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Vismodegib in patients with advanced basal cell carcinoma: Primary analysis of STEVIE, an international, open-label trial

Open AccessPublished:October 24, 2017DOI:https://doi.org/10.1016/j.ejca.2017.08.022

      Highlights

      • Safety consistent with previous experience: TEAEs are tolerable and mostly reversible.
      • No association between CPK abnormalities and muscle spasm.
      • Long-term vismodegib not associated with worsening frequency/severity of new TEAEs.
      • Response rates were 68.5% in locally advanced BCC and 36.9% in metastatic BCC.
      • Patients with Gorlin syndrome responded better to vismodegib.

      Abstract

      Background

      The SafeTy Events in VIsmodEgib study (STEVIE, ClinicalTrials.gov, NCT01367665), assessed safety and efficacy of vismodegib—a first-in-class Hedgehog pathway inhibitor demonstrating clinical benefit in advanced basal cell carcinoma (BCC)—in a patient population representative of clinical practice. Primary analysis data are presented.

      Patients and methods

      Patients with locally advanced or metastatic BCC received oral vismodegib 150 mg/d until progressive disease, unacceptable toxicity, or withdrawal. Primary objective was safety. Efficacy variables were assessed as secondary end-points.

      Results

      Evaluable adult patients (N = 1215, 1119 locally advanced; 96 metastatic BCC) from 36 countries were treated; 147 patients (12%) remained on study at time of reporting. Median (range) treatment duration was 8.6 (0–44) months. Most patients (98%) had ≥1 treatment-emergent adverse event (TEAE). The incidence of the most common TEAEs was consistent with reports in previous analyses. No association between creatine phosphokinase (CPK) abnormalities and muscle spasm was observed. Serious TEAEs occurred in 289 patients (23.8%). Exposure ≥12 months did not lead to increased incidence or severity of new TEAEs. The majority of the most common TEAEs ongoing at time of treatment discontinuation resolved by 12 months afterwards, regardless of Gorlin syndrome status. Response rates (investigator-assessed) in patients with histologically confirmed measurable baseline disease were 68.5% (95% confidence interval (CI) 65.7–71.3) in patients with locally advanced BCC and 36.9% (95% CI 26.6–48.1) in patients with metastatic BCC.

      Conclusions

      The primary analysis of STEVIE demonstrates that vismodegib is tolerable in typical patients in clinical practice; safety profile is consistent with that in previous reports. Long-term exposure was not associated with worsening severity/frequency of TEAEs. Investigator-assessed response rates showed high rate of tumour control.

      ClinicalTrials.gov

      NCT01367665.

      Keywords

      1. Introduction

      Basal cell carcinoma (BCC) constitutes approximately 80% of non-melanoma skin cancers and is the most commonly diagnosed cancer worldwide [
      • Mohan S.V.
      • Chang A.L.
      Advanced basal cell carcinoma: epidemiology and therapeutic innovations.
      ,
      • Rubin A.I.
      • Chen E.H.
      • Ratner D.
      Basal-cell carcinoma.
      ]. Although most BCCs are curable by surgery, disease may progress to advanced BCC (locally advanced/metastatic BCC), for which radiotherapy and surgery are inappropriate because cure is unlikely and/or because surgery might result in substantial deformity [
      • Lear J.T.
      • Corner C.
      • Dziewulski P.
      • Fife K.
      • Ross G.I.
      • Varma S.
      • et al.
      Challenges and new horizons in the management of advanced basal cell carcinoma: a UK perspective.
      ,
      • Peris K.
      • Licitra L.
      • Ascierto P.A.
      • Corvo R.
      • Simonacci M.
      • Picciotto F.
      • et al.
      Identifying locally advanced basal cell carcinoma eligible for treatment with vismodegib: an expert panel consensus.
      ].
      The key molecular driver in the development of BCC is abnormal Hedgehog pathway signalling, exhibited in >90% of BCCs [
      • Epstein E.H.
      Basal cell carcinomas: attack of the hedgehog.
      ]. Vismodegib is a first-in-class inhibitor of the Hedgehog signalling pathway.
      Vismodegib is approved (by the US Food and Drug Administration [FDA] and the European Medicines Agency [EMA]) [
      • US Food and Drug Administration
      , ] for the treatment of adults with metastatic BCC or with locally advanced BCC that is inappropriate for surgery or radiotherapy. The pivotal phase II study ERIVANCE BCC demonstrated vismodegib response rates of 43% and 30% in patients with locally advanced and metastatic BCC, respectively, by independent review [
      • Sekulic A.
      • Migden M.R.
      • Oro A.E.
      • Dirix L.
      • Lewis K.D.
      • Hainsworth J.D.
      • et al.
      Efficacy and safety of vismodegib in advanced basal-cell carcinoma.
      ]. Subsequent analyses from ERIVANCE BCC demonstrated durable responses and a consistent efficacy/safety profile [
      • Sekulic A.
      • Migden M.R.
      • Oro A.
      • Lewis K.D.
      • Hainsworth J.D.
      • Yoo S.
      • et al.
      Pivotal ERIVANCE basal cell carcinoma (BCC) study: 12-month update of efficacy and safety of vismodegib in advanced BCC.
      ,
      • Sekulic A.
      • Migden M.R.
      • Basset-Seguin N.
      • Garbe C.
      • Gesierich A.
      • Lao C.
      • 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.
      ]. The SafeTy Events in VIsmodEgib study (STEVIE, ClinicalTrials.gov, NCT01367665) assesses safety and efficacy of vismodegib in a setting representative of clinical practice, and it is the largest study ever conducted in patients with BCC [
      • Basset-Seguin N.
      • Hauschild A.
      • Grob J.J.
      • Kunstfeld R.
      • Dreno B.
      • Mortier L.
      • et al.
      Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a pre-planned interim analysis of an international, open-label trial.
      ]. We report results from the primary analysis of the total evaluable population (N = 1215, data cut-off March 16, 2015).

      2. Methods

      2.1 Study design and patients

      STEVIE is a single-arm, multicentre, open-label study involving 167 sites in 36 countries. The study design was previously published [
      • Basset-Seguin N.
      • Hauschild A.
      • Grob J.J.
      • Kunstfeld R.
      • Dreno B.
      • Mortier L.
      • et al.
      Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a pre-planned interim analysis of an international, open-label trial.
      ]. Eligible patients (≥18 years old) had a histologically confirmed diagnosis of locally advanced/metastatic BCC, Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, and adequate organ function. For patients with locally advanced BCC, the lesion was deemed inoperable/inappropriate for surgery, and radiotherapy must have been previously administered, unless inappropriate. Patients with measurable and/or non-measurable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, were eligible for enrolment. Patients with Gorlin syndrome who met inclusion criteria were also enrolled.
      The study protocol was approved by the institutional review boards or independent ethics committees of participating centres, and the study was undertaken in accordance with the provisions of the Declaration of Helsinki and Good Clinical Practice guidelines. Patient safety was monitored by an independent data safety monitoring board (DSMB) that reviewed all aspects of safety, including death. All patients provided written informed consent.
      Enrolled patients received oral vismodegib 150 mg/d continuously until disease progression, unacceptable toxicity, withdrawal of consent, death or other reasons for discontinuation. Dose reductions were not allowed; however, treatment interruption of up to 8 weeks was permitted for management of toxicity or temporary inability to swallow capsules.
      Primary end-point was safety. Assessments included treatment-emergent adverse events (TEAEs, defined as occurring between the first administration and 30 days after the last administration of study drug [inclusive] and assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE] version 4.0), limited physical examination, vital signs, ECOG performance status and laboratory parameters. Patients enrolled after approval of study protocol version 2 had five safety follow-up visits at 1, 3, 6, 9 and 12 months after the last dose of vismodegib to assess resolution of TEAEs ongoing at the time of treatment discontinuation and progression-free survival (PFS). Secondary end-points included investigator-assessed objective response according to RECIST v1.1, duration of response (DOR, time from date of earliest response to date of progressive disease [PD] or death), time to response (TTR, time from date of first treatment to date of first documentation of confirmed complete response [CR] or partial response [PR]), PFS (time from date of first therapy to date of progression or death) and overall survival (OS, time from date of first treatment to date of death). Information on quality of life, assessed by Skindex-16 and impact of treatment on disease symptoms in patients with metastatic BCC assessed by MD Anderson Symptom Inventory (MDASI), will be published separately.
      Tumour assessment by physical examination was performed every 4–8 weeks. When necessary, computed tomography (CT) and magnetic resonance imaging (MRI) were performed every 8–16 weeks.

      2.2 Statistical analysis

      The sample size was selected to allow the adverse event (AE) incidence rate to be estimated within 1.6% and 1.8% of the true AE rate, assuming an observed incidence of 10% (i.e. within a 95% Clopper-Pearson confidence interval [CI] of 8.4–11.8) and with a precision to estimate an AE of 1% frequency to within 0.5% and 1% of the true AE rate.
      The efficacy-evaluable population included all patients who received at least one dose of study drug and had histologically confirmed disease at baseline (used for PFS and OS analysis). Patients who also had measurable disease at baseline were included in best overall response rate (BORR) and TTR assessments. All time-to-event end-points were analysed using the Kaplan–Meier method; 95% CIs were calculated using the Brookmeyer and Crowley method.

      3. Results

      3.1 Patient demographics and characteristics

      Between June 2011 and September 2014, 1232 patients were enrolled in STEVIE at 167 sites in 36 countries. Seventeen patients were excluded from the safety and efficacy analysis (no documented exposure based on return of drug dispensed), leaving 1215 evaluable patients (1119 locally advanced, 96 metastatic BCC; Supplementary Fig. S1). Table 1 shows baseline characteristics. At the time of clinical cut-off, 147 patients (12%) were receiving treatment with vismodegib. TEAEs were the main reason for treatment discontinuation (n = 349).
      Table 1Baseline characteristics and demographics of all patients given study drug.
      Locally advanced BCC

      n = 1119
      Metastatic BCC

      n = 96
      All patients

      n = 1215
      Men, n (%)634 (56.7)60 (62.5)694 (57.1)
      Women, n (%)485 (43.3)36 (37.5)521 (42.9)
      Women of childbearing potential, n (%)57 (11.8)5 (13.9)62 (11.9)
      Age, mean (SD), years69.7 (16.1)66.6 (13.0)69.5 (15.9)
      Age, median (range), years72.0 (18–101)67.0 (34–95)72.0 (18–101)
      Age group <65 years, n (%)382 (34.1)43 (44.8)425 (35.0)
      Age group ≥65 years, n (%)737 (65.9)53 (55.2)790 (65.0)
      Baseline ECOG performance status, n (%)
       Grade 0662 (59.2)39 (40.6)701 (57.7)
       Grade 1316 (28.3)42 (43.8)358 (29.5)
       Grade 2138 (12.3)15 (15.6)153 (12.6)
      Gorlin syndrome, n (%)
       Yes214 (19.2)5 (5.2)219 (18.1)
       No899 (80.8)91 (94.8)990 (81.9)
      Median time since first diagnosis, years8.357.828.31
      Diagnosis histologically confirmed, n (%)
       Yes1111 (99.3)89 (92.7)1200 (98.8)
       No8 (0.7)7 (7.3)15 (1.2)
      Ineligibility for surgery, n (%)
       Inoperable433 (38.7)433 (35.6)
       Surgery contraindicated686 (61.3)686 (56.5)
       Substantial morbidity and/or deformity anticipated385 (34.4)385 (31.7)
       Unlikely to be curatively resected, n (%)328 (29.3)328 (27.0)
       Other,
      Patients who refused surgery or had other contraindications for medical or surgical reasons.
      n (%)
      88 (7.9)88 (7.2)
      Previous radiotherapy, n (%)
       Yes312 (27.9)59 (61.5)371 (30.5)
       No806 (72.0)37 (38.5)843 (69.4)
      Contraindicated340 (30.4)11 (11.5)351 (28.9)
      Inappropriate466 (41.6)26 (27.1)492 (40.5)
      Sites of disease, n (%)
       Skin1102 (98.5)32 (33.3)1134 (93.3)
       Extremity141 (12.6)5 (5.2)146 (12.0)
       Head838 (74.9)12 (12.5)850 (70.0)
       Neck125 (11.2)9 (9.4)134 (11.0)
       Trunk245 (21.9)10 (10.4)255 (21.0)
       Other skin194 (17.3)8 (8.3)202 (16.6)
       Bone31 (32.3)31 (2.6)
       Liver8 (8.3)8 (0.7)
       Lung63 (65.6)63 (5.2)
       Lymph nodes30 (31.3)30 (2.5)
       Lymph nodes local regional5 (0.4)5 (0.4)
       Other site28 (2.5)13 (13.5)41 (3.4)
      Disease status, n (%)
       Measurable1085 (97.0)91 (94.8)1176 (96.8)
       Non-measurable26 (2.3)5 (5.2)31 (2.6)
      Total number of target lesions at baseline (median, range)2216 (2, 1–12)221 (2, 1–6)2437 (2, 1–12)
      BCC = basal cell carcinoma; ECOG = Eastern Cooperative Oncology Group.
      a Patients who refused surgery or had other contraindications for medical or surgical reasons.

      3.2 Safety

      Most patients (1192 [98%]) had ≥1 TEAE on study; the most common (>20% incidence) TEAEs were muscle spasms (807 [66%]), alopecia (747 [62%]), dysgeusia (663 [55%]), decreased weight (493 [41%]), decreased appetite (303 [25%]) and asthenia (291 [24%]) (Supplementary Table S1). A similar safety profile was observed regardless of Gorlin syndrome status (Supplementary Table S2). To address the impact of treatment exposure, rate of occurrence of TEAEs per 100 patient–years of exposure was calculated (Table 2). The higher rates observed during the first 12 months suggest that there is no trend towards increased number of new TEAEs or grade ≥3 TEAEs with increased time on treatment. Serious TEAEs were reported in 289 patients (23.8%; 260 locally advanced; 29 metastatic BCC) (Supplementary Table S3).
      Table 2TEAEs by length of exposure.
      TEAE by preferred termNumber of events (events per 100 patient–years)
      Occurring <12 months' treatment (808.9 patient–years)Occurring ≥12 months' treatment (288.1 patient–years)
      Any grade8578 (1060.5)1128 (391.6)
       Muscle spasm793 (98.0)14 (4.9)
       Alopecia732 (90.5)15 (5.2)
       Dysgeusia647 (80.0)16 (5.6)
       Weight decreased454 (56.1)39 (13.5)
       Decreased appetite281 (34.7)22 (7.6)
       Asthenia269 (33.3)22 (7.6)
       Ageusia209 (25.8)4 (1.4)
       Nausea208 (25.7)10 (3.5)
       Fatigue190 (23.5)11 (3.8)
       Diarrhoea160 (19.8)37 (12.8)
       Arthralgia110 (13.6)14 (4.9)
       Constipation105 (13.0)11 (3.8)
       Headache87 (10.8)5 (1.7)
       Vomiting90 (11.1)12 (4.2)
       Anaemia60 (7.4)29 (10.1)
      CPK = creatine phosphokinase; GGT = gamma-glutamyl transferase; TEAE = treatment-emergent adverse event.
      For each preferred term, the total number of TEAEs occurring at a rate of at least 10 events per 100 patient–years is displayed. No grade ≥3 TEAEs occurred at ≥10 events per 100 patient–years. The most common grade ≥3 TEAEs in either time period were muscle spasm, weight decreased, GGT increased, hypertension, dysgeusia, asthenia, fatigue and blood CPK level increased. A patient can be counted in both exposure categories if their total duration is 12 months or more. TEAEs were defined as occurring between the first administration of study drug and 30 days after the last administration of study drug, inclusive.
      A summary of deaths on study is included in Supplementary Table S4. Grade 5 (fatal) TEAEs occurred in 46 patients (3.8%); seven were considered related to vismodegib by the investigator but showed presence of comorbidities/risk factors in each case (Supplementary Table S5). The DSMB determined these cases to be unrelated to vismodegib (n = 6) or not assessable because of insufficient clinical data (n = 1).
      The TEAEs leading to treatment discontinuation reported in 380 patients (31%) were primarily grade 1/2. The most frequently reported TEAEs were muscle spasm (85 [7%]), dysgeusia (55 [5%]), weight decreased (47 [4%]), alopecia (39 [3%]), decreased appetite (37 [3%]), asthenia (35 [3%]), fatigue (27 [2%]), ageusia (23 [2%]) and nausea (13 [1%]).
      Further evaluation of STEVIE showed that 51 patients (4%) with advanced BCC experienced cutaneous squamous cell carcinoma (SCC). Most patients were aged >75 years with lesions located in sun-exposed areas; 18 patients (35%) had a history of cutaneous SCC, three patients (6%) had a history of Bowen disease, and two patients (4%) had a history of actinic keratosis.
      Due to the prevalence of muscle spasm in patients taking Hedgehog pathway inhibitors (HPIs), additional assessment of blood creatine phosphokinase (CPK) levels was performed. The TEAE of increased blood CPK was reported in 60 patients (4.9%) (Supplementary Table S1). The exploratory analysis used quantitative laboratory data from patients for whom ≥1 CPK measurement was available during the treatment period and showed CPK elevations in 36.4% of patients who did not experience muscle spasm and 33.9% of patients who did experience muscle spasm (Supplementary Fig. S2 and Supplementary Table S6).
      An exploratory analysis of AE reversibility after treatment discontinuation included 266 patients who completed their 12-month follow-up. At the time of treatment discontinuation, 97% of patients had ≥1 ongoing AE. This decreased during the post-treatment phase, with 92.5%, 74.8%, 59.0%, 48.9% and 45.5% of patients having ongoing AEs at 1, 3, 6, 9 and 12 months after treatment, respectively (Supplementary Fig. S3). Analysis of the five most common TEAEs associated with vismodegib treatment—muscle spasm, alopecia, ageusia, dysgeusia and decreased weight—in Gorlin syndrome and non-Gorlin syndrome patient subgroups also showed a reduction in the proportion of patients with ongoing AEs during the post-treatment period (Supplementary Table S7). Most instances of muscle spasm resolved 1–3 months after treatment, and most occurrences of ageusia, dysgeusia and alopecia resolved by 6 months after treatment. Events of weight decreased took slightly longer to resolve; most patients experienced resolution by 12 months after treatment. There were no differences in TEAE resolution between patients with Gorlin syndrome and those without, and the pattern of resolution over time in the two subgroups was similar to that seen in the overall population. A number of patients began receiving commercial vismodegib at the 12-month follow-up visit (four patients with muscle spasms; six patients with alopecia; two patients with ageusia, five patients with dysgeusia and seven patients with weight decreased), confounding interpretability. After patients taking commercial vismodegib were excluded, the prevalence of ongoing AEs was 3.4% for muscle spasm, 8.1% for alopecia, 1.5% for ageusia, 3.4% for dysgeusia and 5.4% for weight decreased. Additional medical review of these ongoing cases showed that most were grade 1 and many of the patients with grade 2/3 AEs also had medical history/risk factors in addition to age that confounded the assessment of the AEs and attribution of the AEs to vismodegib treatment.

      3.3 Efficacy

      Median follow-up was 17.9 months, and 1161 patients in the efficacy-evaluable population had histologically confirmed measurable disease. Response rates were 68.5% (95% CI 65.7–71.3) in patients with locally advanced BCC and 36.9% (95% CI 26.6–48.1) in patients with metastatic BCC (Table 3), including CR in 33.4% and 4.8% of patients with locally advanced and metastatic BCC, respectively. Other end-points are described in Table 3 and Supplementary Fig. S4. OS data for patients in the efficacy-evaluable population (both cohorts) are immature; therefore, median OS was not estimable. Response rates in patients with Gorlin syndrome and histologically confirmed measurable disease were 81.7% (95% CI 75.8–86.7) and 80.0% (95% CI 28.4–99.5) in patients with locally advanced and metastatic BCC, respectively (Table 4).
      Table 3Best confirmed overall response rate in patients with histologically confirmed and measurable disease.
      Efficacy parameterLocally advanced BCCMetastatic BCCTotal
      Patients with measurable disease at baseline, n1077841161
      Best overall response rate
       Responder, n (%)738 (68.5)31 (36.9)769 (66.2)
       95% CI(65.66–71.29)(26.63–48.13)(63.43–68.96)
      Complete response, n (%)360 (33.4)4 (4.8)364 (31.4)
      Partial response, n (%)378 (35.1)27 (32.1)405 (34.9)
      Stable disease, n (%)270 (25.1)39 (46.4)309 (26.6)
      Progressive disease, n (%)21 (1.9)9 (10.7)30 (2.6)
      Missing or not evaluable, n (%)48 (4.5)5 (6.0)53 (4.6)
      Median time to response, n

      months (95% CI)
      1077

      3.7 (2.9–3.7)
      84

      NE (5.5–NE)
      1161

      3.7 (3.5–3.7)
      Median duration of response, n

      months (95% CI)
      738

      23.0 (20.4–26.7)
      31

      13.9 (9.2–NE)
      175

      22.7 (20.3–24.8)
      Median progression-free survival, n

      months (95% CI)
      1103

      23.2 (21.4–26.0)
      89

      13.1 (12.0–17.7)
      1192

      22.1 (20.3–24.7)
      BCC = basal cell carcinoma; CI = confidence interval; NE = not estimable.
      Data are n (%) based on the number of patients with measurable disease at baseline.
      Table 4Best confirmed overall response rate in patients with histologically confirmed and measurable disease by Gorlin syndrome status.
      Efficacy parameterLocally advanced BCCMetastatic BCCTotal
      With Gorlin

      n = 213
      Without Gorlin

      n = 884
      With Gorlin

      n = 5
      Without Gorlin

      n = 84
      With Gorlin

      n = 218
      Without Gorlin

      n = 968
      Patients with measurable disease at baseline, n208863579213942
      Best overall response rate
       Responder, n (%)170 (81.7)566 (65.6)4 (80.0)27 (34.2)174 (81.7)593 (63.0)
       95% CI75.8–86.762.3–68.828.4–99.523.9–45.775.8–86.659.8–66.0
      Complete response, n (%)95 (45.7)263 (30.5)1 (20.0)3 (3.8)96 (45.1)266 (28.2)
      Partial response, n (%)75 (36.1)303 (35.1)3 (60.0)24 (30.4)78 (36.6)327 (34.7)
      Stable disease, n (%)31 (14.9)236 (27.3)1 (20.0)38 (48.1)32 (15.0)274 (29.1)
      Progressive disease, n (%)1 (0.5)20 (2.3)9 (11.4)1 (0.5)29 (3.1)
      Missing or not evaluable, n (%)6 (2.9)41 (4.8)5 (6.3)6 (2.8)46 (4.9)
      Median time to response, (95% CI), months2.9 (2.8–3.7)3.7 (3.0–3.7)2.0 (1.0–NE)NE (6.5–NE)2.9 (2.8–3.7)3.7 (3.7–3.8)
      Median duration of response,
      Analysis based on responders only.
      (95% CI), months
      28.8 (24.8–NE)18.7 (16.8–21.1)15.1 (13.9–16.2)11.0 (8.3–NE)28.8 (24.8–NE)18.5 (16.4–20.8)
      BCC = basal cell carcinoma; CI = confidence interval; NE = not estimable.
      Data are n (%) based on the number of patients with measurable disease at baseline.
      a Analysis based on responders only.

      4. Discussion

      The STEVIE patient population is analogous to the real-world setting of advanced BCC because patients were elderly (median 72.0 years in locally advanced BCC) with a high level of comorbidities (91.7%) at baseline. A disease registry evaluating real-world practice in the United States (RegiSONIC study) supports similarities between the STEVIE population and patients treated in routine medical practice, reporting a median age of newly diagnosed patients with locally advanced BCC of 68 years [
      • Yoo S.S.
      • Tang J.
      • Rogers G.
      • Olencki T.
      • Lacouture M.E.
      • Kudchadkar R.R.
      • et al.
      Determination of locally advanced basal cell carcinoma (BCC) in the first 285 patients enrolled in the RegiSONIC disease registry study.
      ]. Epidemiology studies in metastatic BCC have demonstrated a higher predominance of metastatic BCC in males (69%) similar to that in STEVIE (63%) and a similar pattern of disease spread; the most common sites are lymph nodes, lung and bone [
      • McCusker M.
      • Basset-Seguin N.
      • Dummer R.
      • Lewis K.
      • Schadendorf D.
      • Sekulic A.
      • et al.
      Metastatic basal cell carcinoma: prognosis dependent on anatomic site and spread of disease.
      ]. The primary analysis results demonstrate a consistent safety profile with that previously reported for vismodegib in patients with advanced BCC [
      • Sekulic A.
      • Migden M.R.
      • Oro A.E.
      • Dirix L.
      • Lewis K.D.
      • Hainsworth J.D.
      • et al.
      Efficacy and safety of vismodegib in advanced basal-cell carcinoma.
      ,
      • Sekulic A.
      • Migden M.R.
      • Oro A.
      • Lewis K.D.
      • Hainsworth J.D.
      • Yoo S.
      • et al.
      Pivotal ERIVANCE basal cell carcinoma (BCC) study: 12-month update of efficacy and safety of vismodegib in advanced BCC.
      ,
      • Sekulic A.
      • Migden M.R.
      • Basset-Seguin N.
      • Garbe C.
      • Gesierich A.
      • Lao C.
      • 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.
      ,
      • Basset-Seguin N.
      • Hauschild A.
      • Grob J.J.
      • Kunstfeld R.
      • Dreno B.
      • Mortier L.
      • et al.
      Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a pre-planned interim analysis of an international, open-label trial.
      ].
      Commonly occurring AEs are similar to those seen with other HPIs; most patients experience muscle spasm, alopecia and taste disturbances (ageusia/dysgeusia) [
      • Basset-Seguin N.
      • Hauschild A.
      • Grob J.J.
      • Kunstfeld R.
      • Dreno B.
      • Mortier L.
      • et al.
      Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a pre-planned interim analysis of an international, open-label trial.
      ,
      • Dummer R.
      • Guminski A.
      • Gutzmer R.
      • Dirix L.
      • Lewis K.D.
      • Combemale P.
      • et al.
      The 12-month analysis from basal cell carcinoma outcomes with LDE225 treatment (BOLT): a phase II, randomized, double-blind study of sonidegib in patients with advanced basal cell carcinoma.
      ]. Although muscle-related AEs such as muscle spasm are seen with all HPIs, increases in CPK level in patients taking vismodegib in STEVIE were mostly mild and asymptomatic. TEAEs of increased CPK level were reported in 5% of patients in STEVIE (mainly grade 1/2), with increased CPK level in 64 of 432 patients (14.8%) with available laboratory samples included in the exploratory analysis. TEAEs of increased blood CPK level occurred in ≥30% of patients treated with sonidegib despite the exclusion of patients treated with drugs that might cause muscle damage [
      • Dummer R.
      • Guminski A.
      • Gutzmer R.
      • Dirix L.
      • Lewis K.D.
      • Combemale P.
      • et al.
      The 12-month analysis from basal cell carcinoma outcomes with LDE225 treatment (BOLT): a phase II, randomized, double-blind study of sonidegib in patients with advanced basal cell carcinoma.
      ]. There were no reports of rhabdomyolysis in STEVIE. Exploratory analysis did not demonstrate any association between CPK abnormalities and muscle spasm or any clinically relevant sequelae, including renal insufficiency.
      As experience with HPIs has increased, questions have arisen regarding the development of cutaneous SCC after exposure to vismodegib and the persistence of AEs after drug discontinuation [
      • Aasi S.
      • Silkiss R.
      • Tang J.Y.
      • Wysong A.
      • Liu A.
      • Epstein E.
      • et al.
      New onset of keratoacanthomas after vismodegib treatment for locally advanced basal cell carcinomas: a report of 2 cases.
      ,
      • Mohan S.V.
      • Chang J.
      • Li S.
      • Henry A.S.
      • Wood D.J.
      • Chang A.L.
      Increased risk of cutaneous squamous cell carcinoma after vismodegib therapy for basal cell carcinoma.
      ]. Data from this large patient population with advanced BCC provide further understanding regarding these events, such as prevalence and risk factors.
      The causality assessment in SCC is challenging because the observation occurred in a single-arm study and there is a known increased risk for developing new SCCs in patients with a history of BCC [
      • Marcil I.
      • Stern R.S.
      Risk of developing a subsequent nonmelanoma skin cancer in patients with a history of nonmelanoma skin cancer: a critical review of the literature and meta-analysis.
      ,
      • Flohil S.C.
      • van der Leest R.J.
      • Arends L.R.
      • de Vries E.
      • Nijsten T.
      Risk of subsequent cutaneous malignancy in patients with prior keratinocyte carcinoma: a systematic review and meta-analysis.
      ]. However, the incidence of cutaneous SCC in STEVIE was 4.2%, in contrast with the 12.5% observed in ERIVANCE BCC and consistent with the expected incidence based on literature in a similar population [
      • Alkeraye S.
      • Maire C.
      • Desmedt E.
      • Templier C.
      • Mortier L.
      Persistent alopecia induced by vismodegib.
      ]. A recent meta-analysis estimating the risk for subsequent SCC in patients with a history of BCC reported a pooled estimate proportion of 4.3% (95% CI 1.7–10.1%) [
      • Flohil S.C.
      • van der Leest R.J.
      • Arends L.R.
      • de Vries E.
      • Nijsten T.
      Risk of subsequent cutaneous malignancy in patients with prior keratinocyte carcinoma: a systematic review and meta-analysis.
      ]. Nevertheless, the current analysis is limited by the lack of histological data and a control arm in STEVIE.
      Case reports of persistent AEs have been described with vismodegib treatment [
      • Alkeraye S.
      • Maire C.
      • Desmedt E.
      • Templier C.
      • Mortier L.
      Persistent alopecia induced by vismodegib.
      ]. STEVIE showed that the majority of common AEs associated with vismodegib treatment (muscle spasm, alopecia, ageusia, dysgeusia and decreased weight) that were ongoing at the time of treatment discontinuation resolved by 12 months after treatment discontinuation. The remaining cases were mostly mild, and confounding factors were present in all cases. The presence of ongoing AEs >6 months after treatment discontinuation might be related to the persistent blood levels of vismodegib due to the long half-life of this protein-bound drug, or it may be related to the physiological process associated with the AE (e.g. the kinetics of the hair growth cycle).
      In the current study, most TEAEs that led to treatment discontinuation were grade 1/2, and 147 patients remain on treatment at the time of this report, demonstrating that the chronicity of AEs rather than the severity can lead to discontinuation. Management of TEAEs is essential to optimise treatment benefit; educating patients on what to expect and possible management options is important. Management recommendations that provide guidance for healthcare professionals have been published [
      ,
      ,
      • Lacouture M.E.
      • Dreno B.
      • Ascierto P.A.
      • Dummer R.
      • Basset-Seguin N.
      • Fife K.
      • et al.
      Characterization and management of hedgehog pathway inhibitor-related adverse events in patients with advanced basal cell carcinoma.
      ,
      • Fife K.
      • Herd R.
      • Lalondrelle S.
      • Plummer R.
      • Strong A.
      • Jones S.
      • et al.
      Managing adverse events associated with vismodegib in the treatment of basal cell carcinoma.
      ], and physicians should consult their local prescribing information for guidance on management of TEAEs.
      Efficacy in this analysis was consistent with the previously reported efficacy profile of vismodegib in advanced BCC [
      • Sekulic A.
      • Migden M.R.
      • Basset-Seguin N.
      • Garbe C.
      • Gesierich A.
      • Lao C.
      • 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.
      ,
      • Basset-Seguin N.
      • Hauschild A.
      • Grob J.J.
      • Kunstfeld R.
      • Dreno B.
      • Mortier L.
      • et al.
      Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a pre-planned interim analysis of an international, open-label trial.
      ]. Response rates of 68.5% and 36.9% in patients with locally advanced and metastatic BCC, respectively, in STEVIE are consistent with those reported by investigators in ERIVANCE BCC at the final (30-month) analysis (60.3% and 48.5%), respectively [
      • Sekulic A.
      • Migden M.R.
      • Basset-Seguin N.
      • Garbe C.
      • Gesierich A.
      • Lao C.
      • 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.
      ]; DOR and PFS were also consistent with those of the final analysis of ERIVANCE BCC. The Gorlin subgroup analysis indicates that patients with Gorlin syndrome responded better to treatment, with a considerably higher rate of CR (45.1%) than patients without Gorlin syndrome (28.2%), which might be a result of these patients being younger and having a better ECOG performance status than patients without Gorlin syndrome. However, it is clear that response rates in the whole study population were not influenced by the inclusion of patients with Gorlin syndrome because they were similar to response rates in the subgroup of patients without Gorlin syndrome.
      Limitations of STEVIE include the absence of a control arm and the lack of independent central review [
      • Sekulic A.
      • Migden M.R.
      • Oro A.E.
      • Dirix L.
      • Lewis K.D.
      • Hainsworth J.D.
      • et al.
      Efficacy and safety of vismodegib in advanced basal-cell carcinoma.
      ]; however, the STEVIE population is reflective of real-world patients seen in everyday practice. A multidisciplinary approach is essential to the decision to treat patients with advanced BCC with use of HPIs. Close follow-up of patients after treatment initiation is necessary to manage TEAEs and assess continued benefit of treatment.
      Results from the primary analysis of STEVIE show that vismodegib has a manageable and consistent safety profile in a population representative of patients treated in routine clinical practice. Treatment with vismodegib led to tumour response and control and should be considered for this difficult-to-treat patient group.

      Funding support and role of the sponsor

      Funding for this study was provided by F. Hoffmann-La Roche, Ltd. (no grant number). This study was designed by the investigators and representatives of the funder. Funder representatives participated in study design; study steering committee meetings; the gathering, analysis or interpretation of the data; and writing of the report and had access to the raw data. The funder was responsible for data gathering and analysis. All authors contributed to the interpretation of the data and subsequent writing, reviewing and amendment of the manuscript. The funder financed writing and editorial support. All authors vouch for the accuracy and completeness of the reported data and attest that the study conformed to the protocol and statistical analysis plan. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

      Conflict of interest statement

      The authors declare the following: Nicole Basset-Séguin: employee of Genentch/F. Hoffmann-La Roche, Ltd.; honoraria from Galderma, Leo, Pierre Fabre, Novartis and Roche; consulting or advisory role for Galderma, Leo, Pierre Fabre, Novartis, Roche; patents, royalties, or other intellectual property from Genentech/F. Hoffmann-La Roche, Ltd.; travel, accommodations, or expenses from Galderma, Leo and Roche. Natalie Dimier: employee of F. Hoffmann-La Roche, Ltd., and holds stock or other ownership. Alberto Fittipaldo: employee of F. Hoffmann-La Roche, Ltd., and holds stock or other ownership. IoannisXynos: employee of F. Hoffmann-La Roche, Ltd., and holds stock or other ownership. Reinhard Dummer: honoraria from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis and Roche; consulting or advisory role for Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis and Roche; research funding from Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis and Roche. Kate Fife: honoraria from GlaxoSmithKline, Pfizer and Roche; consulting or advisory role for Pfizer and Roche; research funding from AstraZeneca and Roche; travel, accommodations or expenses from Novartis and Roche. Jean-Jacques Grob: honoraria from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis and Roche; consulting or advisory role Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis and Roche; speaker's bureau for GlaxoSmithKline and Roche; research funding from Bristol-Myers Squibb and Roche; travel, accommodations or expenses from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme and Roche. Axel Hauschild: honoraria from Amgen, Bristol-Myers Squibb, Celgene, Eisai, GlaxoSmithKline, MedImmune, MELA Sciences, Merck Serono, Merck Sharp & Dohme/Merck, Novartis, Oncosec and Roche; consulting or advisory role for Amgen, Bristol-Myers Squibb, Celgene, Eisai, GlaxoSmithKline, MedImmune, MELA Sciences, Merck Serono, Merck Sharp & Dohme, Novartis, Oncosec and Roche; research funding from Amgen, Bristol-Myers Squibb, Celgene, Eisai, GlaxoSmithKline, MedImmune, MELA Sciences, Merck Serono, Merck Sharp & Dohme, Novartis, Oncosec and Roche; travel, accommodations, or expenses from Amgen, Bristol-Myers Squibb, Celgene, Eisai, GlaxoSmithKline, MedImmune, MELA Sciences, Merck Serono, Merck Sharp & Dohme, Novartis, Oncosec and Roche. Rainer Kunstfeld: honoraria from Meda, Menarini, Novartis and Roche; consulting or advisory role for Leo, Meda, Menarini, Novartis, Roche and Sprig. Nicolas Meyer: honoraria from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Pierre Fabre and Roche; consulting or advisory role for Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis and Roche; expert testimony for Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis and Roche; travel, accommodations or expenses from Bristol-Myers Squibb and Roche. Paulo A. Ascierto: consulting or advisory role for Amgen, Array, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Genentech/Roche and Ventana; research funding from Bristol-Myers Squibb, Genentech/Roche and Ventana. Brigitte Dreno: consulting or advisory role for Bristol-Myers Squibb, GlaxoSmithKline, Novartis and Roche; speaker's bureau for Bristol-Myers Squibb, GlaxoSmithKline and Roche; research funding from Bristol-Myers Squibb, GlaxoSmithKline and Roche; travel, accommodations or expenses from Amgen, Bristol-Myers Squibb and Roche. Johan Hansson: consulting or advisory role for Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis and Roche; research funding from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis and Roche. Lisa Licitra: consulting or advisory role for AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Merck Serono, Merck Sharp & Dohme, Novartis, Roche and Sobi. Laurent Mortier: consulting or advisory role for Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharpe & Dohme and Roche; research funding from Bristol-Myers Squibb, CSO Pharma (institution), GlaxoSmithKline, Novartis and Roche; travel, accommodations or expenses from Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme and Roche. Ana Raimundo: consulting or advisory role for Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis and Roche; speaker's bureau for Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme and Roche; travel, accommodations or expenses from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme and Roche. Petr Arenberger, Emi Dika, Caroline Dutriaux, Bernard Guillot, Luc Thomas: no conflicts of interest.

      Acknowledgements

      The authors thank all the patients and their families and the investigators and research teams who participated in this study (a full list of investigators is provided in Appendix 1). The authors also thank Laurence Lehuu (Global Study Leader) and Christian Hertig, Daniela Stokmaier and Maneesh Tandon (Clinical Science) for help in cleaning and interpreting the data and Rina Adak (ApotheCom, London, UK) for medical editorial assistance.

      Appendix 1. List of investigators, sites and patients enrolled

      Tabled 1
      InvestigatorCentrePatients enrolled
      Rainer KunstfeldAKH Wien; Klinische Abteilung für allgemeine Dermatologie61
      Jean-Jacques GrobHopital Timone Adultes; Dermatologie61
      Brigitte DrenoHopital Hotel Dieu Et Hme; Clinique Dermatologique50
      Laurent MortierCentre Oscar Lambret; Hopital De Jour41
      Paulo AsciertoIstituto Nazionale Tumori Fondazione G. Pascale37
      Lisa LicitraFondazione IRCCS Istituto Nazionale dei Tumori; S.S. Trattamento MedicoTumori dellaTesta e delCollo33
      Caroline DutriauxHopital Saint Andre CHU De Bordeaux; Dermatologie29
      Luc ThomasCentre Hospitalier Lyon Sud; Dermatologie27
      Nicolas MeyerHôpital Larrey Université Paul Sabatier; Service Dermatologie25
      Bernard GuillotHopital Saint Eloi; CHU de Montpellier; Svc de Dermatologie24
      Reinhard DummerUniversitätsspital Zürich; Dermatologische Klinik23
      Nicole Basset-SeguinHopital Saint Louis; Dermatologie 123
      Pertr ArenbergerFakultni nemocnice Kralovske Vinohrady20
      Kate FifeAddenbrookes Hospital; Cambridge Cancer Trials Centre, S4 Box 27919
      Johan HanssonKarolinska Universitetssjukhuset, Solna18
      Ana RaimundoIPO do Porto; Servico de Oncologia Medica17
      Annalisa PatriziPoliclinico Sant'Orsola Malpighi; U.O. Dermatologia16
      Eric WinquistLondon Regional Cancer Centre, London, Ontario, Canada15
      Verónica Ruiz SolesHospital de la Santa Creu i Sant Pau; Servicio de Dermatologia15
      Carlos Guillen BaronaInstituto Valenciano Oncologia; Oncologia Medica13
      Caroline RobertInstitut Gustave Roussy; Comite 513
      Alfonso Berrocal JaimeHospital General Universitario de Valencia; Servicio de oncologia12
      Ekaterina PeychevaNational Specialized Hospital for Active Oncology Treatment; Dermatology Clinic12
      Pablo Fernandez-PenasSkin and Cancer Foundation Australia11
      Pierre vabresChu Site Du Bocage; Dermatologie11
      Sergio ChimentiFondazione PTV Policlinico Tor Vergata; Dermatologia11
      Ralf GutzmerMedizinische Hochschule Hannover; Klinik für Dermatologie, Allergologie und Venerologie11
      Georgy Moiseevich ManikhasSaint-Petersburg City Clinical Oncology Dispensary11
      Piergiacomo Calzavara PintonUniversità di Brescia; Dipartimento di Dermatologia11
      Claus GarbeUniversitaets-Hautklinik Tuebingen10
      Nowell SolishDr. Nowell Solish Cosmetic Dermatology10
      Maria Concetta FargnoliOspedale San Salvatore (ASL-01); Dip. di Dermatologia U.O.S. di Dermatologia Oncol10
      Ellen de HaasErasmus MC; Dermatology10
      Evgeny LevchenkoFSBI Research Oncology Institute n.a. N.N. Petrov of Ministry of Health and Social Development10
      Peter FoleySkin & Cancer Foundation9
      Franz TrautingerLandesklinikum St. Pölten9
      Alessandro TestoriIrccs Istituto Europeo Di Oncologia (IEO); Oncologia Medica9
      Yves PoulinCentre de Recherche Dermatologique du Quebec Metropolitain (CRDQ)9
      Santora ArmandoIRCCS Istituto Clinico Humanitas; Farmacia8
      Alexander StratigosAndreas Syggros Hospital; 1st University Dermatology Clinic; Oncology Department8
      Dirk SchadendorfUniversitätsklinikum Essen, Klinik für Dermatologie8
      Patrick SchöffskiU.Z. Gasthuisberg; Gezwelziekten – Medische Oncologie8
      Carola BerkingKlinikum der LMU München; Klinik und Poliklinik für Dermatologie und Allergologie8
      Francesco De RosaI.R.S.T. Srl – Meldola – FC; Day Hospital Oncologico8
      Dedee MurrellPremier Specialists8
      Ioannis BassukasUniversity General Hospital of loannina; Dermatology and Venereal Diseases Clinic7
      Eva BrunSkånes Onkologiska Klinik Universitetssjukhusest7
      Robert HerdWestern Infirmary; Division of Cardiovascular and Medical Sciences7
      Martin LeverkusKlinikum Mannheim Klinik fuer Dermatologie, Venerologie und Allergologie7
      Luis De La Cruz MerinoHospital Universitario Virgen Macarena; Servicio de Oncologia7
      Vincenzo De GiorgiOspedale IOT-Palagi Dermatologia 27
      Roland KaufmannKlinikum Johann-Wolfgang-Goethe-Uni.; Klinik für Dermatologie, Venerologie und Allergologie7
      Susana Puig SardáHospital Clinic i Provincial; Servicio de dermatología7
      Gilberto Castro JuniorInstituto do Cancer do Estado de Sao Paulo – ICESP6
      Suayib YalcinHacettepe Uni Medical Faculty Hospital; Oncology Department6
      Mariusz SapijaszkoWestern Canada Dermatology Institute6
      Janja OcvirkInstitute of Oncology Ljubljana6
      Lev DemidovRussian Cancer Research Center6
      Lidija Kandolf SekulovicMilitary Medical Academy6
      Marni WisemanCancer Care Manitoba6
      Zygmunt AdamskiCentrum Diagnostyki Znamion6
      Paola QueiroloIRCCS Istituto Nazionale Per La Ricerca Sul Cancro (IST); Oncologia Medica A6
      Gabriella LiszkayOrszagos Onkologiai Intezet; Borgyogyaszati Osztaly6
      Sari PitkänenHelsinki University Central Hospital; Skin & Allergy Hospital6
      Jessica HasselUniversitaetsklinikum Heidelberg6
      Yvetta VantuchováFakultní nemocnice Ostrava; Kožní oddělení5
      Ivana KrajsováVseobecna fakultni nemocnice v Praze5
      Elkin PeñarandaRiesgo De Fractura; Rheumatology5
      Mirna SitumClinical Hospital Sisters of Mercy5
      Sergio AzevedoHospital das Clinicas – UFRGS5
      Michele MaioA.O.U. Senese Policlinico Santa Maria Alle Scotte5
      Massimo AgliettaFondazione Del Piemonte Per L'oncologia Ircc Di Candiolo; Dipartimento Oncologico5
      Laima PlesnieneNational Cancer Institute5
      Slavomir UrbancekFacultna Nemocnica Roosevelta5
      Ricardo Fernández de MisaComplejo Hospitalario Nuestra Señora de la Candelaria; Servicio de Dermato5
      Teresa Guerrero UrbanoSt Thomas Hospital5
      Rudolf HerbstHELIOS Klinikum Erfurt, Klinik für Hautkrankheiten und Allergologie5
      Uwe MartensKlinikum am Gesundbrunnen; Tumorzentrum5
      Klara MosterdMaastricht University Medical Centre; Dermatologie5
      Javier Medina MartinezComplejo Hospitalario de Toledo-H. Virgen de la Salud; Servicio de Dermatologia5
      Gregorio Carretero HernándezHospital de Gran Canaria Dr. Negrin; Servicio de Dermatologia5
      Julie GehlHerlev Hospital; Onkologisk afdeling5
      Roxana Del AguilaInst. De Oncologia Angel H. Roffo; Servicio De Oncologia4
      Patrizio MulasOspedale Armando Businco; Dermatologia4
      Ruth PlummerFreeman Hospital; Northern Centre for Cancer Care4
      John LearSalford Royal NHS Foundation Trust4
      Tudor Eliade CiuleanuProf. Dr. I. Chiricuta Institutul Oncologic4
      Luciano VianaHospital de Cancer de Barretos4
      Ingrid WolfLKH Graz; Abteilung für allgemeine Dermatologie4
      Axel HauschildUNI-Klinikum Campus Kiel Klinik f.Dermatologie Tagesklinik f.Dermatologie4
      Anja GesierichUniversitätsklinikum Würzburg Klinik und Poliklinik für Dermatologie Venerologie u. Allergologie4
      Laura EibenschutzIstituto Dermatologico San Gallicano IRCCS; Dermatologia Oncolgica4
      Steven BernsteinVictoria Park MediSpa4
      Jose Luis López EstebaranzFundacion Hospital de Alcorcon; Servicio de Dermatologia4
      Erwin SchultzKlinikum Nürnberg Nord; Hautklinik4
      Saverio CinieriOspedale Antonio Perrino; Oncologia Medica4
      Remco van DoornLUMC; Dermatologie4
      Richard MartinWaitemata District Health; General Surgery4
      Michelle MurphyCork University Hospital; Dermatology Dept3
      Giuseppe GulloSt Vincent's Uni Hospital; Medical Oncology3
      Sarolta KarpatiSemmelweis Egyetem; Bor-, Nemikortani es Boronkologiai Klinika3
      Jens UlrichKlinikum Dorothea Ch.Erxleben; Klinik für Dermatologie und Allergologie3
      Peter MohrElbe Kliniken Buxtehude Dermatologisches Zentrum3
      Martin KaatzSRH Wald-Klinikum Gera; Klinik für Hautkrankheiten und Allergologie3
      Danil StroyakovskiyMoscow city oncology hospital #62 of Moscow Healthcare Department3
      Stefano CalvieriAzienda Ospedaliera Umberto I; Clinica Dermatologica3
      Sebnem OzkanDokuz Eylul University Medicine Faculty; Dermatology3
      Isil SomaliDokuz Eylul University Medicine Faculty; Dermatology3
      Maria Luisa Zubiri AraHospital Universitario Miguel Servet; Servicio Dermatologia3
      Andrzej KaszubaDERMED Centrum Medyczne; Sp zoo3
      Cornelia ToganelSpital Clinic Judetean Mures; Oncologie3
      Åse BratlandOslo Universitetssykehus HF; Radiumhospitalet3
      Josef KollerLKH Salzburg; Universitätsklinik für Dermatologie3
      Gergana Shalamanova-DelevaDistrict Oncology Dispensary; Department for Oncology and Dermatology3
      Cornelia MauchKlinik der Uni zu Köln; Klinik & Poliklinik fuer Dermatologie & Venerologie3
      Jose Antonio Lopez Martin

      Jose
      Hospital Universitario 12 de Octubre; Servicio de Oncologia3
      Philippe SaiagHopital Ambroise Pare; SCE Dermatologie3
      Maria Agustina Segurado

      Rodriguez
      Hospital Universitario del Sureste; Servicio de Dermatologia3
      Jacob SchachterSheba Medical Center; Tel Hashomer3
      Eyal FenigRabin Medical Center-Beilinson Campus3
      Armin BenderUniversitätsklinikum Marburg Klinik f. Dermatologie3
      Pedro Mercader GarciaHospital General Universitario J.M Morales Meseguer; Servicio de Dermatologia3
      Alvaro AcostaInst. Nacional de Cancerologia; Clinica de Seno2
      Natalia JaimesHospital Pablo Tobin Uribe2
      Shireen SidhuCMAX A division of IDT Australia Limited2
      Predrag NikolicUniversity Hospital Clinical Center Banja Luka2
      Guillermo JimenezReumalab Sas; Rheumatology2
      Jitka AbrahamovaFacultni Thomayerova Nemocnice; Onkologicke Oddeleni2
      Rauno HarvimaKuopion yliopistollinen sairaala2
      Wolfgang HarthVivantes Klinikum Spandau2
      Patrick TerheydenUniversitätsklinikum Schleswig-Holstein; Klinik für Dermatologie, Allergologie und Venerologie2
      Carsten WeishauptUniversitätsklinikum Münster; Klinik fuer Hautkrankheiten2
      Dorothée NashanKlinikum Dortmund gGmbH Klinikzentrum Mitte2
      Vanna Chiarion SileniIRCCS Istituto Oncologico Veneto (IOV); Oncologia Medica Seconda2
      Roxolyana Adbah-BortnyakRambam Medical Center2
      Andrzej CichockiCentrum Onkologii – Instytut im. Marii Sklodowskiej-Curie; Klinika Onkologiczna2
      Salvatore SienaAsst Grande Ospedale Metropolitano Niguarda; Dipartimento Di Ematologia Ed Oncologia2
      Paolo MarchettiIstituto Dermopatico dell'Immacolata (IDI)-IRCCS; IV Divisione Oncologica e Dermatologia Oncologica2
      Jacek JassemUniwersyteckie Centrum Kliniczne, Klinika Onkologii i Radioterapii2
      Rodica AnghelInstitutul Oncologic Prof. Dr. Al. Trestioreanu Bucuresti2
      Jorge FrankUniversitätsklinikum Düsseldorf; Hautklinik2
      Ivan Marquez RodasHospital General Universitario Gregorio Marañon; Servicio de Oncologia2
      Martin GoreRoyal Marsden Hospital2
      Pablo Coto SeguraHospital Univ. Central de Asturias; Servicio de Dermatologia2
      Rafael Salido VallejoHospital Reina Sofia; Servicio de dermatología2
      José Carlos Moreno GimenezHospital Reina Sofia; Servicio de dermatología2
      Claas UlrichCampus Charité Mitte CharitéCentrum 12 Klinik für Dermatologie Venerologie und Allergologie1
      Ana Francisca RamirezHemato Oncologos S.A.1
      Eva RemenyikDebreceni Egyetem OEC; Borgyogyaszati Klinika1
      Zita BattyaniKaposi Mor Teaching Hospital1
      Sidika KurulIstanbul Uni of Medicine Faculty; Oncology Department1
      Esther De EusebioHospital General Universitario de Guadalajara; Servicio de Dermatologia1
      Andres Garcia-Paolomo PerezComplejo Asistencial Universitario de Leon; Servicio de Onc1
      Javier Martin BrotoHospital Universitario Son Espases; Servicio de Oncologia1
      Guillermo Lopez VivancoHospital de Cruces; Servicio de Oncologia1
      Nada BabovicInstitute for Oncology and Radiology of Serbia; Medical Oncology1
      Geke HospersAcadem Ziekenhuis Groningen; Medical Oncology1
      Lajos KemenySzegedi Tudomanyegyetem; Borgyogyaszati es Allergologiai Klinika1
      Vassilis GeorgouliasUniv General Hosp Heraklion; Medical Oncology1
      Konstantinos PaparzisisEuromedical General Clinic of Thessaloniki; Oncology Department1
      Helen GogasLaiko General Hospital; 1st Pathological Clinic1
      Hans-Robert MetelmannUniversitätsmedizin Greifswald; Klinik für MKG-Chirurgie und Plastische Operationen1
      Rüdiger HeinKlinikum rechts der Isar der TU München; Klinik & Poliklinik für Dermatologie und Allergologie1
      Maja BanjinClinic of Oncology – Clinical Center University of Sarajevo1
      Harald GollnickUniversitätsklinikum Magdeburg Klinik für Dermatologie und Venerologie1
      Friedegund MeierUniversitätsklinikum ‘Carl Gustav Carus’; Klinik und Poliklinik für Dermatologie1
      Annette SteinUniversitätsklinikum ‘Carl Gustav Carus’; Klinik und Poliklinik für Dermatologie1
      Mark BerneburgUniversitätsklinikum Regensburg; Klinik und Poliklinik für Dermatologie1
      Edgar DippelKlinikum d.Stadt Ludwigshafen Hautklinik1
      Jiri HorazdovskyNemocnice Ceske Budejovice0

      Appendix 2. List of ethics committees/institutional review boards

      Tabled 1
      CountryEthics committee/institutional review board
      ArgentinaComite de Docencia e Investigacion del Roffo Av. San martin 5481 C1417DTB Buenos Aires
      AustraliaBellberry Human Research Ethics Committee Bellberry Limited 229 Greenhill Road 5065 Dulwich
      AustriaEthikkommission d. Landes Niederösterreich Landhausplatz 1

      3109 St. Pölten
      AustriaEthikommission des Land Salzburg Sebastian-Stief-Gasse 2 5010 Salzburg
      AustriaEK Graz Med. Fakultaet Universitaet Graz 8036 Graz
      AustriaEthikkommission der Universität Wien /AKH Borschkegasse 8b/E 06 1090 Wien
      BelgiumUZ Leuven – Ethisch comite Herestraat, 49 3000 Leuven
      Bosnia and HerzegovinaEC Clinical Center University of Sarajevo Bolnicka 25 71 000 Sarajevo
      Bosnia and HerzegovinaEC Clinical Center Banja Luka Dvanaest beba bb 78 000 Banja Luka
      BrazilCEP para Analise de Projetos de Pesquisa do HCFMUSP e da FMUSP;Hospital da Universidade de São Paulo Rua Doutor Arnaldo, 455–01246-903 05403-010 São Paulo
      BrazilCEP da Fundacao Pio XII – Hospital de Cancer de Barretos Rua Antenor Duarte Vilela 1331 14784-400 Barretos
      BrazilComitê de Ética em Pesquisa do Hospital de Clínicas de Porto Alegre Hospital de Clínicas de Porto Alegre Rua Ramiro Barcelos, 2350

      90035-003 Porto Alegre
      BulgariaLocal Ethics Committee Specialized Hospital For Active Treatment in Oncology 6 Plovdivsko pole Street 1756 Sofia
      BulgariaLocal Ethics Committee Complex Oncology Center – Plovdiv 2A, Alexander Stamboliisky Str 4004 Plovdiv
      CanadaQuorum Review IRB

      1501 Fourth Ave. Suite 800 98101 Seattle
      CanadaHealth Research Ethics Board University of Alberta 308 Campus Tower 8625-112 Street T6G 1K8 Edmonton
      CanadaUniversity of Western Ontario Office of Research Ethics Support Services Building, 1393 Western Road N6A 3K7 London
      CanadaBiomedical Research Ethics Board Univeristy Of Manitoba – Faculty Of Medicine P126 R3E 0W3 Winnipeg
      ColombiaComité de Etica CAYRE Carrera 12 No. 98-38 Bogotá
      ColombiaComité de Ética en Investigación del Instituto Nacional de Cancerologia Empresa social del Estado Bogotá
      ColombiaComité de Investigaciones y ética en Investigaciones CALLE 78 B NO. 69-240 0 MEDELLIN
      ColombiaCREIMED. Comite de Estudios Medicos S.A.S Carrera 43 A # 34 – 155 Piso 6 Medellin
      ColombiaComité de Etica en Investigacion IDYCIC SAS Carrera 21 # 14 – 80

      Casa G 8 Chia
      CroatiaCentral Ethics Committee Agency for Medicinal Products and Medical Devices, Ksaverska cesta 4 10000 Zagreb
      Czech RepublicEticka Komise Vseobecne fakultni nemocnice Na Bojisti 1 128 08

      Praha 2
      Czech RepublicEtická komise pri IKEM a TN Vídenská 800 14059 Prague
      Czech RepublicEtická komise FNKV Šrobárova 50 100 34 Prague 10
      Czech RepublicEticka komise Nemocnice Ceske Budejovice B. Nemcove 54

      37087 Ceske Budejovice Czech Republic
      Czech RepublicEticka komise Fakultni nemocnice Ostrava 17 Listopadu 1790 70852 Ostrava
      DenmarkVEK København-Frederiksberg Regionsgården Kongens Vænge 2 DK-3400 Hillerød
      FinlandHUS Medisiininen eettinen toimikunta Biomedicum Helsinki 2 C, PL 705 Tukholmankatu 8 C 00029 Hus FINLAND
      FranceCPP Ile de France VI Groupe Hospitalier Pitié Salpétrière – 4 Bat. de la Force 47 Boulevard de l'Hôpital 75651 Paris France
      GermanyEthik-Kommission der Medizinischen Fakultät der Christian-Albrechts-Universität zu Kiel Schwanenweg 20 24105 Kiel
      GermanyEK an der Med. Fakultät d. Eberhard-Karls-Uni und am Uniklinikum Tübingen Gartenstr. 47 72074 Tübingen
      GermanyEK Essen Ethik-Kommission der Medizinischen Fakultät der Universität Duisburg-Essen Robert-Koch-Str. 9-11, 2. Stock

      45147 Essen
      GermanyEthik-Kommission der Medizinischen Hochschule Hannover Carl-Neuberg-Strasse 1 30625 Hannover
      GermanyEthik-Kommission Berlin Landesamt für Gesundheit und Soziales Fehrbelliner Platz 1 10707 Berlin
      GermanyEthikkommission der Medizinischen Fakultät, der Ludwig-Maximilians-Universität München Pettenkoferstr. 8a 80336 Muenchen
      GermanyEK Würzburg Versbacher Str. 9 97078 Würzburg
      GermanyEK Mannheim Maybachstr. 14 68169 Mannheim
      GermanyEthik-Kommission der Landesärztekammer Thüringen Im Semmicht 33 07751 Jena
      GermanyEK Baden-Württemberg LÄK Jahnstr. 40 70597 Stuttgart
      GermanyEK Koeln Kerpener Str. 62 Gebäude 5 50937 Köln
      GermanyEK des Fachbereichs Medizin der Johann Wolfgang Goethe-Uni Frankfurt Theodor-Stern-Kai 7 60596 Frankfurt
      GermanyEK Bayern LAK Muhlbaurstr. 16 81677 Munchen
      GermanyKommission für Ethik in der ärztlichen Forschung des Fachbereichs Humanmedizin Baldingerstraße 35033 Marburg
      GermanyEthikkommission der Medizinischen Fakultät Heidelberg Alte Glockengießerei 11/1 69115 Heidelberg
      GermanyEK Rheinland-Pfalz LÄK Deutschhausplatz 3 55116 Mainz
      GermanyEthik-Kommission an der Universität Regensburg Franz-Josef-Strauß Allee 11 93053 Regensburg
      GermanyEK bei der Ärztekammer Niedersachsen Berliner Allee 20 30175 Hannover
      GermanyEthik-Kommission am Universitätsklinikum Carl-Gustav-Carus Technische Universität Dresden Fiedlerstr. 27 01307 Dresden
      GermanyEthik-Kommission der Landesärztekammer Thüringen Im Semmicht 33 07751 Jena
      GermanyEthik-Kommission an der Medizinischen Fakultät Heinrich-Heine-Universität Düsseldorf Moorenstr. 5 40225 Düsseldorf
      GermanyEthik-Kommission der Otto-von-Guericke-Universität an der Medizinischen Fakultät Leipziger Straße 44 39120 Magdeburg
      GermanyEK München TU Ismaninger Str. 22 81675 München
      GermanyEthik-Kommission der Ärztekammer Westfalen-Lippe u. der Med. Fakultät d. Westf. Wilhelms-Universität Gartenstr. 210 – 214 48147 Münster
      GermanyEthik-Kommission des Landes Sachsen-Anhalt Kühnauer Str. 70 06846 Dessau-Roßlau
      GermanyEK Lübeck Ratzeburger Allee 160 23538 Lübeck
      GermanyEthikkommission an der Medizinischen Fakultät Ernst-Moritz-Arndt-Universität Greifswald Felix-Hausdorff-Str. 3 17487 Greifswald
      GermanyEthik-Kommission Berlin Landesamt für Gesundheit und Soziales Fehrbelliner Platz 1 10707 Berlin
      GreeceNational Ethics Committee Ministry of Health and Social Welfare 284, Messogion Avenue 15562 Cholargos Greece
      HungaryMedical Research Council, Ethics Committee for Clinical Pharmacology Arany J. u. 6-8. 1051 Budapest Hungary
      IrelandSt Vincent's University Hospital Ethics Committee St Vincent's University Hospital Elm Park Dublin 4 Ireland
      IsraelChaim Sheba Medical Center Ethics Committee Sheba M.C,Tel Hashomer 52621 Ramat-Gan Israel
      IsraelHelsinki Committee – Rambam Rambam Health Care Campus, POB 9602 31096 Haifa Israel
      IsraelRabin Medical Center Ethics Committee Beilinson Campus 49372 Petah Tikva Israel
      ItalyCEI INT – Fondazione G. Pascale di Napoli VIA M. SEMMOLA 1 80131 Napoli
      ItalyComitato Etico Irccs Istituto Clinico Humanitas Via Manzoni, 56 20089 Rozzano
      ItalyIrccs Istituto Europeo Di Oncologia (IEO); Comitato Etico VIA RIPAMONTI 435 20141 Milano
      ItalyCe Indip. Presso la fond. Ptv Policl. Tor Vergata Viale Oxford, 81 00133 Roma
      ItalyCE Dell'IRCCS Istituti Fisioterapici Ospitalieri Di Roma VIA ELIO CHIANESI 53 00144 Roma
      ItalyComitato Etico Della Asl 1 Avezzano-Sulmona-L'aquila Presidio Ospedaliero L''aquila, Loc.Vetoio, Coppito 67100 L'AQUILA
      ItalyCEI Ist. Naz. per lo Studio e la Cura dei Tumori VIA VENEZIAN 1 20133 MILANO
      ItalyComitato Etico Di Area Vasta Romagna E Irst Via Piero Maroncelli

      40 47014 Meldola
      ItalyComitato Etico Az Universitaria-Ospedaliera Senese via Bracci, 1 Centro Didattico Le Scotte 53100 Siena
      ItalyCE IRCCS Istituto Nazionale Per La Ricerca Sul Cancro (IST) LARGO ROSANNA BENZI 10 16132 GENOVA
      ItalyComitato Etico Az. Sanitaria di Firenze Viale Michelangelo, 41 50125 Firenze
      ItalyComitato Etico Azienda Spedali Civili di Brescia P.zza Spedali Civili, 1 25123 Brescia
      ItalyComitato Etico Dell'Istituto Oncologico Veneto VIA Gattamelata,

      64 35128 Padova
      ItalyCE Az.Sanitaria Ospedal. S.Luigi Gonzaga-Orbassano Via Regione Gonzole, 10 10043 Orbassano
      ItalyCE Dell'IRCCS Istituti Fisioterapici Ospitalieri Di Roma VIA ELIO CHIANESI 53 00144 ROMA
      ItalyCe Indip Di Etica Medica Della Asl Br Di Brindisi Via Napoli, 8 72100 Brindisi
      ItalyComitato Etico Della Asl Di Cagliari Via Tigellio, 21 09127 Cagliari
      ItalyComitato etico – Az. Policlinico Umberto I – Roma Viale Policlinico,

      155 00161 Roma
      ItalyComitato Etico-Scientifico Dell'Azienda Ospedaliera Ospedale Niguarda Ca' Granda Di Milano Piazza Ospedale Maggiore, 3 20162 Milano
      ItalyComitato Etico del Policlinico S.Orsola Malpighi Viale Albertoni, 15 40138 Bologna
      LithuaniaLietuvos Bioetikos Komitetas Didzioji str. 22 LT-01128 Vilnius Lithuania
      NetherlandsMedisch ethische commissie AZM P. Debyelaan 25 6229 HX Maastricht Netherlands
      New ZealandNorthern A HDEC; Ministry of Health No.1 The Terrace PO BOX 5013 6011 Wellington New Zealand
      NorwayREK sør-øst Posboks 1130. Blindern 0318 Oslo
      PolandKomisja Bioetyki ds. badan na ludziach ul. Zeligowskiego 7/9 90-752 Lodz Poland
      PortugalCEIC – Comissão de Ética para Investigação Clínica Av. do Brasil, 53 – Pav 17-A ,Parque da Saúde de Lisboa 1749-004 Lisboa Portugal
      RomaniaComisia Nationala de Etica Str. Aviator Sanatescu, Nr. 48 Sector 1

      011478 Bucharest Romania
      Russian FederationCity Clinical Oncology Dispensary, SPb SBIH CCOD

      EC/IRB 56, Prospekt Veteranov 198255 Saint-Petersburg Russian Federation
      SerbiaEthics Committee of Institute of Oncol.& Radiology Pasterova 14 11000 Belgrade
      SerbiaMilitary Medical Academy; Ethics Committee of Military Medical Academy Crnotravska 17 11000 Belgrade
      SlovakiaEticka komisia FNsP FDR Banska Bystrica Nam. L.Svobodu 1 975 17 Banska Bystrica Slovakia
      SloveniaKomisija Republike Slovenije za Medicinsko Etiko Zaloska cesta 7 1525 Ljubljana
      SpainCEIC Hospital General Universitario de Valencia Avda. Tres Cruces s/n 46014 Valencia
      SpainCEIC Hospital Universitario 12 de Octubre HOSPITAL MATERNO INFANTIL Avda. de Córdoba, s/n 28041 Madrid
      SpainCEIC del Hospital Virgen de las Nieves C/ Dr. Azpitarte, nº 4, 4ª planta 18012 Granada
      SpainCEIC Virgen Macarena Avenue Dr. Fedriani 3 – Investigation Department 2nd Floor 41071 Sevilla
      SpainCEIC del Hospital Gregorio Marañón C/ Doctor Esquerdo, 46 Oficina Técnica Secretaria CEIC-A1 Pabellón de Gobierno 28007 Madrid
      SpainComité Ético de Investigación Clínica de La Comunidad Autónoma del País Vasco (CEIC-E) Dirección de Farmacia C/ Donostia-San Sebastián, 1 01010 Vitoria
      SpainCEIC Area de Salud de Leon Altos De Nava S/N 24071 Leon
      SpainComité Ético de Investigación Clínica del Hospital Universitario de Gran Canarias Dr. Negrín 35010 Las Palmas de Gran Canaria
      SpainComité Etico de Investigación Clínica Hospital Clinic i Provincial Agencia de Ensayos Clínicos (sótano, escalera 8) 08036 Barcelona
      SpainComité Ético de Investigación Clínica Hospital Universitario Reina Sofía Edificio Consultas Externas, planta -1 (sótano) 14004 Cordoba
      SpainCEIC Instituto Valenciano de Oncología Secretaría del CEIC C/ Profesor Beltrán Báguena, 8 6009 Valencia
      SpainComité Ético de Investigación Clínica Hospital Virgen de la Salud Avda Barber 30 45004 Toledo
      SpainComité Etico de Investigación Clínica
      Recinto Hospital de Navarra Centro de Investigación Biomédica 31008 Pamplona Spain
      SpainCEIC Ntra. Sra. de Candelaria Road Del Rosario, 145 3rd Floor 38010 Santa Cruz de Tenerife
      SpainCEIC del Hospital de Asturias C/Celestino Villamil, s/n Centro de Rehabilitación 5ª planta 33006 Asturias
      SpainCEIC del Hospital Gregorio Marañón C/ Doctor Esquerdo, 46 Oficina Técnica Secretaria CEIC-A1 Pabellón de Gobierno 28007 Madrid
      SpainComité Ético de Ensayos Clínicos del Hospital Univ Crtra. Madrid-Cartagena s/n 30120 Murcia
      SpainComité Etico de Investigación Clínica Hospital de la Santa Creu i Sant Pau Farmacología Clínica 08025 Barcelona
      SpainComité Etico de Investigación Clinica de las Islas Baleares Servicio Balear de Salud (SERBASA) 07003 Palma de Mallorca
      SpainCEIC de la Fundación Hospital de Alcorcón C/ Budapest, 1 28922 Alcorcón
      SpainComité Ético de Investigación Clínica de Aragón Avda Gómez Laguna 25 50009 Zaragoza
      SpainComité Ético de Investigación Clínica del Hospital General de Guadalajara Donantes de sangre, s/n 19002 Guadalajara
      SwedenRegionala Etikprövningsnämnden i Stockholm Box 289 Karolinska Institute, Nobelsväg 12A 171 77 Stockholm Sweden
      SwitzerlandKantonale Ethikkommission Zürich (KEK) Stampfenbachstrasse 121
      8091 Zürich Switzerland
      TurkeyIstanbul Universitesi Istanbul Tip Fakultesi Klinik Arastirmalar Etik Kurulu Istanbul University Istanbul Tip Fakultesi Ethics Committee 34390 Istanbul Turkey
      United KingdomEast of England – Cambridge East The Old Chapel Royal Standard Court NG1 6FS Nottingham United Kingdom

      Appendix A. Supplementary data

      The following is the supplementary data related to this article:

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