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Purpose: To review the efficacy and safety of oral vismodegib (Erivedge; Genentech) in the management of locally advanced orbital and periorbital basal cell carcinoma (BCC)., Methods: A literature search was conducted last in September 2023 in the PubMed database for English language original research that evaluated the effect of oral vismodegib on orbital and periorbital BCC. Sixty articles were identified and 16 met the inclusion criteria., Results: Most studies demonstrated high response rates, with up to 100% of patients responding to the medication in individual studies and initial complete regression occurring in up to 88% of patients. Vismodegib treatment resulted in significant reductions in tumor volume, resulting in globe preservation for most patients. However, in 12% of patients, the response was partial. Recurrences also occurred with substantial frequency, even after an initial complete response. As such, up to 79.4% of patients required surgical intervention, and up to 23% of patients still required exenteration. Use of these agents resulted in reductions in tumor volume that may delay or prevent the need for exenteration in some, but not all, patients. Importantly, molecular analysis of tissue excised after vismodegib therapy revealed persistent tumor in all patients, with frequent accumulation of mutations that may confer resistance to further hedgehog inhibitor therapy. Although most adverse events were rated as level I or II, side effects were common, with up to 100% of patients in studies experiencing at least 1 event. Muscle cramps, alopecia, weight loss, fatigue, and dysgeusia were the most common adverse events, and several patients discontinued therapy because of them. Furthermore, 1 patient died of sepsis that may have resulted from the therapy., Conclusions: Although level I and II evidence are lacking, most studies indicate a benefit from the use of oral vismodegib to treat orbital and periorbital BCC tumor volume. However, patients should be cautioned about the adverse side effects of treatment and the persistence of tumor cells with mutations that may cause long-term resistance. Use of vismodegib as short-term neoadjuvant therapy may be effective in shrinking tumor volume to reduce surgical morbidity while reducing the frequency and severity of side effects., Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Several studies have been published describing development of cutaneous malignancy after vismodegib therapy; no systematic review has been conducted to interpret these data. Our objective was to systemically review reported cases of same-site or different-site cutaneous malignancy after smoothened inhibitor (SMOi) therapy for primary basal cell carcinoma (BCC). PubMed, CINAHL, and Scopus were systematically searched January 1, 2012 - March 28, 2024. Inclusion criteria: primary BCC, SMOi therapy, and biopsy-proven secondary malignancy. Exclusion criteria: non-human subjects. Bias was assessed using Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) tool. Twenty-three cases describing same-site secondary malignancy were included. Average patient age was 67.2 years, mean treatment time 8.4 months, and average latency period to secondary malignancy development of 10.2 months. Five cases describing different-site secondary cutaneous malignancies were included. Mean patient age was 80.4 years, mean treatment time 2.9 months, and mean latency period 4.5 months. Twenty-seven cases were associated with vismodegib, while one case described vismodegib then sonidegib therapy. Pathologies included squamous cell carcinoma, BCC, basosquamous carcinoma, and malignant melanoma. The mechanism(s) by which same-site and different-site secondary malignancy occur are not known; mechanisms may differ depending on location type and secondary tumor type. We discuss multiple mechanistic hypotheses including pharmacologic selective pressure leading to hedgehog pathway mutant cells and activation of pro-growth signaling, and potential protective effect of hedgehog inhibition from melanoma given reports of rapid growth after SMOi discontinuation. This study is limited by the small number of reported cases. Additional research is needed to investigate these hypotheses., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Hedgehog pathway inhibitors (HHIs) have broadened the treatment options available for patients with advanced basal cell carcinoma (BCC) for whom traditional therapeutic approaches are not feasible or effective. Sonidegib and vismodegib are oral HHIs that were approved for treatment of patients with advanced BCC after demonstrating promising efficacy in the pivotal Phase II BOLT (NCT01327053) and ERIVANCE (NCT00833417) trials, respectively. However, the incidence and types of treatment-emergent adverse events (AEs) observed with these agents may limit continuous use of HHIs and ultimately impact clinical outcomes. In this review, we summarize the safety and tolerability profiles of sonidegib and vismodegib and discuss potential management strategies for HHI class-effect AEs, including muscle spasms, creatine phosphokinase increase, alopecia, and dysgeusia. These AEs primarily occur early in treatment and can lead to treatment discontinuation. Differences in the pharmacokinetic profiles of sonidegib and vismodegib may contribute to the variability noted in times to onset and resolution of these and other AEs. Evidence suggests that protocol modifications, such as treatment interruptions and dose reductions, are effective ways to manage AEs while maintaining disease control. Nonpharmacologic and pharmacologic interventions may also be considered as part of an AE management strategy. Overall, healthcare providers and patients with advanced BCC should be aware of the HHI class-effect AEs and plan effective management strategies to avoid treatment discontinuation and optimize therapeutic response., (© 2024. The Author(s).)

Purpose: Locally advanced, unresectable basal cell carcinoma (LA BCC) can be treated with radiation therapy (RT), but locoregional control (LRC) rates are unsatisfactory. Vismodegib is a hedgehog pathway inhibitor (HPI) active in BCC that may radiosensitize BCC. We evaluated the combination of vismodegib and RT for patients with LA BCC., Methods: In this multicenter, single-arm, phase II study, patients with unresectable LA BCC received 12 weeks of induction vismodegib, followed by 7 weeks of concurrent vismodegib and RT. The primary end point was LRC rate at 1 year after the end of treatment. Secondary end points included objective response, progression-free survival (PFS), overall survival (OS), safety, and patient-reported quality of life (PRQOL)., Results: Twenty-four patients received vismodegib; five were unable to complete 12 weeks of induction therapy. LRC was achieved in 91% (95% CI, 68 to 98) of patients at 1 year. The response rate was 63% (95% CI, 38 to 84) after induction vismodegib and 83% (95% CI, 59 to 96) after concurrent vismodegib and RT. With a median follow-up of 5.7 years, 1-year PFS and OS rates were 100% and 96%, and at 5 years PFS and OS rates were 78% and 83%, respectively. Distant metastasis or BCC-related death has not been observed. The most frequent treatment-related adverse events (AEs) were dysgeusia, fatigue, and myalgias occurring in 83%, 75%, and 75% of patients. No grade 4 to 5 treatment-related AEs occurred. PRQOL demonstrated clinically meaningful improvements in all subscales, with emotions and functioning improvements persisting for a year after the end of treatment., Conclusion: In patients with unresectable LA BCC, the combination of vismodegib and RT yielded high rates of LRC and PFS and durable improvements in PRQOL.

Introduction: In advanced basal cell carcinoma (BCC), the issue of whether Hedgehog inhibitors (HHIs) should be stopped or not after clinical complete response (cCR) achievement remains an unmet clinical need., Materials and Methods: We conducted a retrospective, multicenter study across 7 Italian dermato-oncology units including patients with BCC who continued vismodegib after cCR between 2012 and 2019. We assessed the relationship between the duration of vismodegib intake (days to cCR [DTCR], days to stop after cCR [DTS], total treatment days [TTD]), and disease-free survival (DFS). Reasons to stop vismodegib were (R1) toxicity and (R2) disease recurrence. The relationship between DTCR, DTS, TTD, and DFS in the whole population and in R1 subgroup was assessed by Pearson's correlation coefficient (P < .05) and Bayesian statistics (BF10)., Results: Sixty-eight BCC patients with a median (m) age of 75.5 years (39-100) were included. Most patients were male (N = 43, 63%), without Gorlin syndrome (N = 56, 82%) and with head and neck area as primary site (N = 51, 75%). After cCR, out of 68 patients, 90% (N = 61/68) discontinued vismodegib: 82% (N = 50/61) due to toxicity (R1), and 18% (N = 11/61) due to recurrence (R2). Conversely, 10% (N = 7/68) continued vismodegib until last follow-up. In the whole population (N = 68), cCR was achieved with a mDTCR of 180.50 days. DFS showed a significant correlation with DTS (P < .01, BF10 = 39.2) and TTD (P < .01, BF10 = 35566), while it was not correlated to DTCR (BF10 < 0.1). The analysis of R1 subgroup (N = 50) confirmed these results. DFS correlated with DTS in all recurrent patients (N = 38, r = 0.44, P < .01) and in the recurrent patients who stopped vismodegib for toxicity (N = 26, r = 0.665, P < .01). DFS was longer when vismodegib was maintained for >2 months after cCR (mDFS > 2 months, N = 54 vs. ≤ 2 months, N = 14: 470 vs. 175 d, P < .01)., Conclusions: Our retrospective results suggest that HHIs should be continued after cCR to improve DFS in BCC., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Basal cell carcinoma (BCC) is the most prevalent cancer. A minority of BCCs have an aggressive behaviour (laBCC) and may require hedgehog pathway inhibitors such as sonidegib as its treatment., Objective: To describe the use of sonidegib in a large number of patients and provide more data on its real-life efficacy and safety profile., Methods: We conducted a retrospective and multicentric study that included patients treated with sonidegib. Epidemiological, effectiveness and safety data were collected., Results: A total of 82 patients with a mean age of 73.9 years were included. Ten patients had Gorlin syndrome. Median treatment duration was 6 months. Median follow-up duration was 34.2 months. Globally, 81.7% of the patients showed clinical improvement (52.4% partial response and 29.3% complete response), 12.2% clinical stability and 6.1% disease progression. There was no statistically significant difference in clinical improvement between the 24h and 48h sonidegib posology. After 6 months of treatment, 48.8% of the patients discontinued sonidegib. Prior vismodegib treatment and recurrent primary BCC were associated with a poorer response to sonidegib. At 6 months of treatment, 68.3% of the patients experienced at least one adverse effect., Conclusion: Sonidegib shows good effectiveness and acceptable safety profile in usual clinical practice., (Copyright © 2023 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Introduction: Surgery is the standard management for most of basal cell carcinomas (BBCs). In some cases, also radiotherapy may be a valuable weapon as well as ablative and topical treatments. However, all these approaches may be limited by some tumor features. In this scenario, locally advanced BCCs (laBCC) and metastatic BCC, also defined as 'difficult-to-treat' BCC, remain the real treatment challenge. New knowledge on BCC pathogenesis, particularly the Hedgehog (HH) pathway, led to the development of new selective therapies such as vismodegib and sonidegib. In particular, sonidegib is an orally administered small molecules, which inhibits the HH signaling pathway through the binding to SMO receptor, recently approved for the management of adult patients with laBCC who are not amenable to curative surgery or radiation therapy., Areas Covered: The purpose of this review is to analyze and discuss the efficacy and safety of sonidegib for the management of BCC, to provide a broad perspective on the currently available data., Expert Opinion: Sonidegib is a valuable weapon for the management of difficult-to-treat BCC. Current data showed promising results in terms of effectiveness and safety. However, more studies are needed to underline its role in BCC management, also considering the presence of vismodegib, and to investigate its use in a long-term period.

Introduction: Sonidegib and vismodegib are currently the only US Food and Drug Administration and European Medicines Agency-approved small-molecule Hedgehog pathway inhibitors (HHIs)for treating adults with advanced or refractory basal cell carcinoma (BCC) that is not amenable to conventional surgery or radiotherapy. At this time, there are no head-to-head clinical trials comparing these two HHIs for efficacy and safety to assist clinicians with determining which HHI may be best suited for their patients., Areas Covered: This review briefly describes the pathogenesis of BCC, provides a detailed overview of the key pharmacokinetic profile differences between sonidegib and vismodegib, explains their pharmacodynamics, and highlights the therapeutic considerations when either HHI is used to treat special patient populations., Expert Opinion: Although both HHIs act at the same molecular target in the Hedgehog pathway, there are significant differences in their pharmacokinetic profiles that may play a potential role in their efficacy and safety. Evidence-based recommendations serve to inform clinicians until direct comparative clinical trials of sonidegib versus vismodegib are conducted to determine the clinical relevance of the reported differences in their pharmacokinetic properties.

Background: Basal cell carcinoma (BCC) is the most prevalent cancer. A minority of BCCs have an aggressive behaviour (laBCC) and may require hedgehog pathway inhibitors such as sonidegib as its treatment., Objective: To describe the use of sonidegib in a large number of patients and provide more data on its real-life efficacy and safety profile., Methods: We conducted a retrospective and multicentric study that included patients treated with sonidegib. Epidemiological, effectiveness and safety data were collected., Results: A total of 82 patients with a mean age of 73.9 years were included. Ten patients had Gorlin syndrome. Median treatment duration was 6 months. Median follow-up duration was 34.2 months. Globally, 81.7% of the patients showed clinical improvement (52.4% partial response and 29.3% complete response), 12.2% clinical stability and 6.1% disease progression. There was no statistically significant difference in clinical improvement between the 24 h and 48 h sonidegib posology. After 6 months of treatment, 48.8% of the patients discontinued sonidegib. Prior vismodegib treatment and recurrent primary BCC were associated with a poorer response to sonidegib. At 6 months of treatment, 68.3% of the patients experienced at least one adverse effect., Conclusion: Sonidegib shows good effectiveness and acceptable safety profile in usual clinical practice., (Copyright © 2023 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Purpose: To establish a model to predict treatment outcome of periocular locally advanced basal cell carcinoma (POLA BCC) based on initial response to treatment with vismodegib (Erivedge TM ), a sonic hedgehog inhibitor., Design: Subgroup analysis of data from the STEVIE study database., Methods: Analysis of medical history, treatment protocol, and treatment outcome of POLA BCC tumours in a STEVIE study population of 244 POLA BCC patients treated with ≥1 dose of vismodegib., Results: A predictive model for complete response (CR) was established based on the initial treatment response. A cutoff value of 20% reduction in tumour size at 3 months of treatment identified the patients with a high probability (82.76%) to achieve CR. A second cutoff value of 67.7% reduction in tumour size at 6 months of treatment improved the prediction to a 95.42% probability of a CR outcome., Conclusions: A treatment model was constructed based on the prediction of a CR outcome and the initial response to vismodegib treatment at 3 and 6 months. The study result provide significant new insights can facilitate decision-making on treatment management according to tumour response in patients with POLA BCC., (© 2022. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Background: 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., Objectives: 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., Methods: 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., Results: 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 &gt;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., Conclusions: Our results demonstrate the effectiveness and safety profile of HHI and confirm the reproducibility of pivotal trial results in real-life clinical setting., (© 2023 S. Karger AG, Basel.)

Background: Vismodegib is a first-in-class inhibitor of the hedgehog pathway for treatment of locally advanced basal cell carcinoma (laBCC) and metastatic BCC., Objectives: The purpose of this study is to report outcomes of patients with laBCC, with basal cell carcinoma nevus syndrome (Gorlin Goltz syndrome [G-G Syn]) treated with vismodegib in routine clinical practice in Slovenia in 8.3-year period., Methods: In this retrospective cohort study, we analyzed baseline characteristics, outcomes, and treatment-related adverse events from locally advanced BCC. The patients were divided into two cohorts: 39 laBCC or multiple BCC patients and 7 patients with G-G Syn who were treated with vismodegib from November 2012 till January 2021., Results: During 100-month period, 46 patients were diagnosed with laBCC (26), multiple BCC (13), and G-G Syn (7), all inappropriate for surgery or radiotherapy. Baseline characteristics: median age was 72.8 years in laBCC + multiple BCC cohort and 47.4 years in G-G Syn cohort. The objective response rate was 80% in laBCC + multiple BCC and 86% in G-G Syn cohort. Disease control rate (DCR) was 95% in laBCC + multiple BCC and 100% in G-G Syn cohort. Median duration of treatment was 9.9 months (range: 1.5-43.1) in laBCC and multiple BCC cohort and 19.5 months (range: 3.6-94.1) in G-G Syn cohort. Majority of treatment-emergent adverse events (TEAEs) in laBCC or multiple BCC cohort were grade 1 or 2 (96%), only 4% of AEs were grade 3. Majority of TEAEs in G-G Syn cohort were also grade 1 or 2 (87%), 13% of AEs were grade 3. No grade 4 or 5 vismodegib-related AEs were reported., Conclusion: Vismodegib has shown meaningful efficacy with DCR from 95% to 100% in patients with laBCC, multiple BCC, and G-G Syn in Slovenia. TEAEs were successfully alleviated with multidisciplinary approach and early supportive care., (© 2022 The Author(s) Published by S. Karger AG, Basel.)

Background: Basal cell carcinoma (BCC) is the most frequent non-melanoma skin cancer. The basis of treatment is surgical resection. The treatment of locally advanced and metastatic disease is currently based on sonidegb or vismodegib, small molecule inhibitors of the hedgehog signalling pathway., Objectives: The study aimed to retrospectively analyse the efficacy and safety of treatment with vismodegib in 108 patients with locally advanced or metastatic disease treated from August 1st, 2017 to December 31st, 2020. The primary objective was to evaluate the objective response rate (ORR), overall survival (OS) and progression-free survival rates. The secondary aims of the study were the disease control rate, the incidence of adverse events (AEs) and the estimation of the factors that potentially impact the treatment outcome and patient survival., Methods: Patients treated in national drug programme were enrolled into this retrospective cohort study. Evaluation of the treatment efficacy was performed according to CT/MRI scans and by the response evaluation criteria in solid tumours (RECIST) 1.1. The safety evaluation was performed according to the Common Terminology Criteria for Adverse Events v. 5.0 (CTCAE) classification and severity assessment., Results: The median duration of treatment was 14 months (range 1-94 months). The median progression-free survival reached 30.5 months (95% CI; 24.8-36.3), and the progression-free survival rate after 6, 12 and 24-months were 92%, 78% and 61%, respectively. The median overall survival was 41.5 months (95% CI; 31.6-51.3), and the overall survival rate after 1, 2 and 3 years accordingly 86%, 73% and 60%. The univariant and multivariant analysis indicated that the female gender is an independent positive prognostic factor of progression-free survival., Conclusions: The response to treatment is the prognostic factor for response maintenance and better overall survival. The therapy was well tolerated with the safety profile consistent in general with known from previous studies., (© 2022 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

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., (Copyright © 2022 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Most patients with advanced basal cell carcinomas (BCCs) may not benefit sufficiently from standard treatment comprising surgery and radiation. Vismodegib, an oral selective hedgehog pathway inhibitor, is approved for treatment of patients with locally advanced BCC inappropriate for surgery or radiotherapy, or for patients with symptomatic metastatic BCC. In order to enhance understanding of the effectiveness, safety and utilization of vismodegib in clinical practice in Germany, a non-interventional study, JONAS, was conducted. A total of 53 patients with locally advanced BCC who initiated treatment with vismodegib between 2016 and 2018 were included in the study, which was embedded in the German ADOReg skin cancer registry. Duration of response, the primary endpoint, was 12.4 months, progression-free survival 32.2 months and overall response rate 77.4%. Most adverse events were mild to moderate. Overall, results confirmed previous findings, demonstrating favourable responses and manageable safety of vismodegib in patients with locally advanced BCC in clinical practice.

Introduction: The standard treatment of basal cell carcinoma (BCC) consists of conventional excision or Mohs micrographic surgery. However, surgical excision is not feasible in specific cases, particularly in patients with several BCCs such as those with Gorlin syndrome or individuals receiving immunosuppression after solid-organ transplantation. Additionally, the geriatric population may not be appropriate candidates for surgery. Thus, alternative therapies are needed for these populations., Areas Covered: Hedgehog (Hh) inhibitors are approved and effective but are currently available only in oral formulations. These agents such as vismodegib and sonidegib are associated with short-lived responses as well as significant adverse effects including myalgias, dysgeusia, and alopecia. Patidegib and itraconazole are two topical Hh inhibitors agents emerging as alternatives to oral Hh inhibiton for difficult-to-treat BCCs. These agents exhibit limited systemic absorption, leading to improved tolerability; however, an optimal formulation is needed to maximize efficacy and is currently being investigated., Expert Opinion: Ongoing and recent clinical studies on topical Hedgehog inhibitors show great promise for the development of an agent with a high therapeutic index and limited adverse effects. If patidegib continues to show clinical efficacy in randomized controlled trials, it may become a universal therapy for all subtypes of difficult-to-treat BCC.

Introduction: Vismodegib (Erivedge; Roche), a Hedgehog pathway inhibitor (HPI), is indicated for the treatment of symptomatic metastatic basal cell carcinoma (BCC) and locally advanced BCC inappropriate for surgery or radiotherapy. Due to the known risk of HPI teratogenicity, the Erivedge Pregnancy Prevention Program (PPP) was introduced at approval (2013) as part of the EU Risk Management Plan., Methods: Structured, quantitative Web-based surveys were conducted in 2015 (Wave 1), 2016 (Wave 2), and 2017/2018 (Wave 3) among prescribing oncologists and dermato-oncologists in Austria, France, Germany, Hungary, and the United Kingdom to assess the effectiveness of the Erivedge PPP., Results: Overall, 95%, 87%, and 91% of respondents in Waves 3 ( N  = 181), 2 ( N  = 214), and 1 ( N  = 207), respectively, were vismodegib prescribers. The surveys consistently showed a high awareness about the risk of teratogenicity associated with vismodegib (98%, Wave 3; 95%, Wave 2) and that a high proportion of prescribing physicians took appropriate precautions to minimize this risk (95%, Wave 3; 92%, Wave 2; 88%, Wave 1). Physicians were also highly aware of the Erivedge PPP (70%, Wave 3; 67%, Wave 2; 71%, Wave 1)., Conclusion: Survey data suggest that the risk of teratogenicity with vismodegib has been effectively communicated to the prescribing community.

Background: Limited information is available regarding real-world treatment patterns and their effectiveness and safety in patients with locally advanced basal cell carcinoma, including patients not typically represented in clinical trials. The purpose of the current study was to describe how clinicians diagnose and treat locally advanced basal cell carcinoma in the United States., Methods: This prospective, multicenter, observational registry study included patients with newly diagnosed, Hedgehog pathway inhibitor-naive locally advanced basal cell carcinoma without basal cell carcinoma nevus syndrome (n = 433) treated at 75 US academic and community practices, including dermatology, Mohs surgery, and medical oncology sites. The main outcomes of this study were treatment patterns and associated effectiveness and safety for patients with locally advanced basal cell carcinoma in real-world settings., Results: Determination of locally advanced basal cell carcinoma was mainly based on lesion size (79.6% of patients), histopathology (54.3%), extent of involvement (49.0%), and location (46.2%). Within 90 days of determination of locally advanced disease, 115 patients (26.6%) received vismodegib, 251 (58.0%) received surgery/other (non-vismodegib) treatment, and 67 (15.5%) had not yet received treatment (observation). Vismodegib-treated patients had a higher prevalence of high-risk clinical features predictive for locoregional recurrence than those with non-vismodegib treatment or observation. Clinical response rate was 85.1% with vismodegib and 94.9% with non-vismodegib treatment (primarily surgery). The most common adverse events with vismodegib were ageusia/dysgeusia, muscle spasms, alopecia, and weight loss. Rates of cutaneous squamous cell cancers were comparable between vismodegib and non-vismodegib treatment., Conclusions: This prospective observational study offers insight on real-world practice, treatment selection, and outcomes for a nationally representative sample of US patients with locally advanced basal cell carcinoma. For patients with lesions that were not amenable to surgery, vismodegib treatment was associated with effectiveness and safety that was consistent with that observed in clinical trials., Competing Interests: A. Sekulic has no conflict of interest to declare. S. Yoo has no conflict of interest to declare. R. Kudchadkar has served on advisory boards and received honoraria from Bristol Myers Squibb and has received grants/research funding from Merck. J. Guillen has no conflict of interest to declare. G. Rogers has no conflict of interest to declare. A.L.S. Chang has served as a clinical investigator for research studies funded by Roche/Genentech, Merck, Novartis, and Regeneron. S. Guenthner has served on advisory boards and received grants/research funding and honoraria from Genentech, Pfizer, AbbVie, Amgen, LEO Pharma, Lilly, Dermira, Sun Pharma, UCB, Vanda, and Janssen. B. Raskin has no conflict of interest to declare. K. Dawson, Y. Mun, L. Chu, and E. McKenna are employees of Genentech and hold stock/stock options in Roche/Genentech. M. Lacouture has received royalties from Legacy Healthcare Services, Apricity Health, Azitra, Deciphera, Galderma, Johnson & Johnson, NCODA, Novocure, Kyowa Kirin, Loxo, Merck Sharp & Dohme, Janssen, Menlo Therapeutics, Novartis, QED Therapeutics, F. Hoffmann-La Roche, Amgen, AstraZeneca, Genentech, Seagen, Lutris, Paxman Collers, OnQuality Pharmaceuticals, and Takeda Millennium and has received research funding from Veloce, US Biotest, Lutris, Paxman, and Novocure.

Background: Hedgehog inhibitor therapy (HHIT) is considered first-line treatment for locally advanced, unresectable basal cell carcinoma (laBCC). HHIT often results in a partial response, which requires adjunctive therapy (AT) post HHIT. We present real-world data for laBCCs undergoing HHIT ± AT., Methods: Retrospective review at Duke University from 11/01/2007 through 5/20/2020 revealed 13 patients treated with systemic HHIT (sonidegib or vismodegib) for laBCC., Results: Fourteen laBCCs were identified in 13 patients. LaBCCs were treated with sonidegib (n = 10, 71%) or vismodegib (n = 4, 29%) for a median (IQR) of 9.4 (9.3) or 9.8 (8.5) months, respectively. The median (IQR) follow-up time from HHIT initiation was 15.5 (8.7) months. Tumors were most often located on the trunk (43%), followed by head and neck (29%), extremities (21%), and orbit/periorbital area (7%). Nine laBCCs (64%) were treated with HHIT alone, of which five (36%) achieved complete response (CR), four (29%) achieved partial response (PR), and five (36%) achieved CR with combined HHIT and AT post-HHIT. Duration of HHIT treatment (IQR) was 7.5 (3.5) months in the 10 CR patients, versus 15.1 (6.3) months in the four PR patients (P = 0.024). Nine patients (69%) experienced adverse events from HHIT, most commonly ageusia/dysgeusia, muscle spasms, and alopecia., Conclusion: As a single institutional experience, we report 10/14 laBCCs (71%) with CRs without recurrence and 4/14 laBCCs (29%) with PRs with HHIT ± AT over median follow-up of 15.5 months. Longer follow-up and larger cohorts evaluating responses with HHIT followed by AT are needed to substantiate our findings., (© 2021 the International Society of Dermatology.)

Introduction: Basal cell carcinoma (BCC) is a cancer that arises from the basal layer of the epidermis and is most often caused by exposure to UV radiation. Most BCCs are localized and can be fully treated by surgical removal or topical treatment. In the last decade, it has been found that the hedgehog pathway, a signaling pathway that regulates embryonic development, has a pivotal role in the pathogenesis of BCC in adults. Therefore, two drugs that inhibit the hedgehog pathway have been developed. These drugs, indicated for metastatic or locally advanced BCC, may cause a rapid clinical and imaging response, but have an adverse reaction that includes muscle spasms, alopecia, dysgeusia and fatigue, and often leads to drug discontinuation. Due to the high rates of treatment discontinuation, the possibility of administering the drug intermittently was examined and, indeed, a decrease in adverse reactions together with tumor response was observed. Additionally, it seems that patients who discontinue treatment may benefit from long-term remission. These cases indicate the possibility of changing the schedule of administration of the drug. We hereby report two cases of patients who were treated with radiation therapy for ringworm in their childhood and developed BCC. The patients were treated with a hedgehog pathway inhibitor with complete tumor regression. After treatment was discontinued due to adverse reactions, no recurrence of the tumor was observed over a period of almost two years.

The study aims to evaluate the vismodegib treatment in local advanced (laBCC) and metastatic (mBCC) basal cell carcinoma. The data of 29 patients were retrospectively reviewed. The clinical and histopathological features of the patients and adverse events of vismodegib were recorded. Overall survival (OS) and progression-free survival (PFS) were evaluated with Kaplan-Meier analysis. The median follow-up period was 17 months (range: 1.6-57.3), and the median age at diagnosis 73 years (range: 39-88). The most common disease location was head and neck (86.2%), and the most common non-skin sites of disease were lymph nodes (13.8%), bone (13.8%), lung (6.9%), and brain (6.9%). Three (10.3%) patients had Gorlin's syndrome. The number of metastatic patients was 5 (17.2%). With vismodegib treatment, the complete response rate was 27.6%, partial response 55.2%, and stable response 10.3%. Treatment responses were most frequently seen within 2 months from the beginning of vismodegib. The median OS was 43.3 ± 9.0 months (25.6-61.1) for all patients. The median PFS in the laBCC was 15.7 ± 1.8 months (12.2-19.3), and 12.1 ± 4.6 months (2.9-21.2) in the mBCC. In the univariable analysis for the OS, only the treatment after the vismodegib was statistically significant, showing chemotherapy was better comparing to no treatment or surgery. The most common adverse events were fatigue-58.6%, muscle spasms-48.3%, alopecia-13.8%, and weight loss-13.8%. This real-life data study shows that vismodegib treatment in locally advanced and metastatic BCC was well tolerated and effective., (© 2021 Wiley Periodicals LLC.)

Management of patients with locally advanced basal cell carcinoma (laBCC) with traditional strategies has yielded suboptimal outcomes. Targeted treatments including hedgehog inhibitor therapy (HHIT) present limitations when utilized as monotherapy. Herein, we report evidence-based outcomes from available literature on multimodality treatments adjuvant to HHIT in laBCC management. Utilizing a systematic search strategy in PubMed, we identified studies published from inception to April 15, 2020, screened for definitive inclusion/exclusion criteria, and performed individual study quality assessment and pooled analysis to assess impact of adjunctive treatment-based responses post-HHIT on clinical response and recurrence outcomes. Twenty-nine studies (n = 103) were included. Primary findings include a complete response (CR) rate of 90.5%, the median follow-up of 12 months post-HHIT completion. The recurrence rate was 10.8% with 12-month median time to recurrence. Mohs micrographic surgery (MMS) had 100% CR post-HHIT, while no difference was observed between surgery and radiation therapy (RT). MMS and surgery had comparable 2-year recurrence free rates (RFR) at 87% and 86% respectively, while RT had the lower 2-year RFR at 67%. Male gender portended a more advanced stage at diagnosis and worse outcomes. In a subset analysis, periorbital laBCCs with orbital involvement had a CR rate of 81.8% versus 100% in those without orbital involvement, with similar rates of recurrence. Limited available quantitative data and possible publication bias were limitations. Pooled analysis of observational data supports use of adjunctive therapies post-HHIT to improve treatment response in patients with laBCC. Longer-term follow-up is needed to study recurrence rates after combination therapy., (© 2021 Wiley Periodicals LLC.)

Background: Basal cell carcinoma (BCC) can arise by the uncontrolled proliferation of cells from multiple epidermal compartments due to aberrant activation of the Hedgehog (Hh) signalling pathway. Vismodegib, a small-molecule inhibitor of this pathway, is approved for treatment of patients with locally advanced (la) BCC inappropriate for surgery or radiotherapy or patients with symptomatic metastatic (m) BCC., Objectives: The aim of this non-interventional study was to assess effectiveness with a special focus on duration of response (DOR), safety and utilization of vismodegib for treatment of laBCC in daily practice in Germany., Methods: This non-interventional study (NIS) observed treatment of laBCC with vismodegib according to the German label in clinical practice. All available patients who had received at least one dose of vismodegib between commercial availability of vismodegib in Germany (02 August 2013) and 3 years before end of study (31 March 2016) could be included and were documented retrospectively and/or prospectively for up to 3 years. Primary effectiveness variable was DOR. Assessment of tumour response was carried out by the treating physicians. Exploratory variables included utilization of vismodegib, decision makers for therapy and method of tumour response evaluation. All statistical analyses were descriptive., Results: Between September 2015 and March 2019, 66 patients were observed at 26 German centres. The objective response rate (ORR) was 74.2% and the disease control rate (DCR) was 90.9%. The median DOR was 15.9 months (95% CI: 9.2; 25.7; n = 49 patients with response). The median progression-free survival (PFS) was 19.1 months and the median time to response (TTR) 2.7 months. A total of 340 adverse events were reported in 63 (95.5%) patients; no new safety signals were identified., Conclusions: The NIS NIELS shows effectiveness and safety of vismodegib in patients with laBCC. It confirms the transferability of the results of the pivotal trial into routine clinical practice., (© 2021 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Introduction : Hedgehog inhibitors are an alternative treatment option for patients with advanced BCCs not eligible for standard therapies due to lack of efficacy, high recurrence risk, and high-rate morbidity. Sonidegib, an oral smoothened antagonist, has been approved for the treatment of adult patients with locally advanced basal cell carcinoma. Several studies and randomized controlled trials have been conducted in order to evaluate the efficacy, safety, and tolerability of this new molecule. Areas covered : The aim of this article is to provide a complete overview on the use of sonidegib for the treatment of advanced BCCs describing the efficacy, safety, and drug tolerability of this drug. Expert opinion : Sonidegib, with a different pharmacokinetics profile from that of the other SMO-inhibitor vismodegib, demonstrated to be an efficacious and well-tolerated treatment in patients with locally advanced BCC. Although several drug-related adverse events have already been described, different strategies should be taken into account to better manage this small molecule while avoiding treatment discontinuation. The use of sonidegib as neoadjuvant therapy or combined with other hedgehog pathway inhibitors targeting different sites and to date, only available for pre-clinical studies, should also be considered.

Background: Before February, 2021, there was no standard treatment regimen for locally advanced basal cell carcinoma after first-line hedgehog inhibitor (HHI) therapy. Cemiplimab, a PD-1 antibody, is approved for treatment of advanced cutaneous squamous cell carcinoma and has shown clinical activity as monotherapy in first-line non-small-cell lung cancer. Here, we present the primary analysis data of cemiplimab in patients with locally advanced basal cell carcinoma after HHI therapy., Methods: We did an open-label, multicentre, single-arm, phase 2 trial across 38 outpatient clinics, primarily at academic medical centres, in Canada, Europe, and the USA. Eligible patients (aged ≥18 years and with an Eastern Cooperative Oncology Group performance status of 0 or 1) with a histologically confirmed diagnosis of metastatic basal cell carcinoma (group 1) or locally advanced basal cell carcinoma (group 2) who had progressed on or were intolerant to previous HHI therapy were enrolled. Patients were not candidates for further HHI therapy due to progression of disease on or intolerance to previous HHI therapy or having no better than stable disease after 9 months on HHI therapy. Patients received cemiplimab 350 mg intravenously every 3 weeks for up to 93 weeks or until progression or unacceptable toxicity. The primary endpoint was objective response by independent central review. Analyses were done as per the intention-to-treat principle. The safety analysis comprised all patients who received at least one dose of cemiplimab. The primary analysis is reported only for group 2; group 1 data have not reached maturity and will be reported when the timepoint, according to the statistical analysis plan, has been reached. This study is registered with ClinicalTrials.gov, NCT03132636, and is no longer recruiting new participants., Findings: Between Nov 16, 2017, and Jan 7, 2019, 84 patients were enrolled and treated with cemiplimab. At data cutoff on Feb 17, 2020, median duration of follow-up was 15 months (IQR 8-18). An objective response per independent central review was observed in 26 (31%; 95% CI 21-42) of 84 patients, including two partial responses that emerged at tumour assessments before the data cutoff and were confirmed by tumour assessments done subsequent to the data cutoff. The best overall response was five (6%) patients with a complete response and 21 (25%) with a partial response. Grade 3-4 treatment-emergent adverse events occurred in 40 (48%) of 84 patients; the most common were hypertension (four [5%] of 84 patients) and colitis (four [5%]). Serious treatment-emergent adverse events occurred in 29 (35%) of 84 patients. There were no treatment-related deaths., Interpretation: Cemiplimab exhibited clinically meaningful antitumour activity and an acceptable safety profile in patients with locally advanced basal cell carcinoma after HHI therapy., Funding: Regeneron Pharmaceuticals and Sanofi., Competing Interests: Declaration of interests AJS reports advisory board or steering committee roles with Janssen, Regeneron Pharmaceuticals, Roche, and Sanofi; and research support from Abbvie, Bristol Myers Squibb, Genesis Pharma, and Novartis. AS reports advisory roles with Regeneron Pharmaceuticals and Roche. KP reports advisory board roles with Abbvie, LEO Pharma, Janssen, Almirall, Eli Lilly, Galderma, Novartis, Pierre Fabre, Sun Pharma, and Sanofi, outside the submitted work. OB has advisory board roles with Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, and Ultimovacs. KDL reports grants from the University of Colorado; and grants and personal fees from Regeneron Pharmaceuticals. ALSC reports advisory roles with Regeneron Pharmaceuticals and Merck; and research funding from Regeneron Pharmaceuticals, Merck, Novartis, and Galderma. SD reports that their spouse is an employee of Sanofi. LL reports institutional grants and personal fees from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Debiopharm International SA, Eisai, Novartis, and Roche; institutional grants from Celgene International, Exelixis, Hoffmann-La Roche, IRX Therapeutics, Medpace, Merck-Serono, and Pfizer; and personal fees from Sobi, Ipsen, Incyte Biosciences Italy SRL, Doxa Pharma, Amgen, Nanobiotics SA, GlaxoSmithKline, AccMed, Medical Science Fundation G. Lorenzini, Associazione Sinapsi, Think 2 IT, Aiom Servizi, Prime Oncology, WMA Congress Education, Fasi, DueCi Promotion SRL, MI&T, Net Congress & Education, PRMA Consulting, Kura Oncology, Health & Life SRL, and Immuno-Oncology Hub. CR reports grants and personal fees advisory board roles with Bristol Myers Squibb, Pierre Fabre, Novartis, Amgen, Merck, Roche, Merck Sharp & Dohme, Sanofi, Biothera, and Ultimovacs. CU reports advisory board and speaker roles for Roche, Sanofi, Regeneron Pharmaceuticals, and Sun Pharma. AH reports institutional funding and personal fees from Amgen, Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme, Merck & Co, Philogen, Pierre Fabre, Provectus, Regeneron Pharmaceuticals, Roche, Sanofi Genzyme, and Novartis; and consultancy fees from OncoSec, Almirall Hermal, and Sun Pharma. MRM reports advisory roles with and travel fees from Regeneron Pharmaceuticals and Sun Pharmaceuticals; advisory role with Rakuten Medical; and research funding from Regeneron Pharmaceuticals and PellePharm. RD has intermittent, project focused consultant and advisory roles with Novartis, Merck Sharp & Dohme, Bristol Myers Squibb, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron Pharmaceuticals, Alligator, MaxiVAX SA, and touchIME outside the submitted work. SL, S-YY, KM, EC, VJ, NF, EO, FS, DMW, and TB are employees and shareholders of Regeneron Pharmaceuticals. CL reports personal fees from Roche, Sun Pharma, Bristol Myers Squibb, Merck Sharp & Dohme, Merck, Novartis, Pierre Fabre, Kyowa Kirin, Almiral Hermal, and Biontech. ZE reports advisory board fees from Regeneron Pharmaceuticals, Novartis, Array, Genentech, and SunPharma; and grants from Novartis. RG reports documentation fees to institution from Regeneron Pharmaceuticals; personal fees and non-financial support from Amgen, Bristol Myers Squibb, Roche Pharma, Merck Serono, Pierre Fabre, Sanofi, and Regeneron Pharmaceuticals; grants, personal fees, and non-financial support from Novartis; grants and personal fees from Pfizer; grants from Johnson & Johnson; and personal fees from Merck Sharp & Dohme, Almirall Hermal, SUN Pharma, 4SC, and Bayer. JU reports grants and personal fees from Sanofi, Bristol Myers Squibb, Novartis, and Merck Sharp & Dohme; and personal fees from Roche, medac, and Sun Pharma. SPu reports personal fees and non-financial support from Sanofi; other (clinical trials) from Regeneron Pharmaceuticals; grants from Avene; non-financial support from Abbie; grants, personal fees, and non-financial support from ISDIN, La Roche-Posay, and Roche; grants and personal fees from Sun Pharma; non-financial support from Eli Lilly and Merck Sharp & Dohme; personal fees, non-financial support, and other (related to clinical trials) from Pfizer; grants, personal fees, and other from Leo Pharma and Almirall; personal fees and other (related to clinical trials) from Ojer Pharma; personal fees from Pierre Fabre; and non-financial support from MAVIG, FotoFinder, and 3Gen. GDY is an employee of, shareholder in, and a member of the Board of Directors at Regeneron Pharmaceuticals. GT is an employee of, patent holder, and shareholder of Regeneron Pharmaceuticals. IL and MGF are employees of, have patents pending, and are shareholders of Regeneron Pharmaceuticals. SPr, MK, NB-S, AFO, IB, and VDG declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Locally-advanced periocular basal cell carcinoma (BCC) pose many therapeutic challenges due to the need to preserve functionality and cosmesis of the orbit and periocular area. Surgical excision and subsequent orbital exenteration are two recognized modalities of treatment. Vismodegib is currently an FDA-approved monotherapy for locally-advanced and metastatic BCC. We present a case of the use of vismodegib as neoadjuvant therapy prior to surgical excision of a locally-advanced periocular recurrent BCC in a 75-year-old male. The patient&rsquo;s tumor successfully responded to vismodegib allowing surgical excision with clear margins. The orbit was saved in a patient who otherwise would have required complete orbital exenteration. J Drugs Dermatol. 20(5):552-554. doi:10.36849/JDD.5661.

Basal cell carcinoma (BCC) is the most common malignancy in fair-skinned populations. Most cases are successfully treated with surgery, but in advanced BCC&mdash;including locally advanced BCC and metastatic BCC&mdash;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&ndash;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.

Locally advanced basal cell carcinoma (laBCC) represented an uncommon, difficult-to-treat form of skin cancer until the recent approval of the Hedgehog inhibitor vismodegib. Approximately 80% of laBCCs occur in the head and neck region, causing disfiguring skin changes that have an impact on patient quality of life (QoL). Because the lives of patients with advanced BCCs are severely disrupted, it would be expected that the QoL family members involved in caregiving would also be affected. The aim of our study was to quantify the QoL of both patients and family members during vismodegib treatment using the Dermatology Life Quality Index and the Family Dermatology Life Quality Index, respectively., (© 2020 British Association of Dermatologists.)

Introduction: 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., Areas Covered: 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., Expert Opinion: 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.

Basal cell carcinoma (BCC) is the most common skin cancer in humans. Pigmented basal cell carcinoma (pBCC) is a rare variant of BCC. Vismodegib, was the first drug to be approved for the treatment of locally advanced (laBCCs) or metastatic basal cell carcinoma. The aim of this study was to evaluate the efficacy of Vismodegib in patients with pBCCs. We retrospectively analyzed patients receiving Vismodegib as treatment for laBCCs presenting also various pBCCs. After 6 months of treatment, we performed excisional biopsies of pBCCs, that apparently at clinical and dermoscopic assessment did not respond to therapy. A total of nine patients were assessed. After 6 months of treatment, locally advanced target BCCs showed complete remission in four out of nine patients (44.4%), four patients (44.4%) were considered in partial remission and one patient (11%) showed no response to treatment. On the contrary, all the pBCCs showed both clinically and dermoscopically resistance to treatment. Therefore, clinically persistent pBCCs were surgically removed in three patients. Histology showed a complete elimination of the neoplastic cells together with features of previous regression. Our findings indicate that the efficacy of Vismodegib is higher than that documented by clinical or even dermatoscopic observation alone., (© 2020 Wiley Periodicals LLC.)

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., (© 2020 European Academy of Dermatology and Venereology.)

Sonic hedgehog pathway inhibitor Vismodegib is the first systemic treatment to be approved for metastatic or locally advanced basal cell carcinoma non-subsidiary of surgical treatment, and appears to be a promising treatment option for patients with nevoid basal cell carcinoma syndrome. In these patients, where repeated or prolonged treatment may be necessary, the psychological exhaustion caused by the chronicity of less severe adverse effects appears as the main limiting factor in the persistence of the drug in the long term and in the willingness of patients to take the drug again after its suspension. We report our experience with three cases where a drug holiday approach was effective in decreasing the intensity of adverse effects or improving the patient's subjective tolerance to the drug while maintaining clinical response., (© 2020 Wiley Periodicals LLC.)

Aim: To assess safety and efficacy of vismodegib in the Italian cohort from the SafeTy Events in VIsmodEgib study. Materials & methods: Data from Italian patients with locally advanced basal cell carcinoma (laBCC) or metastatic BCC were analyzed. Results: Among 182 Italian patients, adverse events occurred with similar incidence to the overall population. Overall response rate was 67.1% in laBCC, 20% in metastatic BCC; complete response rate was 33.1% overall and 37.4% in laBCC. Median time to response was 2 months in complete responders versus 3.6 months overall. Quality of life improved from baseline. Conclusion: In the Italian cohort of STEVIE, vismodegib showed a safety profile consistent with the whole population; older age did not affect safety or efficacy. ClinicalTrials.gov registration: NCT01367665.

Background: Smoothened receptor inhibitor vismodegib is indicated to treat locally advanced basal cell carcinoma (laBCC) and lesions in nevoid basal cell carcinoma syndrome (NBCCS). Methods: We treated 11 patients - including four NBCCS and seven laBCC patients - with vismodegib at our department. Results: Complete remission was achieved in three cases, without relapse after discontinuation. Two of the aforementioned patients had NBCCS, in their cases further treatment might be needed. Two patients showed improvement, but later passed away due to unrelated conditions. Two patients with laBCC initially showed remission, then the treatment was suspended due to side effects. After re-administration of the drug, loss of efficacy was observed. We did not observe therapy resistance in our NBCCS group. The rest of the patients showed good response to therapy, but have not reached full remission yet. The main side effects of vismodegib were muscle cramps, dysgeusia, nausea and alopecia. The frequency of adverse events did not show significant differences between the patient groups. Conclusions : Our results show that vismodegib therapy is effective in the treatment of BCC; however, side effects are often severe. Since the suspension of treatment can lead to therapy resistance, the management of side effects is of great importance.

Introduction and Objectives: Vismodegib (Erivedge ® ), a hedgehog pathway inhibitor, is approved to treat metastatic or locally advanced basal cell carcinoma (BCC) not suitable for surgery or radiotherapy. Our main objectives were to study the objective response rate (ORR) assessed by treating physicians and safety of vismodegib in a real-world practice setting in Argentina., Material and Methods: This is a prospective cohort study in real-world practice. We included consecutive adult patients treated in Argentina with locally advanced or metastatic BCC not suitable for surgery or radiotherapy. Patients were followed until the end of the study, death, or loss to follow-up, whichever occurred first. Patients received 150 mg vismodegib PO daily., Result: We included in the analysis 63 patients who received treatment. Locally advanced BCC was present in 57 (90.4%) and metastatic disease in two (3.2%). ORR was observed in 46 patients (73%; 95% CI: 60.3-83.4), with partial response in 36 (57%; 95% CI: 44-69.5) and complete response in 10 (16%; 95% CI: 7.8-27.2). As to safety, 48 (76.2%) patients had at least one adverse event (AE). The most frequently observed AEs were muscular spasms in 25 (39.6%); dysgeusia in 23 (36.5%); alopecia in nine (14.2%); weight loss in seven (11.1%); and ageusia in (9.5%) patients. Serious AEs were observed in 11 (17%) patients with one episode of deep vein thrombosis and pulmonary embolism resulting in death., Conclusion: Our study provides additional evidence of the efficacy and tolerability of vismodegib in patients with locally advanced or metastatic BCC in a real-world practice., (© 2020 The International Society of Dermatology.)

Background: Vismodegib demonstrated 60% response rates in the ERIVANCE trial. Basal cell carcinoma has various histopathologies. Their effect on response is unclear., Objective: The purpose of this study was to determine whether basal cell carcinoma histopathology affected vismodegib response., Methods: This phase 2b, single-center, prospective case series study compared the efficacy of vismodegib in infiltrative, nodular, and superficial basal cell carcinomas treated for 12 or 24 weeks in 27 patients. Patients had 1 target lesion and up to 3 nontarget lesions., Results: Twenty-seven patients were enrolled, with 65 tumors (27 target lesions/38 nontarget lesions). At 24 weeks, most basal cell carcinomas achieved histologic clearance, with positive biopsy results in 10.5% of target lesions, 30.4% of nontarget lesions, and 21.4% overall. No statistical differences were observed between histopathologic subtypes. One hundred percent of patients experienced an adverse event, 94% grade 1 or 2. The most common adverse events were dysgeusia/loss of taste (86%), muscle spasms (82%), and alopecia (71%). Clinically progressive disease during treatment was low (1.5%). Two patients had recurrence within 1 year of treatment., Limitations: Limitations included sample size of basal cell carcinoma histopathologic subtypes, sampling punch biopsies, and short follow-up., Conclusions: Basal cell histopathologic subtype did not significantly affect response to vismodegib. Each subtype was observed to completely respond at 12 weeks of therapy, 24 weeks, or both., (Copyright © 2019 American Academy of Dermatology, Inc. All rights reserved.)

Purpose: Vismodegib is a hedgehog pathway inhibitor indicated for the treatment of locally advanced basal cell carcinoma (laBCC), with an objective response rate of 65%, including a 32% complete response (CR). However, adverse effects often lead to drug discontinuation. The objective of our study was to evaluate long-term responses, predictive factors, and management of relapse after vismodegib discontinuation., Methods: An observational retrospective study was conducted in nine French oncodermatology units. We included patients with laBCC with CR on vismodegib who discontinued treatment between March 2012 and January 2016; we reviewed charts up to June 2016. The primary objective was to evaluate median relapse-free survival (RFS). Secondary objectives were risk factors associated with RFS, relapse, and death and treatment modalities after relapse and their efficacy., Results: One hundred sixteen patients with laBCC were included. The median RFS was 18.4 months (95% CI, 13.5 to 24.8 months). The RFS rate at 36 months was 35.4% (95% CI, 22.5% to 47.9%) for the total population and 40.0% (95% CI, 25.7% to 53.7%) for patients without Gorlin syndrome. LaBCC to the limbs and trunk was the only variable independently associated with a higher risk of relapse (hazard ratio, 2.77; 95% CI, 1.23 to 6.22; P = .019). Twenty-seven patients (50%) who experienced relapse during follow-up were retreated with vismodegib, with an objective response in 23 (objective response rate, 85%; CR rate, 37%; partial response rate, 48%) and eligibility for surgery in 24 (42%)., Conclusion: Long-term response after vismodegib discontinuation is frequent. Most patients who experience a relapse still respond to vismodegib rechallenge.

Basal cell carcinoma (BCC) is the most common malignancy in Caucasians, and its incidence is increasing. Most BCCs are treated surgically, nevertheless surgery is not an effective treatment for locally advanced or metastatic BCC. Alterations in hedgehog signaling pathway, a key regulator of cell growth and differentiation during development, are implicated in the pathogenesis of basal-cell carcinoma. Vismodegib is a small-molecule inhibitor of smoothened (SMO), a key component of the hedgehog (Hh) signaling pathway, administered in BCC patients, especially when surgery and radiotherapy treatments have failed. We report a series of eight elderly patients treated with vismodegib for advanced BCC and affected by concomitant multiple comorbidities. The efficacy and tolerability of vismodegib in patients with single and/or multiple comorbidities has been poorly studied. In our observation an overall high safety and tolerability has been observed over the course of treatment, with side effects of grade I and II and no changes in vital parameters, electrocardiography and echocardiogram. Vismodegib has been shown to be a safe and well tolerated treatment option for elderly patients affected by multiple comorbidities and advanced BCC., (© 2019 Wiley Periodicals, Inc.)