10.5826/dpc.1302a211
Introduction: Real-life data on vismodegib in advanced basal cell carcinoma (aBCC) are limited. Optimal treatment duration is left to the discretion of the physician.
Objectives: To assess the effectiveness, safety and treatment pattern for vismodegib in aBCC in clinical practice.
Methods: In this multicenter, non-interventional, prospective study, 49 Swedish patients planned for vismodegib treatment were included. The treatment pattern observed was treatment until remission, allowing unlimited discontinuations/pauses.
Results: The majority of patients (93.8%), discontinued at least once during the study. Compared to earlier studies there was a decrease of more than 2 months with actual drug intake, reducing the patients burden and costs, at the same time as a high number of responses were seen (87.8%). Median progression-free-survival was 16.7 months, and 90% of the patients were alive at 13.3 months. Ten patients were re-challenged with vismodegib at recurrence or progression, resulting in five partial remissions and three complete remissions. 
Conclusions: Clinical response rates with vismodegib for aBCC were similar to those of similar trials despite a shorter and more intermittent treatment duration. The majority of re-challenges lead to partial or complete remissions.
text/xml
2160-9381
3032
en
Maria Wolodarski
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
cohort-study
A Non-interventional Study on Vismodegib for Basal Cell Carcinoma With A Treat-To-Target Regimen In Swedish Patients
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2023-04-29
2022-11-30
2023-04-29
2023-06-05
e2023211
Dermatol Pract Concept
Introduction: Real-life data on vismodegib in advanced basal cell carcinoma (aBCC) are limited. Optimal treatment duration is left to the discretion of the physician.
Objectives: To assess the effectiveness, safety and treatment pattern for vismodegib in aBCC in clinical practice.
Methods: In this multicenter, non-interventional, prospective study, 49 Swedish patients planned for vismodegib treatment were included. The treatment pattern observed was treatment until remission, allowing unlimited discontinuations/pauses.
Results: The majority of patients (93.8%), discontinued at least once during the study. Compared to earlier studies there was a decrease of more than 2 months with actual drug intake, reducing the patients burden and costs, at the same time as a high number of responses were seen (87.8%). Median progression-free-survival was 16.7 months, and 90% of the patients were alive at 13.3 months. Ten patients were re-challenged with vismodegib at recurrence or progression, resulting in five partial remissions and three complete remissions. 
Conclusions: Clinical response rates with vismodegib for aBCC were similar to those of similar trials despite a shorter and more intermittent treatment duration. The majority of re-challenges lead to partial or complete remissions.
Maria Wolodarski
2023/04/29
10.5826/dpc.1302a211
e2023211
Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden
2160-9381
cohort-study
en
e2023211
Peris K, Fargnoli MC, Garbe C, et al. Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines. European journal of cancer (Oxford, England : 1990), 2019; 118: 10-34. doi:10.1016/j.ejca.2019.06.003
A Non-interventional Study on Vismodegib for Basal Cell Carcinoma With A Treat-To-Target Regimen In Swedish Patients
https://dpcj.org/index.php/dpc/article/download/3032/2116
          A Non-Interventional Study on Vismodegib
         for Basal Cell Carcinoma in Swedish Patients
      Niels Bendsöe1, John Paoli2,3, Karin Söderkvist4, Bertil Persson1, Christina Halldin2,3,
                             Linda Ihrlund5, Maria Wolodarski6,7


1 Skåne University Hospital, Department of Dermatology and Venereology, Lund, Sweden
2 Department of Dermatology and Venereology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg,
  Sweden
3 Region Västra Götaland, Sahlgrenska University Hospital, Department of Dermatology and Venereology, Gothenburg, Sweden
4 Department of Radiation sciences, Umeå University, Umeå, Sweden
5 Roche AB, Sweden
6 Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden
7 Theme Cancer, Patient Area Head and Neck, Lung, and Skin, Karolinska University Hospital Solna, Stockholm, Sweden



Key words: Non-interventional, prospective, cohort-study, effectiveness, safety
Citation: Bendsöe N, Paoli J, Söderkvist K, Persson B, Halldin C, Ihrlund L, Wolodarski. A Non-Interventional Study on Vismodegib for
Basal Cell Carcinoma in Swedish Patients. Dermatol Pract Concept. 2023;13(2):e2023211. DOI: https://doi.org/10.5826/dpc.1302a211
Accepted: April 9, 2023; Published: April 2023
Copyright: ©2023 Bendsöe et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use,
distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: Roche AB sponsored this study. We would like to thank all research nurses who assisted with patient inclusion and follow-up.
Medical writing support was provided by Eva Karlsson (Scientific Consulting AB) in the preparation of this paper. Responsibility for
opinions, conclusions and interpretation of data lies with the authors.
Competing Interests: Linda Ihrlund is employed at Roche AB. The other authors have nothing to declare.
Authorship: All authors have contributed significantly to this publication.
Corresponding Author: John Paoli, M.D., Professor; Department of Dermatology and Venereology, Institute of Clinical Sciences,
Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Tel: +46730404044 E-mail: john.paoli@gu.se




  ABSTRACT             Introduction: Real-life data on vismodegib in advanced basal cell carcinoma (aBCC) are limited.
                       ­Optimal treatment duration is left to the discretion of the physician.
                       Objectives: To assess the effectiveness, safety and treatment pattern for vismodegib in aBCC in c­ linical
                       practice.
                       Methods: In this multicenter, non-interventional, prospective study, 49 Swedish patients planned for
                       vismodegib treatment were included. The treatment pattern observed was treatment until remission,
                       allowing unlimited discontinuations/pauses.
                       Results: The majority of patients (93.8%), discontinued at least once during the study. Compared
                       to earlier studies there was a decrease of more than 2 months with actual drug intake, reducing the
                       patients burden and costs, at the same time as a high number of responses were seen (87.8%). Median
                       progression-free-survival was 16.7 months, and 90% of the patients were alive at 13.3 months. Ten
                       patients were re-challenged with vismodegib at recurrence or progression, resulting in five partial
                       ­remissions and three complete remissions.



Original article | Dermatol Pract Concept. 2023;13(2):e2023211                                                                            1
                     Conclusions: Clinical response rates with vismodegib for aBCC were comparable to those of similar
                     ­trials despite a shorter and more intermittent treatment duration. The majority of re-challenges lead
                      to ­partial or complete remissions.




Introduction                                                     Methods
Basal cell carcinoma (BCC) is the most common human              Study Population, Cohorts and Data Collection
cancer. In Sweden, the number of histopathologically ver-        This study was a non-interventional, prospective cohort
ified BCC cases have increased 10-fold during the last           study in adult patients with aBCC. All patients were planned
30 years. In 2019, the number of patients reported to the        for vismodegib treatment within normal routine practice
Swedish Cancer Registry were >61 000, compared to 36 500         according to the current product label. Following non-­
in 2008 [1].                                                     interventional study guidelines, study assessments and tim-
    The most common reason for BCC is chronic or in-             ing of visits were not mandatory, but performed according
termittent exposure of UV-radiation, where the disease           to routine care at each participating clinic (www.encepp.
development is driven by an abnormal activation of the           eu 2011). Guidelines for Good Pharmaco-epidemiological
Hedgehog signaling pathway [2-6]. The majority of BCCs           Practice (GPP) were followed and approval by the Swedish
occur sporadically, but a rare autosomal dominant inherited      Ethical Review Authority was obtained prior to study start
condition, Gorlin syndrome, also exists [7-9]. Vismodegib        in December 2014 (www.pharmacoepi.org). An overview of
(Erivedge®, Hoffmann-La Roche Ltd, Basel, Switzerland) is        the study details is published on www.clinicaltrials.gov, NCT
a first-in-class, oral small molecule inhibitor of the Hedge-    02371967.
hog signaling pathway, developed to treat hedgehog mutated          The study enrolled 50 patients at four university hospitals
tumors. The European approval of vismodegib was based            in Sweden between April 2015 and September 2017, with a
on the pivotal study ERIVANCE, an international, phase-2,        follow-up period of 3 years. The trial sites were two derma-
open-label, non-comparative clinical trial that showed high      tology clinics (Skåne University Hospital and Sahlgrenska
efficacy and acceptable tolerability in patients with met-       University Hospital) and two oncology clinics (Karolinska
astatic or locally advanced BCC with or without Gorlin           University Hospital and Norrland University Hospital).
syndrome [10, 11]. The results were confirmed in a larger           Patients included were ≥18 years old, with a diagnosed
multicenter safety study, STEVIE [12]. Both trials included      aBCC, defined as metastatic or locally advanced (where
continuous treatment with vismodegib 150 mg once daily,          other therapy such as surgery or radiotherapy were not an
until disease progression or intolerable toxicity. Thirty-one    option), or Gorlin syndrome requiring systemic treatment
percent of the patients discontinued treatment due to toxic-     and planned for treatment with vismodegib. A signed in-
ity, although treatment interruptions/pauses up to 4-8 weeks     formed consent for collection of data was obtained from
were allowed. To overcome the toxicity with maintained           all patients before enrolment. All patients were divided into
efficacy, the dosing regimen has been further evaluated in       three cohorts: cohort 1 included patients with aBCC without
several trials, as intermittent dosing, or reduced dosing [13-   Gorlin syndrome and not previously exposed to a hedgehog
16]. However, there is no established guideline for optimal      pathway inhibitor (HPI), cohort 2 included patients with
treatment duration with vismodegib.                              aBCC without Gorlin syndrome that previously had been
    At the time of initiation of this non-interventional study   exposed to an HPI and cohort 3 included patients with Gor-
(NIS), data on treatment in a real-life setting was lacking in   lin syndrome independent of previous exposure to an HPI.
Sweden as well as world-wide. Implementing a systematic          Patients previously included in other clinical trials within 90
data collection was encouraged by the necessity to increase      days were excluded, with exceptions for patients in cohort 2.
knowledge of current treatment patterns, effectiveness and          The aim of the study was to assess effectiveness, safety
safety. Since then, three similar European studies with data     and treatment patterns of vismodegib treatment in a re-
collected both retrospectively and prospectively have been       al-life setting. Clinical outcomes included: clinical response,
published: one from Greece with 67 patients and two from         time to response, duration of response, recurrence rate,
Germany with 66 and 53 patients, respectively, have been         ­progression-free survival and overall survival. Safety objec-
published [17-19]. The current study intends to add more         tives included: incidence, severity, and relationship of adverse
data to the growing collection of evidence on real-life treat-   and serious adverse events (SAEs) including pregnancies,
ment with vismodegib.                                            and adverse events leading to treatment interruption or



2                                                                    Original article | Dermatol Pract Concept. 2023;13(2):e2023211
discontinuation. Toxicity was graded using National Cancer          In total, 40 patients were diagnosed with aBCC without
Institute Common Terminology Criteria for Adverse Events         Gorlin syndrome. The majority of these, 37 patients, were
(NCI CTCAE) version 4. Adverse events of special interest        not previously exposed to an HPI and allocated to cohort
(AESI) included: muscle spasms, alopecia, dysgeusia/ageusia,     1. Thus, three patients were allocated to cohort 2. Nine pa-
weight loss, fatigue of grade ≥2, amenorrhea, gastrointes-       tients with Gorlin syndrome were allocated to cohort 3 in-
tinal events grade ≥2, cardiovascular events and secondary       dependent of previous exposure to an HPI. Baseline patient
malignancies.                                                    characteristics can be found in Table 1. One patient of child-
    Patient data were collected from the patient’s medical re-   bearing potential was included and followed with monthly
cords into an electronic case report form (CRF) (Viedoc™,        pregnancy tests up to 1 year after treatment completion. All
Viedoc Technologies, Uppsala, Sweden) and data quality was       tests were negative.
checked by on-site and remote monitoring. Analysis of data          All patients had an ongoing locally advanced or meta-
was done after a clean file report and database lock.            static BCC or Gorlin syndrome at enrollment, and two pa-
                                                                 tients had recurrent disease following previous treatment.
                                                                 Six patients (12.2%) had other prior cancer history (fibro-
Statistical Analysis
                                                                 sarcoma, lymphoma, melanoma, nasopharyngeal cancer,
The statistical analysis was done according to the ICH E9
                                                                 prostate cancer and squamous cell carcinoma). The most fre-
guideline for Statistical Principles of Clinical Trials using
                                                                 quent non-cancer condition was hypertension. Six patients
SAS® (version 9.4 or higher). The intention-to-treat (ITT)
                                                                 (12.2%) were reported to have received vismodegib previ-
population used for the effectiveness analysis was defined
                                                                 ously, all patients in cohort 2 and three patients in cohort 3.
as all patients enrolled in the study. The safety population
                                                                 At baseline, the extent of the disease was clinically assessed
was defined as all patients who received at least one dose
                                                                 in 34 patients whereas 14 patients also required radiological
of vismodegib during the study. MedDRA terminology was
                                                                 assessment.
used for adverse events and NCI CTCAE version 4 was used
                                                                    More than half of the study population, 28 patients
for toxicity grading. Tumor assessments were done by radio-
                                                                 (57.1%) completed the study with a 3-year follow-up pe-
logical assessment using RECIST v 1.1. and/or by clinical
                                                                 riod. The remaining study population (21 patients, 42.9%)
assessment.
                                                                 withdrew prematurely from the study. The most common
    The analysis of the study was exploratory and descriptive
                                                                 reasons were death (not related to treatment) or progressive
methods were used, presenting data by cohort and in total.
                                                                 disease.
No pre-specified hypotheses were defined, the sample size
                                                                    Treatment discontinuations and pauses were frequent
of 50 patients was regarded as sufficient to characterize the
                                                                 and reported at least once by 45 patients (93.8%) during
treatment pattern considering the rare indication of aBCC.
                                                                 the study. The most common reasons were complete remis-
Continuous data were summarized as the number of subjects
                                                                 sions (22 patients) and adverse events (14 patients). Median
with evaluable observations and missing observations, arith-
                                                                 duration of exposure (including days off treatment) was 5.7
metic mean and standard deviation, median with first and
                                                                 months (range 1-35.9 months) and 5.2 months (range 1-35.5
third quartiles, minimum and maximum. Categorical data
                                                                 months) excluding days off treatment (Table 2). The over-
were presented using frequency and percentage. Confidence
                                                                 all treatment pattern with number of days of treatment and
intervals were 2-sided with a 95% confidence interval.
                                                                 pauses from treatment per patient showed high variability
    Drug exposure was summarized with number and per-
                                                                 (Table 3).
centage of patients for the total exposure, maximum treat-
                                                                    Of the 49 included patients, 43 (87.8%) achieved a clin-
ment duration, including breakdowns for treatment pauses
                                                                 ical response (95% CI; 75.2-95.4%). Clinical response was
and dose modifications. More than one treatment discon-
                                                                 observed in 34 patients (91.9%) in cohort 1, two patients
tinuation or dose modification could be reported for each
                                                                 (66.7%) in cohort 2 and seven patients (77.8%) in cohort 3.
patient.
                                                                 Approximately half of the responses were complete remis-
                                                                 sions as best response. At 2 months of treatment (60 days),

Results                                                          approximately half of the study population had achieved a
                                                                 clinical response, and at 3.3 months (100 days), 80% of the
In total, 50 patients were enrolled. One patient was found       patients had achieved a clinical response. Median duration
non-eligible prior to drug intake and excluded from the          of response was approximately 14.3 months (430 days).
study. The remaining 49 patients comprised the ITT pop-             Recurrence during the study occurred in 14 patients
ulation. One of these patients withdrew consent prior to         (28.6%), 11 of these patients were in cohort 1 and three
first administration of vismodegib. Thus, the remaining          patients were in cohort 3. The median time to recurrence was
48 ­patients constituted the safety population.



Original article | Dermatol Pract Concept. 2023;13(2):e2023211                                                                3
                                                Table 1. Baseline characteristics.
                                                                   Cohort 1        Cohort 2         Cohort 3            Total
                                                                    (N=37)          (N=3)            (N=9)             (N=49)
      Age, years, mean (SD)                                         78 (11)         66 (20)          56 (11)           73 (14)
      Age, years, min-max                                            50-97           46-85            43-74            43-97
      Female, n (%)                                                 16 (43)            0              2 (22)           18 (37)
      Male, n (%)                                                   21 (57)         3 (100)           7 (78)           31 (63)
      Height, mean (SD), cm                                        171 (11)         179 (8)          184 (9)          173 (11)
      Weight, mean (SD), kg                                         76 (19)         91 (11)          96 (25)           80 (21)
    ECOG performance status, n (%)
      ECOG 0-1                                                      31 (84)         3 (100)           8 (89)           42 (86)
      ECOG 2                                                         1 (3)             0              1 (11)            2 (4)
      ECOG 3                                                        4 (11)             0                 0              4 (8)
      ECOG 4                                                         1 (3)             0                 0              1 (2)
    BCC assessment at time of diagnose, n (%)
      Clinical, histopathology                                         0               0              2 (22)            2 (4)
      Clinical                                                       2 (5)             0              2 (22)            4 (8)
      Histopathology                                                23 (62)          1 (33)              0             24 (49)
      Unknown                                                       10 (27)          2 (67)           5 (56)           17 (35)
      Missing data                                                   2 (5)             0                 0              2 (4)
                                          a
    Previous medical treatments, n (%)
      Imiquimod                                                      1 (3)             0                 0              1 (2)
      Vismodegib                                                       0            3 (100)           3 (33)              4
                                           b
    Previous surgical procedures, n (%)
      Surgery                                                      14 (37.8)           0             1 (11.1)         15 (30.6)
      Cryotherapy                                                   2 (5.4)            0                 0             2 (4.1)
      Cryosurgery                                                   1 (2.7)            0                 0             1 (2.0)
      Cardiac pacemaker insertion                                      0            1 (33.3)             0             1 (2.0)
                                                            b
    Previous radiotherapy and photodynamic therapy n (%)
      Radiotherapy                                                  5 (13.5)           0                 0            5 (10.2)
      Photodynamic therapy                                          1 (2.7)            0                 0             1 (2.0)
a
reflect at least 14 days prior to study start
b
last 10 years prior to study start



approximately 20 months (600 days) and there was a 20%            events (77.3%) were regarded to be at least possibly related
probability of an early recurrence at 6.7 months (200 days).      to vismodegib treatment. Most adverse events were mild or
      Ten patients were re-challenged due to progression after    moderate and commonly reported as muscle spasms, dys-
an initially achieved response. Eight reached new remissions,     geusia and alopecia. Severe adverse events were reported
five with partial remissions and three with complete remis-       on 17 occasions, where three events (ageusia, dysgeusia and
sions. Both complete and partial responses were achieved.         ­fatigue) were deemed as related to vismodegib treatment.
Two patients were even re-challenged twice with repeated             The frequencies of predefined AESIs can be found in
partial remissions as response.                                   Table 4.
      The median progression-free survival (PFS) was estimated       A total of 19 SAEs were reported during the entire study
to be 16.6 months (500 days). The 80% overall survival rate       period by 16 patients (33.3%). Of these, 11 SAEs had a
was 2.7 years and the 90% overall survival rate (OS) was 13       fatal outcome. Causes of death included natural causes (3
months. A median overall survival was not reached within          patients), cardiac failure (2 patients), stroke, complications
the study period (Figure I).                                      after brain surgery, gastrointestinal bleeding, metastatic dis-
      There were 45 patients (93.8%) that experienced at least    ease and in two patients the cause was unknown. One pa-
one adverse event, with a total of 194 events. Of these, 150      tient died while on treatment due to natural causes and 10



4                                                                     Original article | Dermatol Pract Concept. 2023;13(2):e2023211
                           Table 2. Disposition of patients, exposure of drug and efficacy.
                                                                         Cohort 1          Cohort 2           Cohort 3             Total
 Patients enrolled                                                         n=37               n=3                 n=9              n=49
   Completed the study, n (%)                                            20 (54.1)          2 (66.7)           6 (66.7)          28 (57.1)
   Prematurely withdrawn from the study, n (%)                           17 (45.9)          1 (33.3)           3 (33.3)          21 (42.9)
 Patients treated                                                          n=37               n=3                 n=8              n=48
  Discontinued treatment at least once during the study,                35 (94.6)         3 (100.0)           7 (87.5)          45 (93.8)
   n (%)
 Reason of discontinuation from treatment, n (%)
   Complete remission                                                    15 (42.9)          1 (33.3)           6 (85.7)          22 (48.9)
   Adverse Event / Serious Adverse Event                                 10 (28.6)          1 (33.3)           3 (42.9)          14 (31.1)
   Death                                                                  1 (2.9)               0                  0              1 (2.2)
   Progressive disease                                                    3 (8.6)               0                  0              3 (6.7)
   Lack of efficacy                                                      4 (11.4)               0              1 (14.3)           5 (11.1)
   Physician decision                                                    5 (14.3)           1 (33.3)               0              6 (13.3)
   Other                                                                 4 (11.4)               0              5 (71.4)            9 (20)
 Exposure of drug
   Treatment duration, (incl days off treatment), months
   Mean (SD)                                                           11.7 (11.5)        12.5 (19.2)        16.2 (13.3)        12.4 (12.0)
   Median (range)                                                      5.8 (1-35.9)     1.4 (1.4-34.8) 15.2 (2.8-35.7)         5.7 (1-35.9)
   Treatment duration (excl days off treatment), months
   Mean (SD)                                                             8.1 (7.0)        11.1 (16.8)          8.8 (8.2)         8.4 (7.8)
   Median (range)                                                      5.6 (1-35.5)     1.4 (1.4-30.6)      4.1 (2.8-23.9)     5.2 (1-35.5)
 Effectiveness                                                             n=37               n=3                 n=9              n=49
   Clinical response (complete or partial remission), n (%)              34 (91.9)          2 (66.7)           7 (77.8)          43 (87.8)
   95% CI                                                              (78.1-98.3)         (9.4-99.2)        (40.0-97.2)        (75.2-95.4)
   Recurrence during the study, n (%)                                    11 (29.7)              0              3 (33.3)          14 (28.6)
   95% CI                                                              (15.9-47.0)         (0.0-70.8)         (7.5-70.1)        (16.6-43.3)
   Median time to response, all patients, months                                                                                      2
   Median duration of response, all patients, months                                                                                14.3
   Median time to recurrence, all patients, months                                                                                   20
   Median progression-free survival, all patients, months                                                                           16.6
   Median overall survival, all patients, months                                                                                    Not
                                                                                                                                  reached

n, number of patients; SD, standard deviation.

Since this was an observational study, patients were taking treatment according to normal routine practice. Because of this, each patient could
report more than one treatment discontinuation (i.e. a patient can discontinue and then restart treatment several times). The table summarizes
the number of patients who discontinued at least once including each unique reason for discontinuation.



patients died during the follow-up period. None of the fatal             dysgeusia, upper limb fracture, loss of effect and weight
events were assessed as related to vismodegib.                           loss (Table 4).
    Ten patients (20.8%) withdrew treatment due to an ad-
verse event (Table 4). The reasons were ageusia/dysgeusia,
weight loss, asthenia, fatigue, muscle spasms/weakness, nau-
                                                                         Conclusions
sea, pruritus and back pain.                                             The aim of the current study was to systematically collect
    There were 12 adverse events reported by seven                       data on effect, safety and treatment patterns of vismode-
patients (14.6%) that resulted in an interruption or                     gib in a real-world setting. The resulting study population
discontinuation of vismodegib. The reasons were gastro-                  correlates well in general to other studies on the use of
intestinal disorders, nausea, vomiting, diarrhoea, fatigue,



Original article | Dermatol Pract Concept. 2023;13(2):e2023211                                                                               5
         Table 3. Extent of exposure including duration of treatment and pauses from treatment.
                                                                   Cohort 1             Cohort 2           Cohort 3              Total
                                                                    n=37                  n=3                n=8                 n=48
 Total duration of exposure in days
    n/nmiss                                                          37/0                  3/0                7/1                 47/1
    Mean (SD)                                                   350.1 (344.0)        376.3 (577.4)      485.0 (399.8)       371.8 (361.0)
    Median                                                           173.0                43.0               456.0               173.0
    Q1, Q3                                                       85.0, 441,0         43.0, 1043.0        104.0, 840.0         85.0, 717.0
    Min, Max                                                       30, 1076             43, 1043           85, 1070            30, 1076
 Total number of days on treatment
    Mean (SD)                                                   241.9 (210.8)        334.3 (504.6)      262.6 (245.8)       250.9 (232.9)
    Median                                                            167                  43                 124                 156
    Q1, Q3                                                       85.0, 361.0          43.0, 917.0        104.0, 497.0         85.0, 374.0
    Min, Max                                                        0, 716               43, 917            85, 717            30, 1066
 Total number of days on pause from treatment
    Mean (SD)                                                   108.1 (230.2)         42.0 (72.7)       222.4 (293.6)       120.9 (234.6)
    Median                                                            0.0                  0.0                0.0                  0.0
    Q1, Q3                                                          0.0, 0.0            0.0, 126.0        0.0, 573.0            0.0, 0.0
    Min, Max                                                        0, 716               0, 126              0, 652              0, 716

n/nmiss, number of subjects with evaluable/missing data; Q1, first quartile; Q3, third quartile; SD, standard deviation. The same patient could
report more than one treatment discontinuation.



vismodegib for aBCC, including the pivotal study ERIVANCE                in the pivotal study [11] and comparable or slightly shorter
[10, 11], the safety study STEVIE [12, 20] and the more re-              than the median time to response of 2.7 months in the Ger-
cently published non-interventional studies from Germany                 man real-world study [18]. Again, the differences between a
[18, 19] and Greece [17]. In the current study, the group with           controlled and a real-world setting is probably the main rea-
Gorlin syndrome were markedly younger than the overall                   son for the shorter time to response reported in the non-in-
populations, as could be expected with the greater severity              terventional studies. The results illustrate the relatively short
and earlier onset of disease for these patients [7, 8]. The pre-         time to a clinically relevant effect when used in everyday
dominance of men compared to women in the current study                  healthcare.
is similar to most studies [11-13, 17-19, 21] and the base-                    Interestingly, ten patients were re-challenged with vismo-
line comorbidity and concomitant treatments as could be                  degib resulting in five partial remissions and three complete
expected with respect to the ages and the disease indication.            remissions. Two patients were even re-challenged twice with
    The obtained study data support previous knowledge of                repeated remissions. These data are in line with the Greek
vismodegib as highly effective; the PFS and OS levels are in             study that reported responses after re-challenging in 8 pa-
line with the pivotal ERIVANCE and STEVIE trials [18, 12]                tients [17].
whereas the clinical response of 95.4% in this trial is high                   Of the predefined AESIs, the frequencies of alopecia,
compared to other studies, where 50-77% clinical respond-                fatigue, nausea and weight-loss were lower or much lower
ers were observed [11, 13, 18, 19] and similar to the Greek              compared to those reported in the ERIVANCE and STEVIE
study that reported 95.6% responders [17]. The variability               studies. Other adverse events were as expected in frequency
in clinical response rate between studies is most likely due             and most events were mild to moderate [11, 12]. Ten patients
to differences in response evaluation methods. The current               (20.8%) discontinued treatment due to adverse events, while
study pragmatically allowed for physician assessment to de-              seven patients (14.6%) interrupted or discontinued treat-
termine clinical response in order to reflect the real-world             ment but could remain on treatment regimen. Compared
practice and thus a resulting higher response rate than when             to previously reported trials, this is a low frequency. There
using strict radiologic criteria is to be expected.                      were more SAEs reported in this study (33.3%) compared
    Approximately half of the patients had reached a clin-               to the German studies that reported 22.7% and 17.0%, re-
ical response after 2 months (60 days), and 80% after 3.3                spectively. Nevertheless, the majority of the SAEs were not
months (100 days) of treatment. This is a shorter time to                related to vismodegib in any of the studies [18, 19]. Of the
response, compared to the median time of 5.5-6.7 months



6                                                                              Original article | Dermatol Pract Concept. 2023;13(2):e2023211
      A                                                          Time to clinical response

                         1.0                                                                                                 Censored

                         0.9

                         0.8
Proportion of subjects




                         0.7

                         0.6

                         0.5

                         0.4

                         0.3

                         0.2

                         0.1

                         0.0
                               0     50         100        150    200          250       300        350      400           450       500
                                                                          Time (days)

                                                      Cohort 1          Cohort 2               Cohort 3            Total




       B                                                          Duration of Response

                         1.0                                                                                                 Censored

                         0.9

                         0.8
Proportion of subjects




                         0.7

                         0.6

                         0.5

                         0.4

                         0.3

                         0.2

                         0.1

                         0.0
                               0   100    200     300      400   500     600       700   800       900    1000     1100    1200    1300
                                                                         Time (days)

                                                      Cohort 1          Cohort 2               Cohort 3            Total


Figure 1. Kaplan-Meier plots of (A) time to clinical response, (B) duration of response and (C) time to recurrence on cohorts 1, 2, 3 and in
total.




Original article | Dermatol Pract Concept. 2023;13(2):e2023211                                                                             7
       C                                                      Time to recurrence - All applicable patients

                          1.0                                                                                                         Censored

                          0.9

                          0.8
Proportion of subjects




                          0.7

                          0.6

                          0.5

                          0.4

                          0.3

                          0.2

                          0.1

                          0.0
                                0     100     200     300      400    500     600       700     800        900    1000       1100    1200        1300
                                                                               Time (days)

                                                          Cohort 1           Cohort 2              Cohort 3                  Total


Figure 1. Kaplan-Meier plots of (A) time to clinical response, (B) duration of response and (C) time to recurrence on cohorts 1, 2, 3 and
in total. (Continued)




                                                          Table 4. Adverse events, safety population.
                                                                            Cohort 1          Cohort 2            Cohort 3               Total
                                                                             (n=37)            (n=3)               (n=8)                (n=48)
                     Any adverse event, n (%)                               35 (94.6)          3 (100.0)           7 (87.5)           45 (93.8)
                     Any adverse event of special interest, n (%)           28 (75.7)          1 (33.3)            7 (87.5)           36 (75.0)
                     Any serious adverse event, n (%)                       13 (35.1)          1 (33.3)            2 (25.0)           16 (33.3)
                         SAEs with fatal outcome, n (%)                     11 (29.7)              0                   0              11 (22.9)
    Adverse event leading to withdrawal of study                            8 (21.6)               0               2 (25.0)           10 (20.8)
    treatmentb, n (%)
    Number of events                                                           14                  0                   2                    16
                     Ageusia/dysgeusia                                      4 (21.6)               0                2 (25)
                     Abnormal weight loss                                    2 (5.4)               0                   0
                     Asthenia                                                1 (2.7)               0                   0
                         Fatigue                                             2 (5.4)               0                   0
                         Muscular weakness                                   1 (2.7)               0                   0
                         Muscular spasm                                      3 ( 8.1)              0                   0
                         Nausea                                              1 (2.7)               0                   0
                         Pruritus                                               0                  0               1 (12.5)
                         Back pain                                              0                  0               1 (12.5)
    Adverse events leading to interruption of study                         5 (13.5)           1 (33.3)            1 (12.5)            7 (14.6)
    treatment, n
    Number of adverse events leading to interruption                            9                  2                   1                    12
    of study treatment
                         Nausea                                              1 (2.7)           1 (33.3)                0                2 (4.2)




8                                                                                       Original article | Dermatol Pract Concept. 2023;13(2):e2023211
                                   Table 4. Adverse events, safety population. (Continued)
                                                                   Cohort 1                Cohort 2             Cohort 3                Total
                                                                    (n=37)                  (n=3)                (n=8)                 (n=48)
      Diarrhoea                                                     1 (2.7)                     0                    0                 1 (2.1)
      Gastrointestinal disorder                                     1 (2.7)                     0                    0                 1 (2.1)
      Vomiting                                                      1 (2.7)                     0                    0                 1 (2.1)
      Drug ineffective                                              2 (5.4)                     0                    0                 2 (4.2)
      Fatigue                                                             0                 1 (33.3)                 0                 1 (2.1)
      Dysgeusia                                                     2 (5.4)                     0                    0                 2 (4.2)
      Upper limb fracture                                                 0                     0                1 (12.5)              1 (2.1)
      Abnormal loss of weight                                       1 (2.7)                     0                    0                 1 (2.1)

n = number of subjects

a
  10 of the fatal SAEs occurred during the follow-up period and 1 during the treatment phase. 3 fatal SAEs occurred during the follow-up
study phase but were found after database lock and are included here.
b
  The same patient can report more than one event.




life-threatening or fatal events, none were judged to be re-                        The journal of investigative dermatology Symposium proceed-
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       In all, a non-interventional study design cannot be com-
                                                                                    ­Nature reviews Cancer, 2008; 8: 743-754. doi:10.1038/nrc2503
pared to the strength of a controlled clinical trial. The data
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collection follows the standard care at each study site and                          hedgehog pathway in advanced basal-cell carcinoma. The New
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