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

ABSTRACT: 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.

SUBMITTER: Dummer R

PROVIDER: S-EPMC7500103 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

Dummer Reinhard R Liu Li L Squittieri Nicholas N Gutzmer Ralf R Lear John J

Oncotarget 20200915 37

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 <i>Glioma-associated oncogene homolog 1 (GLI1)</i> as a biomarker to assess the extent of Hedgehog pathway inhibition by sonidegib in patients with locally advanced BCC (laBCC) and metastatic BCC (mBCC). ...[more]

PMID: 32973971

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Project description:IntroductionSonidegib 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.MethodsThis 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.ResultsOver 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.ConclusionThis 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.

Dataset Information

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

Publications

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

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