Expression of Glioma-associated oncogene homolog 1 as biomarker with sonidegib in advanced basal cell carcinoma

The pivotal BOLT (Basal cell carcinoma Outcomes with LDE225 [sonidegib] Treatment) study established the durable efficacy and manageable toxicity of sonidegib 200 mg once daily (QD) through 42 months in patients with advanced basal cell carcinoma (BCC). This secondary analysis used expression of Glioma-associated oncogene homolog 1 (GLI1) as a biomarker to assess the extent of Hedgehog pathway inhibition by sonidegib in patients with locally advanced BCC (laBCC) and metastatic BCC (mBCC). The study enrolled 230 patients, 79 and 151 receiving sonidegib 200 and 800 mg QD, respectively. At week 17, GLI1 expression was reduced from baseline by a median percentage (95% confidence interval) of 88.7% (54.6%-93.0%) and 97.0% (77.5%-98.9%) for aggressive laBCC, 97.5% (80.3%-98.8%) and 95.0% (80.7%-97.5%) for nonaggressive laBCC, and 99.1% (96.4%-99.6%) and 99.3% (95.9%-99.9%) for mBCC in the 200 and 800 mg groups, respectively. Substantial repression of GLI1 was observed in patient subgroups stratified by age, sex, BCC cytological subtype, Eastern Cooperative Oncology Group performance status, lesion site, baseline number of BCCs, and prior radiotherapy. Results support further studies on the inhibition of Hedgehog pathway genes by sonidegib in patients with laBCC and mBCC. Keywords: Glioma-associated oncogene homolog 1; Hedgehog pathway inhibitor; basal cell carcinoma; biomarker; sonidegib

Effects of Sonidegib Following Dose Reduction and Treatment Interruption in Patients with Advanced Basal Cell Carcinoma During 42-Month BOLT Trial

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

Efficacy and Safety of Sonidegib in Adult Patients with Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome): Results from a Phase 2, Double-Blind, Randomized Trial

Nevoid basal cell carcinoma syndrome (NBCCS), or Gorlin syndrome, is a rare hereditary disease characterized by the development of multiple cutaneous basal cell carcinomas (BCCs) from a young age.1 Loss-of-function germline mutations in the hedgehog-related patched 1 (PTCH1) tumor suppressor gene are the most common cause of NBCCS.1 The hedgehog signaling pathway plays a major role in embryonic development, and in adulthood, is involved in the renewal and maintenance of distinct tissues, including hair follicles, muscle stem cells, and gastric epithelium.2 Its abnormal activation is thought to drive the formation of both sporadic BCCs and those resulting from NBCCS.1 Patients with NBCCS inherit one inactive copy of PTCH1 and then acquire a “second-hit” mutation, resulting in hedgehog pathway activation and BCC formation.1 Mutations in Suppressor of fused (SUFU) or the PTCH1 homolog PTCH2 have also been found in a subset of patients meeting criteria for NBCCS.1,

Assessment of various efficacy outcomes using ERIVANCE-like criteria in patients with locally advanced basal cell carcinoma receiving sonidegib: results from a preplanned sensitivity analysis

Background 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. Methods 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. Results 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). Conclusions Overall, applying ERIVANCE-like criteria to patients with laBCC receiving sonidegib 200 mg daily yielded higher response rates vs mRECIST criteria

Is There a Clinically Relevant Risk of Hyperkalemia with Topical Clascoterone Treatment?

Clascoterone cream 1% is an androgen receptor inhibitor approved for the treatment of acne vulgaris in patients aged 12 years or older with clinical studies completed in subjects aged nine years or older. Blood potassium levels above the upper limit of normal (i.e., hyperkalemia) were reported in both clascoterone-treated and vehicle-treated patients; reported rates of hyperkalemia were approximately five percent and four percent, respectively. None of the cases of hyperkalemia were reported as adverse events and none led to study discontinuation or adverse clinical sequelae. An exposure-response analysis showed no correlation between plasma concentrations of clascoterone or its metabolite cortexolone and cases of hyperkalemia. Based on the laboratory safety profile of clascoterone demonstrated in the Phase I and Phase II studies, baseline or subsequent laboratory monitoring was not required in the Phase III studies or recommended in the FDA-approved prescribing information. The frequency of shifts to elevated potassium levels was highest in patients younger than 12 years of age treated with clascoterone, for whom clascoterone 1% is not FDA approved

A Review of Hedgehog Inhibitors Sonidegib and Vismodegib for Treatment of Advanced Basal Cell Carcinoma

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

Sonidegib improved quality of life in patients with advanced basal cell carcinoma: results from the phase 2 Basal Cell Carcinoma Outcomes with LDE225 Treatment trial through 73 weeks

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CO125 Efficacy of Clascoterone Cream 1% for up to 12 Months in Patients ≥9 Years of Age with Acne vulgaris: Results from a Long-Term Extension Study

Objectives: Clascoterone cream 1% is approved for the treatment of acne vulgaris in patients aged ≥12 years. Efficacy data from an open-label extension study are presented. Methods: The open-label, multicenter extension study (CB-03-01/27) enrolled male and female patients aged ≥9 years who completed one of the 12-week Phase 3 trials (CB-03-01/25 and CB-03-01/26) in patients with moderate-to-severe acne vulgaris. All patients applied 1% clascoterone cream twice daily to the face for 9 months; in the extension study, patients with truncal acne could also treat affected areas of the shoulders, chest, and/or back. Total time on clascoterone was up to 12 months for patients originally randomized to clascoterone in the Phase 3 trials. A 5-point Investigator’s Global Assessment (IGA; 0, clear; 4, severe) was performed at extension Days 29, 85, 183, and 274; clascoterone treatment could be discontinued if IGA was 0 or 1 (IGA 0/1) and reinstated if/when acne worsened. Efficacy was analyzed in the intention-to-treat (ITT) population. Results: The ITT population included 609 patients, of whom 251 patients were treated for truncal acne. At baseline/Day 29/85/183/274, the proportion of ITT patients achieving facial IGA 0/1 was 9.9%/8.5%/10.1%/17.3%/29.8% and the proportion of ITT patients achieving truncal IGA 0/1 was 4.8%/17.1%/20.7%/25.9%/31.5%. In the ITT population, 539/417/304/123 patients used clascoterone for a total of 3/6/9/12 months. By total time on clascoterone, 13.1%/18.9%/39.2%/56.1% of ITT patients achieved facial IGA 0/1 and 13.6%/37.6%/43.4%/59.2% of ITT patients achieved truncal IGA 0/1 after 3/6/9/12 months on clascoterone treatment. Conclusions: Clascoterone cream 1% maintained a favorable efficacy profile for up to 12 months in patients aged ≥9 years with acne vulgaris