Elsevier

The Lancet Oncology

Volume 18, Issue 3, March 2017, Pages 404-412
The Lancet Oncology

Articles
Two intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas (MIKIE): a randomised, regimen-controlled, double-blind, phase 2 trial

https://doi.org/10.1016/S1470-2045(17)30072-4Get rights and content

Summary

Background

Vismodegib, a first-in-class Hedgehog-pathway inhibitor, is approved for use in adults with advanced basal-cell carcinoma. Patients with multiple basal-cell carcinomas, including those with basal-cell nevus (Gorlin) syndrome, need extended treatment. We assessed the safety and activity of two long-term intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas.

Methods

In this randomised, regimen-controlled, double-blind, phase 2 trial, we enrolled adult patients with multiple basal-cell carcinomas, including those with basal-cell nevus syndrome, who had one or more histopathologically confirmed and at least six clinically evident basal-cell carcinomas. From a centralised randomisation schedule accessed via an interactive voice or web-based response system, patients were randomly assigned (1:1) to treatment group A (150 mg oral vismodegib per day for 12 weeks, then three rounds of 8 weeks of placebo daily followed by 12 weeks of 150 mg vismodegib daily) or treatment group B (150 mg oral vismodegib per day for 24 weeks, then three rounds of 8 weeks of placebo daily followed by 8 weeks of 150 mg vismodegib daily). Treatment assignment was stratified by diagnosis of basal-cell nevus syndrome, geographical region, and immunosuppression status. The primary endpoint was percentage reduction from baseline in the number of clinically evident basal-cell carcinomas at week 73. The primary analysis was by intention to treat. The safety population included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01815840, and the study is ongoing.

Findings

Between April 30, 2013, and April 9, 2014, 229 patients were randomly assigned treatment, 116 in treatment group A and 113 in treatment group B. The mean number of basal-cell carcinoma lesions at week 73 was reduced from baseline by 62·7% (95% CI 53·0–72·3) in treatment group A and 54·0% (43·6–64·4) in treatment group B. 216 (95%) of 227 patients included in the safety analysis had at least one treatment-emergent adverse event deemed to be related to study treatment (107 [94%] of 114 in treatment group A and 109 [97%] of 113 in treatment group B). The most common grade 3 or worse treatment-related adverse events were muscle spasms (four [4%] patients in treatment group A vs 12 [11%] in treatment group B), increased blood creatine phosphokinase (one [1%] vs four [4%]), and hypophosphataemia (zero vs three [3%]). Serious treatment-emergent events were noted in 22 (19%) patients in treatment group A and 19 (17%) patients in treatment group B. Four (2%) patients died from adverse events; one (pulmonary embolism in treatment group A) was possibly related to treatment.

Interpretation

Both intermittent dosing schedules of vismodegib seemed to show good activity in long-term regimens in patients with multiple basal-cell carcinomas. Further study is warranted.

Funding

F Hoffmann-La Roche.

Introduction

Basal-cell carcinoma is the most commonly diagnosed human cancer, accounting for around 80% of all non-melanoma skin cancers.1, 2 Abnormal Hedgehog-pathway signalling is the key molecular driver of the development of basal-cell carcinoma, and is seen in more than 90% of cases. The role of abnormal Hedgehog-pathway signalling in cancer was first identified in patients with basal-cell nevus (Gorlin) syndrome.2, 3 Patients with this syndrome have a genetic predisposition to develop multiple basal-cell carcinomas from a young age, which can result in a substantial physical and psychological burden.4

Vismodegib is a small-molecule antagonist of the Hedgehog signalling pathway that binds to and inhibits Smoothened homologue (SMO), which prevents subsequent pathway signalling.5 The pivotal phase 2 registration study, ERIVANCE BCC,6 showed that 27 (43%) of 63 patients with locally advanced basal-cell carcinoma and ten (30%) of 33 patients with metastatic disease had objective responses to vismodegib when assessed by independent reviewers. The 30-month update from ERIVANCE BCC7 confirmed consistency in treatment activity and safety profile, and showed a median duration of response of 26·2 months in patients with locally advanced basal-cell carcinoma. On the basis of these results, vismodegib was approved by the US Food and Drug Administration in January, 2012, and by the European Medicines Agency in July, 2013, for the treatment of adults with metastatic basal-cell carcinoma or locally advanced basal-cell carcinoma that was unsuitable for surgery or radiotherapy.8, 9 The activity and safety profiles for vismodegib have since been strongly corroborated.7, 10, 11 Another Hedgehog-pathway inhibitor, sonidegib, has also been approved for use in patients with locally advanced basal-cell carcinoma.12

Research in context

Evidence before this study

We searched MEDLINE and Embase with the search terms “basal cell carcinoma”, “BCC”, “vismodegib”, “multiple BCC”, and “Gorlin syndrome” for peer-reviewed articles and abstracts published from Jan 1, 2010, to Oct 1, 2016. Most investigations of vismodegib in clinical trials have been in patients with advanced basal-cell carcinoma. The pivotal ERIVANCE BCC phase 2 trial also included patients with multiple basal-cell carcinomas, including some with basal-cell nevus (Gorlin) syndrome, and showed clinical benefit in this population. Another study by Tang and colleagues showed the efficacy of vismodegib versus placebo in managing basal-cell carcinoma in patients with basal-cell nevus syndrome. Nevertheless, chronic low-grade toxic effects make long-term treatment intolerable for most patients. Therefore, there is a high unmet need for long-term efficacious treatments for patients with multiple basal-cell carcinomas and basal-cell nevus syndrome.

Added value of this study

To the best of our knowledge, the MIKIE study includes the largest population of patients with basal-cell nevus syndrome and multiple basal-cell carcinomas so far. We investigated whether an intermittent regimen of vismodegib could balance activity and toxicity so that growth of basal-cell carcinomas would be inhibited, while improving the overall tolerability to limit the number of patients who discontinued treatment. The primary analysis shows that intermittent dosing of vismodegib was efficacious and tolerable in patients with multiple basal-cell carcinomas. Patients showed meaningful clinical benefit in both treatment groups. The safety profiles of the two regimens were similar, and the range of adverse events was consistent with previous clinical experience.

Implications of all the available evidence

Our results suggest that intermittent dosing schedules could be useful for patients with multiple basal-cell carcinomas who need long-term treatment.

Vismodegib was assessed in a randomised, double-blind, placebo-controlled, phase 2, investigator-sponsored study in 42 patients with basal-cell nevus syndrome.13 Tumour burden and growth of basal-cell carcinomas were reduced in patients with basal-cell nevus syndrome. However, chronic low-grade toxic effects led about half of the patients to discontinue vismodegib within 12 months of starting treatment.

A high unmet need remains in the management of basal-cell carcinoma in patients who require long-term treatment. Clinical studies of vismodegib have allowed treatment interruptions as a means of managing toxic effects.7, 11 An intermittent dosing regimen might, therefore, benefit patients who need long-term treatment by providing a balance between treatment activity and toxicity and limit the number who stop treatment. In the MIKIE study, we assessed two long-term intermittent vismodegib dosing regimens in patients who had multiple basal-cell carcinomas, including those with basal-cell nevus syndrome. Here, we report the safety and activity results from the primary analysis.

Section snippets

Study design and patients

MIKIE was a randomised, double-blind, regimen-controlled, phase 2 study of vismodegib, done in 52 hospitals or clinics in ten countries: Austria, Canada, France, Germany, Italy, Mexico, Netherlands, the Russian Federation, Spain, and the USA (appendix pp 6–8). The study protocol is available in the appendix. Eligible patients were adults (age ≥18 years) with multiple basal-cell carcinomas amenable to surgery, including those with basal-cell nevus syndrome. We excluded patients who had locally

Results

Between April 30, 2013, and April 9, 2014, 263 patients were screened, of whom 229 were randomly assigned to treatment group A (n=116) and treatment group B (n=113, figure 2). The two groups had similar clinical characteristics and demographics at baseline (table 1). Clinical cutoff, when the final patient completed 72 weeks of treatment, was Aug 27, 2015.

Of the 229 patients randomly assigned, 120 (52%) completed treatment and 137 (60%) entered the 1-year follow-up period (figure 2). Treatment

Discussion

The primary analysis of the MIKIE study showed that both intermittent regimens controlled disease for the entire treatment period in most patients. In the intention-to-treat population, results for the primary endpoint did not differ between treatment groups, although, a significant difference was seen between treatment groups in the subgroup of patients without basal-cell nevus syndrome. Tumour shrinkage was similar in both treatment groups between the week 9 (end of cycle two) and week 17

References (16)

  • AI Rubin et al.

    Basal-cell carcinoma

    N Engl J Med

    (2005)
  • EH Epstein

    Basal cell carcinomas: attack of the hedgehog

    Nat Rev Cancer

    (2008)
  • SV Mohan et al.

    Advanced basal cell carcinoma: epidemiology and therapeutic innovations

    Curr Dermatol Rep

    (2014)
  • Basal cell nevus syndrome

    BCNS

    (2012)
  • JA Low et al.

    Clinical experience with Hedgehog pathway inhibitors

    J Clin Oncol

    (2010)
  • A Sekulic et al.

    Efficacy and safety of vismodegib in advanced basal-cell carcinoma

    N Engl J Med

    (2012)
  • A Sekulic et al.

    Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update (30-month) of the pivotal ERIVANCE BCC study

    Proc Am Soc Clin Oncol

    (2014)
  • Erivedge: prescribing information

There are more references available in the full text version of this article.

Cited by (144)

  • Targeted Therapy and Immunotherapy in Nonmelanoma Skin Cancer

    2023, Dermatologic Clinics
    Citation Excerpt :

    Notably, no deaths were reported as related to vismodegib. The efficacy and safety of vismodegib was further reinforced with the Safety Events in Vismodegib (STEVIE) and MIKIE trials.22,23 The STEVIE trial evaluated 147 patients with advanced BCC treated with vismodegib with safety as a primary endpoint.22

View all citing articles on Scopus
View full text