Brigitte Dréno1, Rainer Kunstfeld2, Axel Hauschild3, Scott Fosko4, David Zloty5, Bruno Labeille6, Jean-Jacques Grob7, Susana Puig8, Frank Gilberg9, Daniel Bergström10, Damian R Page11, Gary Rogers12, Dirk Schadendorf13. 1. Service de Dermato-Cancérologie, Nantes University, Nantes, France. Electronic address: brigitte.dreno@wanadoo.fr. 2. University Dermatology Clinic, Medical University of Vienna, Vienna, Austria. 3. Department of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany. 4. Department of Dermatology, Saint Louis University Medical School, St Louis, MO, USA; Department of Dermatology, Mayo Clinic, Jacksonville, FL, USA. 5. Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada. 6. Dermatology, University Hospital of Saint-Etienne, Saint-Priest-en-Jarez, France. 7. Service de Dermatologie, Aix Marseille University and Timone Hospital, Marseille, France. 8. Department of Dermatology, Hospital Clinic de Barcelona, University of Barcelona, Barcelona, Spain; Research, Oncology and Haematology, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. 9. Biostatistics, F Hoffmann-La Roche, Basel, Switzerland. 10. Global Product Development, Medical Affairs, Oncology, F Hoffmann-La Roche, Basel, Switzerland. 11. Global Product Development, Medical Affairs, Oncology and Haematology, F Hoffmann-La Roche, Basel, Switzerland. 12. Department of Surgery, Oncology Center, Tufts University School of Medicine, Boston, MA, USA. 13. Klinik für Dermatologie, Venereologie und Allergologie, Universitätsklinikum Essen, Essen, Germany.
Abstract
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.
RCT Entities:
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.
Authors: B J A Verkouteren; B Cosgun; M G H C Reinders; P A W K Kessler; R J Vermeulen; M Klaassens; S Lambrechts; J R van Rheenen; M van Geel; M Vreeburg; K Mosterd Journal: Br J Dermatol Date: 2021-11-08 Impact factor: 11.113