title: Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a pre-planned interim analysis of an international, open-label trial.
abstract: BACKGROUND
  The Hedgehog pathway inhibitor vismodegib has shown clinical benefit in patients with advanced basal cell carcinoma and is approved for treatment of patients with advanced basal cell carcinoma for whom surgery is inappropriate. STEVIE was designed to assess the safety of vismodegib in a situation similar to routine practice, with a long follow-up.
  
  
  METHODS
  In this multicentre, open-label trial, adult patients with histologically confirmed locally advanced basal cell carcinoma or metastatic basal cell carcinoma were recruited from regional referral centres or specialist clinics. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and adequate organ function. Patients with locally advanced basal cell carcinoma had to have been deemed ineligible for surgery. All patients received 150 mg oral vismodegib capsules once a day on a continuous basis in 28-day cycles. The primary objective was safety (incidence of adverse events until disease progression or unacceptable toxic effects), with assessments on day 1 of each treatment cycle (28 days) by principal investigator and coinvestigators at the site. Efficacy variables were assessed as secondary endpoints. The safety evaluable population included all patients who received at least one dose of study drug. Patients with histologically confirmed basal cell carcinoma who received at least one dose of study drug were included in the efficacy analysis. An interim analysis was pre-planned after 500 patients achieved 1 year of follow-up. This trial is registered with ClinicalTrials.gov, number NCT01367665. The study is still ongoing.
  
  
  RESULTS
  Between June 30, 2011, and Nov 6, 2014, we enrolled 1227 patients. At clinical cutoff (Nov 6, 2013), 499 patients (468 with locally advanced basal cell carcinoma and 31 with metastatic basal cell carcinoma) had received study drug and had the potential to be followed up for 12 months or longer. Treatment was discontinued in 400 (80%) patients; 180 (36%) had adverse events, 70 (14%) had progressive disease, and 51 (10%) requested to stop treatment. Median duration of vismodegib exposure was 36·4 weeks (IQR 17·7-62·0). Adverse events happened in 491 (98%) patients; the most common were muscle spasms (317 [64%]), alopecia (307 [62%]), dysgeusia (269 [54%]), weight loss (162 [33%]), asthenia (141 [28%]), decreased appetite (126 [25%]), ageusia (112 [22%]), diarrhoea (83 [17%]), nausea (80 [16%]), and fatigue (80 [16%]). Most adverse events were grade 1 or 2. We recorded serious adverse events in 108 (22%) of 499 patients. Of the 31 patients who died, 21 were the result of adverse events. As assessed by investigators, 302 (66·7%, 62·1-71·0) of 453 patients with locally advanced basal cell carcinoma had an overall response (153 complete responses and 149 partial responses); 11 (37·9%; 20·7-57·7) of 29 patients with metastatic basal cell carcinoma had an overall response (two complete responses, nine partial responses).
  
  
  CONCLUSIONS
  This study assessed the use of vismodegib in a setting representative of routine clinical practice for patients with advanced basal cell carcinoma. Our results show that treatment with vismodegib adds a novel therapeutic modality from which patients with advanced basal cell carcinoma can benefit substantially.
  
  
  BACKGROUND
  F Hoffmann-La Roche.
authors.affiliation: Hôpital Saint Louis, Paris, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Basset-Seguin
authors.affiliation: University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Hauschild
authors.affiliation: Aix Marseille University and Timone Hospital, Marseille, France.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Grob
authors.affiliation: Medical University of Vienna, Vienna, Austria.
authors.forename: Rainer
authors.initials: R
authors.lastname: Kunstfeld
authors.affiliation: CHRU Hotel Dieu, Nantes, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Dréno
authors.affiliation: University of Lille 2, Lille Regional University Hospital, Hopital Huriez, Lille, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Mortier
authors.affiliation: Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy.
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Ascierto
authors.affiliation: Fondazione IRCCS Instituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Lisa
authors.initials: L
authors.lastname: Licitra
authors.affiliation: University Hospital of Bordeaux, Bordeaux, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Dutriaux
authors.affiliation: LYON 1 University-Centre Hospitalier Lyon Sud and Lyons Cancer Research Center (Pr Puisieux), Lyon, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Thomas
authors.affiliation: Saint Andre Hospital CHU de Bordeaux, Bordeaux, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jouary
authors.affiliation: Paul Sabatier University and Toulouse University Cancer Institute, Toulouse, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Meyer
authors.affiliation: University Hospital of Montpellier, Montpellier, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Guillot
authors.affiliation: University Hospital Zurich, Zurich, Switzerland.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.affiliation: Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Kate
authors.initials: K
authors.lastname: Fife
authors.affiliation: London Regional Cancer Program, London, ON, Canada.
authors.forename: D Scott
authors.initials: DS
authors.lastname: Ernst
authors.affiliation: Roche Products, Welwyn Garden City, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Williams
authors.affiliation: Roche Products, Welwyn Garden City, UK.
authors.forename: Alberto
authors.initials: A
authors.lastname: Fittipaldo
authors.affiliation: Roche Products, Welwyn Garden City, UK.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Xynos
authors.affiliation: Karolinska University Hospital, Solna, Stockholm, Sweden. Electronic address: Johan.Hansson@ki.se.
authors.forename: Johan
authors.initials: J
authors.lastname: Hansson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000813:Anilides / Q000008:administration & dosage* / Q000009:adverse effects; D002280:Basal Cell Carcinoma / Q000188:drug therapy* / Q000473:pathology; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000813:Anilides; C538724:HhAntag691; D011725:Pyridines