Elsevier

The Lancet Oncology

Volume 16, Issue 6, June 2015, Pages 716-728
The Lancet Oncology

Articles
Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial

https://doi.org/10.1016/S1470-2045(15)70100-2Get rights and content

Summary

Background

Patients with advanced basal cell carcinoma have limited treatment options. Hedgehog pathway signalling is aberrantly activated in around 95% of tumours. We assessed the antitumour activity of sonidegib, a Hedgehog signalling inhibitor, in patients with advanced basal cell carcinoma.

Methods

BOLT is an ongoing multicentre, randomised, double-blind, phase 2 trial. Eligible patients had locally advanced basal cell carcinoma not amenable to curative surgery or radiation or metastatic basal cell carcinoma. Patients were randomised via an automated system in a 1:2 ratio to receive 200 mg or 800 mg oral sonidegib daily, stratified by disease, histological subtype, and geographical region. The primary endpoint was the proportion of patients who achieved an objective response, assessed in the primary efficacy analysis population (patients with fully assessable locally advanced disease and all those with metastatic disease) with data collected up to 6 months after randomisation of the last patient. This trial is registered with ClinicalTrials.gov, number NCT01327053.

Findings

Between July 20, 2011, and Jan 10, 2013, we enrolled 230 patients, 79 in the 200 mg sonidegib group, and 151 in the 800 mg sonidegib group. Median follow-up was 13·9 months (IQR 10·1–17·3). In the primary efficacy analysis population, 20 (36%, 95% CI 24–50) of 55 patients receiving 200 mg sonidegib and 39 (34%, 25–43) of 116 receiving 800 mg sonidegib achieved an objective response. In the 200 mg sonidegib group, 18 (43%, 95% CI 28–59) patients who achieved an objective response, as assessed by central review, were noted among the 42 with locally advanced basal cell carcinoma and two (15%, 2–45) among the 13 with metastatic disease. In the 800 mg group, 35 (38%, 95% CI 28–48) of 93 patients with locally advanced disease had an objective response, as assessed by central review, as did four (17%, 5–39) of 23 with metastatic disease. Fewer adverse events leading to dose interruptions or reductions (25 [32%] of 79 patients vs 90 [60%] of 150) or treatment discontinuation (17 [22%] vs 54 [36%]) occurred in patients in the 200 mg group than in the 800 mg group. The most common grade 3–4 adverse events were raised creatine kinase (five [6%] in the 200 mg group vs 19 [13%] in the 800 mg group) and lipase concentration (four [5%] vs eight [5%]). Serious adverse events occurred in 11 (14%) of 79 patients in the 200 mg group and 45 (30%) of 150 patients in the 800 mg group.

Interpretation

The benefit-to-risk profile of 200 mg sonidegib might offer a new treatment option for patients with advanced basal cell carcinoma, a population that is difficult to treat.

Funding

Novartis Pharmaceuticals Corporation.

Introduction

Aberrant activation of Hedgehog pathway signalling plays an important part in the pathogenesis of basal cell carcinoma,1, 2, 3 which is the most commonly diagnosed cancer in fair-skinned individuals worldwide.4, 5, 6 Most sporadic basal cell carcinomas have mutations in PTCH1 (more than 85%) or SMO (around 10%) that lead to activation of signalling and expression of the Hedgehog pathway and its targets, including GLI family transcription factors.1, 2, 3

Most basal cell carcinomas are effectively treated with topical therapy, surgery, radiotherapy, or a combination of these,4, 6, 7 but, treatment of locally advanced disease with large, neglected, and locally aggressive or recurrent tumours or metastatic disease is challenging.5, 8 Patients with advanced basal cell carcinoma might have substantial morbidity and disfigurement caused by tissue invasion and destruction.5 Treatment options for these patients are limited and include the SMO inhibitor vismodegib,9, 10, 11 chemotherapy, or a clinical trial.4, 6, 7

Sonidegib blocks Hedgehog signalling by selective inhibition of SMO expression.12, 13 This drug showed anti-tumour activity in patients with advanced basal cell carcinoma in a phase 1 study.14 Exposure to the drug increased proportionally with low-dose increases (100, 200, and 400 mg daily) but less than proportionally at higher doses up to 3000 mg daily.14 The Basal cell carcinoma Outcomes with LDE225 Treatment (BOLT) trial was started to assess the safety and antitumour activity of two doses of sonidegib, 200 mg and 800 mg daily, in patients with advanced disease. We report here the results of the BOLT primary analysis, which was based on data collected up to 6 months after randomisation of the last patient.

Section snippets

Study design and patients

BOLT is an ongoing multicentre, randomised, double-blind, phase 2 study that is being done in 58 centres in 12 countries (appendix).

Eligible patients were aged 18 years or older and had histologically confirmed, locally advanced basal cell carcinoma not amenable to radiotherapy or curative surgery, or metastatic basal cell carcinoma for which all existing available treatment options had been exhausted, and a WHO status grade of 0 (capable of all normal activity), 1 (ambulatory and capable of

Results

Between July 20, 2011 and Jan 10, 2013, we enrolled 230 patients, 194 with locally advanced and 36 with metastatic basal cell carcinoma, of whom 79 were randomly assigned to receive 200 mg sonidegib and 151 to receive 800 mg sonidegib (figure 1). Baseline characteristics were generally similar in the two groups (table 1). The median total size of target lesions was 12·1 cm2 (range 0·7–639·3) in patients with locally advanced disease assessed by standard annotated photography, and 4·9 cm

Discussion

In this study, both 200 mg and 800 mg sonidegib showed antitumour activity in patients with advanced basal cell carcinoma, which is a population with limited therapeutic options.4, 6, 7, 9, 10 The proportion of patients who achieved an objective response exceeded prespecified criteria for activity, and was consistent in the primary efficacy analysis and ITT populations.

The modified RECIST criteria we used for locally advanced disease were stringent, as classification of complete response

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