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Introduction: Basal cell carcinoma (BCC) is the most common skin malignancy in Caucasians. Globally, about 20% of BCCs involve the periocular region. The treatment of periocular BCC may be very challenging because of its proximity to the intracranial structures. Thus, early diagnosis and early treatment is mandatory. Recently, the introduction of Hedgehog pathway inhibitor therapy revolutionized the management of unresectable BCCs. The aim of our study was to evaluate the outcome of sonidegib treatment in patients affected by periocular locally advanced (la) BCC at our skin cancer center. Methods: A 3-year retrospective study was carried out enrolling patients with periocular laBCC treated with sonidegib. Therapeutic response was defined as complete remission (CR) in case of complete regression of the tumor, partial remission (PR) in case of tumor regression not achieving complete remission, and stable disease (SD). Results: A total 16 patients (11 men and 5 women; medium age 71.6 ± 11.5 years) with periocular laBCCs undergoing treatment with 200 mg/day of sonidegib were included in our study. Patients included in the study were treated for at least 6 months for a median duration of 9 months. Overall, CR was reported in 9/16 (56.2%) patients, PR was reported in 4/16 patients (25%), and tumor remained stable in 3 patients (18.8%). No cases of disease progression were collected. Fourteen out of 16 patients experienced multiple adverse events (AEs): dysgeusia was reported in 12 (75%) patients, muscle spasms in 13 (81%) patients, and 7 (43.7%) patients presented with alopecia. However, all of the AEs were mild and none required treatment discontinuation. Conclusion: To the best of our knowledge, this is the first study investigating the effectiveness and safety of sonidegib in the management of BCC localized at the periocular region. Even if limited, our study suggests this drug as a valuable and safe option in periocular BCC management. [ABSTRACT FROM AUTHOR]

Introduction: Until recently, patients discontinuing first-line (1L) hedgehog inhibitors (HHIs) for basal cell carcinoma (BCC) had few subsequent treatment options. The objective of this study was to describe the treatment journey and prognosis of patients discontinuing 1L HHI for BCC. Methods: This was a retrospective cohort study of patients with BCC who discontinued 1L HHI treatment in The US Oncology Network between 1 January 2012 and 1 January 2019 (with follow-up until 1 May 2020). Two cohorts were identified: patients who initiated a second-line (2L) treatment (2L initiators), and patients with 1L progression or toxicity without pathology-confirmed complete response who did not initiate 2L treatment (2L non-initiators). Patient demographics, treatment characteristics, and outcomes are reported for each cohort. Results: Among 115 patients with BCC who received 1L HHI treatment, 63.5% (n = 73/115) discontinued 1L HHIs. Of those, 50.7% (n = 37/73) discontinued because of documented toxicity or progression, without evidence of a complete response. We identified 4 patients who initiated 2L systemic treatment (median age 68.7 years, 100.0% female) and 15 patients who were eligible for the 2L non-initiator cohort (median age 80.2 years, 20.0% female). Median 1L HHI duration was 6.8 months (range 1.9–20.6 months) for the 2L non-initiator cohort and 8.6 months (range 6.8–42.2 months) for 2L initiators. At the end of follow-up, among 2L non-initiators (median follow-up duration 9.7 months), 40.0% were lost to follow-up, 33.3% had died, 20.0% continued observation, and 6.7% transitioned to an academic medical center or hospital; among 2L initiators (median follow-up duration 6.3 months), 50.0% were lost to follow-up, 25.0% had died, and 25.0% continued observation. Conclusions: Following 1L HHI discontinuation, lack of standardized care and suboptimal outcomes were observed, including limited receipt of 2L treatment. Further studies are necessary to evaluate the impact of newer BCC treatment options. [ABSTRACT FROM AUTHOR]

Introduction: Sonidegib is a Hedgehog pathway inhibitor approved to treat locally advanced basal cell carcinoma and, depending on regulatory approval, metastatic basal cell carcinoma. Results from the BOLT study demonstrated robust efficacy and continued tolerability through 42 months. This analysis evaluated the impact of sonidegib dose reductions and interruptions in patients with advanced basal cell carcinoma through 42 months. Methods: BOLT was a randomized, double-blind, multicenter, phase 2 study. Adults with no previous Hedgehog pathway inhibitor therapy were randomized 1:2 to sonidegib 200 or 800 mg once daily. Primary endpoint was objective response rate. Dose modifications were permitted in patients unable to tolerate the dosing schedule or if a treatment-related adverse event was suspected. Results: The incidence of dose interruptions was similar between the 200- and 800-mg groups (68.4% vs 65.3%, respectively). Dose reductions occurred more frequently in patients receiving sonidegib 800 mg (36.7%) than 200 mg (16.5%). Overall response rate for all patients receiving sonidegib 200 mg daily was 48.1% and was similar to those of patients without dose reduction or interruption (48.5%) and patients with at least one dose reduction or interruption (46.2%). Conclusion: Dose reductions and interruptions were practical and did not impact the efficacy of sonidegib. In patients with advanced basal cell carcinoma who necessitate long-term treatment, dose interruptions may be beneficial for continued treatment and disease control. Trial registration: ClinicalTrials.gov identifier, NCT01327053. [ABSTRACT FROM AUTHOR]

Introduction: Sonidegib is approved to treat locally advanced basal cell carcinoma (laBCC) in the USA, EU, Switzerland, and Australia and metastatic basal cell carcinoma (mBCC) in Switzerland and Australia in patients not amenable to surgery or radiotherapy. Vismodegib is approved to treat patients with mBCC, recurrent laBCC, or those not candidates for surgery or radiation. There is no head-to-head trial comparing Hedgehog inhibitors. We describe time to onset and severity of adverse events (AEs) in two studies reporting cumulative AE incidence every treatment cycle: the sonidegib phase 2 BOLT study and the expanded-access, open-label vismodegib study. Methods: This analysis included patients with histologically confirmed laBCC or mBCC from BOLT who received sonidegib 200 mg once daily (QD) and patients from the vismodegib study who received vismodegib 150 mg QD. Cumulative occurrence of AEs and median time to AE onset were calculated on 30-day cycles for sonidegib and 28-day cycles for vismodegib. AEs were graded for severity using the Common Terminology Criteria for Adverse Events. Only common (at least 15% incidence) AEs were analyzed in this study. Results: Over 18 treatment cycles, the most common all-grade AEs for sonidegib and vismodegib were muscle spasm (54.4% vs 70.6%; P = 0.0236), alopecia (49.4% vs 58.0%; no significant difference [NS]), and dysgeusia (43.0% vs 70.6%; P = 0.0003); incidences of diarrhea, nausea, fatigue, and weight decrease were 31.6% vs 25.2% (NS), 39.2% vs 19.3% (P = 0.0032), 32.9% vs 19.3% (P = 0.0429), and 30.4% vs 16.0% (P = 0.0217), respectively. Sonidegib-treated patients had more delayed median time to onset for all AEs than vismodegib-treated patients, except fatigue and weight decrease (NS). Most AEs reported were grade ≤ 2. Conclusion: This post hoc analysis suggests lower overall incidence and slower onset of certain AEs in patients treated with sonidegib compared with vismodegib. In the absence of head-to-head comparisons, the relevance of these findings needs further studies to provide conclusive evidence. [ABSTRACT FROM AUTHOR]

Hedgehog inhibitors are promising alternative treatments for patients with advanced basal cell carcinomas. Sonidegib (Odomzo®), an oral smoothened (SMO) antagonist, is indicated for the treatment of adult patients with locally advanced basal cell carcinoma (laBCC) who present recurrence following surgery or radiation therapy, or those who are not candidates for surgery or radiotherapy. Several studies and randomized controlled trials have been conducted to evaluate the efficacy, safety, and tolerability of this new molecule that has demonstrated a good response rate (44%). Grade 1–2 adverse events have also been reported. Further studies of real-world experiences are needed to better understand the correct management of the drug, alternative dosing regimens, and differences with other hedgehog inhibitors. This article provides a complete overview of the pharmacology and pharmacokinetics of sonidegib and a report of the trials and studies conducted. The most frequent adverse events and their correct management are also discussed. [ABSTRACT FROM AUTHOR]

The primary cilium is a cell surface organelle that is an important component of cellular biology. While it was once believed to be a vestigial structure without biologic function, it is now known to have essential roles in critical cellular signaling pathways such as Hedgehog (HH) and Wnt. The HH and Wnt pathways are involved in pathogenesis of basal cell carcinoma and melanoma, respectively, and this knowledge is now beginning to inform therapeutic and diagnostic options for patients. The purpose of this review is to familiarize clinicians with primary cilia biology and how this complex cellular organelle has started to translate into clinical care. [ABSTRACT FROM AUTHOR]

Basal cell carcinoma (BCC) is the most commonly diagnosed malignancy in humans, and as such it poses a significant healthcare burden. The majority of BCC cases are amenable to cure by surgical extirpation. However, until recently there have been no good treatment options for a significant minority of advanced BCC cases, including locally advanced BCC and metastatic BCC. The introduction of a novel class of drugs, the Hedgehog pathway inhibitors, into clinical practice has ushered in a new treatment algorithm for the treatment of difficult BCC cases. In this review we present the latest available evidence and discuss areas for further research in this rapidly evolving field. [ABSTRACT FROM AUTHOR]

Basal cell carcinoma (BCC) is the most common cancer globally, with the incidence increasing worldwide by approximately 1% annually. While most cases of BCC can be treated surgically, advanced BCC often poses treatment challenges for patients unsuitable for, or refractory to, radiotherapy and surgery. Since the majority of cases of BCC demonstrate Hedgehog signaling hyperactivation, Hedgehog pathway inhibitors provide durable treatment options and improved clinical outcomes for patients with advanced BCC. One of the most common adverse events seen in patients taking Hedgehog inhibitors includes muscle spasms, which are hypothesized to occur because of calcium influx into the muscle cells. Here we present a case series of patients with muscle spasms during treatment with sonidegib and propose an alternate etiology related to increased actin expression. [ABSTRACT FROM AUTHOR]