of hedgehog pathway inhibitor (HHI) has shown great results in patients with advanced basal cell carcinoma (aBCC), but few real-life data on efficacy and safety profile of sonidegib are available. We report our management of locally advanced BCCs (laBCCs) with sonidegib, also describing the favorable response of locally advanced basosquamous carcinomas (laBSCs) treated with this hedgehog signaling inhibitor. Sonidegib was generally well tolerated and it achieved high response rates, improving quality of life. Our single-center experience could be useful to better delineate long-term efficacy and tolerability profile demonstrated in the trials described in literature. Moreover, our cases provide preliminary evidence that sonidegib might be effective for laBSC.

Topics: Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Hedgehog Proteins; Humans; Pyridines; Quality of Life; Skin Neoplasms

Topics: Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Hedgehog Proteins; Humans; Pyridines; Skin Neoplasms

Topics: Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Humans; Pyridines; Skin Neoplasms; Spasm

Sonidegib, a hedgehog pathway inhibitor, is indicated for treatment of locally advanced basal cell carcinoma, based on the results of the BOLT study. However, to date, no real-world study of sonidegib has been reported. An observational, retrospective, single-centre study (PaSoS study) was conducted. The primary objective was to evaluate the efficacy of sonidegib for treatment of locally advanced basal cell carcinoma in a real-world setting. Secondary objectives included modalities of use, tolerability, tumour evolution, and management after discontinuation. A total of 21 patients treated with sonidegib were included from March 2018 to January 2021. The median follow-up was 18.7 months and median exposure 7.0 months. Objective response (OR) rate was 81.0% (n = 17) including 6 (29%) patients with a complete response (CR). Disease control rate was 100%. First tumour response was rapid, with a median time of 2.3 months. Nine (43%) patients underwent surgery after sonidegib discontinuation, and no relapse was observed. All the patients experienced at least 1 adverse event (AE). Muscle spasms were the most frequent AE (n = 14; 67%), followed by dysgeusia (n = 8; 38%) and alopecia (n = 12; 57%). The efficacy and safety profile of sonidegib in this first-to-date real-life trial are consistent with prior results. Overall, real-world evidence corroborated sonidegib efficacy and tolerability as a first-line treatment for locally advanced basal cell carcinoma.

Topics: Antineoplastic Agents; Carcinoma, Basal Cell; Hedgehog Proteins; Humans; Neoplasm Recurrence, Local; Retrospective Studies; Skin Neoplasms

Topics: Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Female; Humans; Pyridines; Skin Neoplasms; Vulva

Topics: Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Humans; Pyridines; Skin Neoplasms

Topics: Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Dermoscopy; Female; Hamartoma Syndrome, Multiple; Humans; Middle Aged; Pyridines; Skin Neoplasms

Topics: Aged; Aged, 80 and over; Alopecia; Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Drug Tapering; Dysgeusia; Female; Hedgehog Proteins; Humans; Male; Molecular Targeted Therapy; Neoplasm Proteins; Pyridines; Retrospective Studies; Skin Neoplasms; Smoothened Receptor; Spasm; Treatment Outcome; Weight Loss

Topics: Biphenyl Compounds; Carcinoma, Basal Cell; Hamartoma Syndrome, Multiple; HIV Infections; Humans; Pyridines; Skin Neoplasms

Locally advanced basal cell carcinoma (laBCC) represents a rare but possible occurrence in the vast scenario of dermatological diseases. It is well known that most BCC has a pathological activation of the hedgehog pathway, making them susceptible to targeted therapy with selective inhibitors. Sonidegib, approved for the treatment of laBCC on the basis of the results of the basal cell carcinoma outcomes with LDE225 treatment study, demonstrated rapid efficacy and a manageable safety profile. Here, we describe the case of a patient affected by multiple laBCC treated with Sonidegib. The patient experienced an important regression of tumors after only 2 months of therapy, with few side effects. This result confirms the role of Sonidegib as a valid and well-tolerated therapeutic option for laBCC.

Topics: Aged; Biphenyl Compounds; Carcinoma, Basal Cell; Clinical Trials, Phase II as Topic; Hedgehog Proteins; Humans; Male; Molecular Targeted Therapy; Pyridines; Randomized Controlled Trials as Topic; Skin Neoplasms

Topics: Biphenyl Compounds; Carcinoma, Basal Cell; Humans; Pyridines; Skin Neoplasms

Topics: Anilides; Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Humans; Pyridines; Skin Neoplasms

Topics: Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Communicable Diseases; Humans; Pyridines; Skin Neoplasms

Topics: Biphenyl Compounds; Carcinoma, Basal Cell; Humans; Pyridines; Skin Neoplasms

Topics: Aged; Anilides; Biphenyl Compounds; Carcinoma, Basal Cell; Dysgeusia; Female; Humans; Male; Middle Aged; Muscle Cramp; Nausea; Pyridines; Skin Neoplasms

Topics: Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Double-Blind Method; Hedgehog Proteins; Humans; Pyridines; Skin Neoplasms

Topics: Anilides; Antineoplastic Agents; Antineoplastic Agents, Immunological; Biphenyl Compounds; Carcinoma, Squamous Cell; Clinical Trials as Topic; Drugs, Investigational; Humans; Molecular Targeted Therapy; Pyridines; Skin Neoplasms

Topics: Aged; Anilides; Betacoronavirus; Biphenyl Compounds; Carcinoma, Basal Cell; Coronavirus Infections; COVID-19; Disease Management; Female; Hedgehog Proteins; Humans; Italy; Male; Medication Adherence; Pandemics; Pneumonia, Viral; Pyridines; SARS-CoV-2; Skin Neoplasms; Telemedicine

Topics: Aged; Biphenyl Compounds; Carcinoma, Basal Cell; COVID-19; Humans; Male; Pyridines; SARS-CoV-2; Skin Neoplasms

Topics: Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Hospitals; Humans; Italy; Pyridines; Skin Neoplasms

Topics: Aged; Aged, 80 and over; Anilides; Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Female; Follow-Up Studies; Hedgehog Proteins; Humans; Male; Middle Aged; Progression-Free Survival; Pyridines; Retrospective Studies; Signal Transduction; Skin Neoplasms

Topics: Aged; Aged, 80 and over; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Biphenyl Compounds; Carcinoma, Basal Cell; Cohort Studies; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Morpholines; Neoplasm Invasiveness; Neoplasm Staging; Prognosis; Prospective Studies; Pyridines; Skin Neoplasms; Survival Analysis; Treatment Outcome

Topics: Alopecia; Anilides; Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Creatine Kinase; Dysgeusia; Female; Hedgehog Proteins; Humans; Muscular Diseases; Ovarian Diseases; Pyridines; Skin Neoplasms; Weight Loss

Topics: Biphenyl Compounds; Carcinoma, Basal Cell; Humans; Pyridines; Skin Neoplasms

Topics: Biphenyl Compounds; Carcinoma, Basal Cell; Humans; Pyridines; Skin Neoplasms

Topics: Animals; Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Cell Differentiation; Cell Proliferation; Chorda Tympani Nerve; Disease Models, Animal; Dysgeusia; Hedgehog Proteins; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Pyridines; Recovery of Function; Signal Transduction; Skin Neoplasms; Smoothened Receptor; Stem Cells; Taste; Taste Buds; Tongue

Topics: Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Drug Interactions; Humans; Pyridines; Rhabdomyolysis; Skin Neoplasms; Smoothened Receptor; Teratogens

The hedgehog (Hh) signaling pathway is aberrantly activated in a majority of basal cell carcinomas (BCC). Vismodegib and sonidegib are targeted inhibitors of Smoothened (SMO). Both drugs are approved for use in locally advanced BCC (laBCC), with vismodegib also approved for metastatic BCC (mBCC).

Topics: Anilides; Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Hedgehog Proteins; Humans; Pyridines; Receptors, G-Protein-Coupled; Signal Transduction; Skin Neoplasms; Smoothened Receptor; Translational Research, Biomedical

Basal cell carcinoma (BCC), although mostly locally confined, is the most common cancer. Most BCCs harbor inactivating mutations in the membrane receptor/gene Ptch, thereby activating the Hedgehog signaling pathway (Hh) via the essential signaling molecule Smoothened (SMO). Novel small-molecule inhibitors or antagonists of SMO have shown excellent response rates in patients with locally advanced, unresectable and metastatic BCC in roughly 35-60% of patients, with disease control rates and clinical benefit being even higher. Sonidegib is the second-in-class SMO inhibitor approved for locally advanced, unresectable and metastatic BCC. Sonidegib is given once daily continuously, with specific side effects as listed in the label indication. Resistance develops over time and knowledge gleaned from other SMO inhibitors indicates that SMO mutations preventing drug binding as well as mechanisms activating the Hh pathway downstream of SMO are responsible, ultimately reactivating Hh pathway signaling. The next challenge will be to define novel salvage and SMO combination strategies for BCC and other tumors.

Topics: Biphenyl Compounds; Carcinoma, Basal Cell; Clinical Trials as Topic; Drug Interactions; Hedgehog Proteins; Humans; Pyridines; Receptors, G-Protein-Coupled; Signal Transduction; Skin Neoplasms; Smoothened Receptor

Medications in dermatology are used in a variety of different methods and dosages and for numerous different diseases entities that are not approved by the US Food and Drug Administration (FDA); however, there are medications that have only recently hit the market that require our attention, as they are either FDA approved for the intended dermatologic use or could be effective in treating conditions that previously have been poorly managed.

Topics: Aminolevulinic Acid; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Arthritis, Psoriatic; Azetidines; Biphenyl Compounds; Carcinoma, Basal Cell; Cosmetic Techniques; Deoxycholic Acid; Dermatologic Agents; Drug Approval; Facial Dermatoses; Humans; Keratosis, Actinic; Melanoma; Oncolytic Virotherapy; Piperidines; Psoriasis; Pyridines; Scalp Dermatoses; Skin Neoplasms; United States; United States Food and Drug Administration

Topics: Adult; Aged; Alopecia; Anilides; Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Female; Hedgehog Proteins; Humans; Male; Middle Aged; Pyridines; Skin Neoplasms

Basal cell carcinomas (BCCs) are tumors ignored by immune surveillance. Activated Hedgehog (Hh) signaling within primary cilia is a key driver in the pathogenesis of BCCs. We examined immune alterations during treatment with systemic Hh inhibitors.. We investigated biopsies from patients with BCC before (23 patients) and after 4 weeks of treatment (5 patients) with Hh signaling inhibitor. Ber-Ep4, BCL-2, Ki-67, CD4, CD8, MHC class I, HLA-DR-class II, and SOX9 were analyzed by immunohistochemistry. Primary cilia were analyzed by double immunofluorescence of acetylated tubulin and SOX9. Differential gene expression for 84 cytokines and chemokines was analyzed in 3 patients.. After 4 weeks of treatment, we found reduction of Ki-67, SOX9, Ber-EP4, and BCL-2 expression in tumors associated with morphologic signs of squamous differentiation. In addition, the number of cilia-positive BCC cells was significantly decreased. An upregulation of MHC I expression on the cell membranes of residual tumor cells and an influx of CD4(+), HLA-DR-class II(+), and CD8(+) cells with invasion into the tumor cell nests were found. Finally, qPCR arrays showed the differential expression of genes involved in modulating immune responses.. We show that Hh pathway inhibitor-induced tumor regression is accompanied by a dynamic change of the microenvironment with a disruption of immune privilege involving an influx of cytotoxic T cells, activation of the adaptive immune functions, and a profound alteration of the local chemokine/cytokine network.

Topics: Adaptive Immunity; Aged; Aged, 80 and over; Anilides; Biopsy; Biphenyl Compounds; Carcinoma, Basal Cell; CD4-Positive T-Lymphocytes; Cilia; Cytokines; Female; Hedgehog Proteins; HLA-DR Antigens; Humans; Lymphocyte Activation; Male; Middle Aged; Pyridines; Receptors, G-Protein-Coupled; Signal Transduction; Skin Neoplasms; Smoothened Receptor; T-Lymphocytes, Cytotoxic

Oral hedgehog inhibitors (HHIs) have shown significant efficacy in the treatment of basal cell carcinoma (BCC). The evaluation of tumor regression has been performed using clinical photography and radiographic scans. Noninvasive imaging techniques, such as reflectance confocal microscopy (RCM) and high-definition optical coherence tomography (HD-OCT), have been shown to be valuable in detecting BCC in the skin.. We monitored HHI-treated BCC using RCM and HD-OCT in vivo and correlated morphologic changes seen on imaging to changes in traditional histopathology.. Six BCCs in 5 patients receiving HHIs (vismodegib or sonidegib) were examined by RCM and HD-OCT before and during treatment. Characteristic features were compared to histopathologic findings, including immunohistochemical analysis.. Characteristic features of BCC in RCM and HD-OCT decreased or disappeared completely during HHI treatment. Half of the clinically complete responding tumors still featured tumor residue. Pseudocystic structures ("empty" tumor nests in imaging) and widespread fibrosis (coarse bright fibers) were new findings and could be confirmed by histopathology.. Our study was limited by the number of tumor samples and imaging timepoints.. Using RCM and HD-OCT, HHI-induced regression of BCC can be visualized noninvasively in the skin. The formation of pseudocysts and fibrosis were characteristic signs of BCC response to HHIs.

Topics: Administration, Oral; Aged; Anilides; Biopsy; Biopsy, Needle; Biphenyl Compounds; Carcinoma, Basal Cell; Cysts; Female; Follow-Up Studies; Germany; Hedgehog Proteins; Humans; Immunohistochemistry; Male; Microscopy, Confocal; Middle Aged; Monitoring, Physiologic; Neoplasm Invasiveness; Neoplasm Staging; Predictive Value of Tests; Prospective Studies; Pyridines; Remission Induction; Sampling Studies; Skin Neoplasms; Tomography, Optical Coherence; Treatment Outcome; Tumor Burden