Dermatology: Practical and Conceptual Original article | Dermatol Pract Concept. 2023;13(2):e2023211 1 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 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. ABSTRACT 2 Original article | Dermatol Pract Concept. 2023;13(2):e2023211 Introduction Basal cell carcinoma (BCC) is the most common human cancer. In Sweden, the number of histopathologically ver- ified BCC cases have increased 10-fold during the last 30 years. In 2019, the number of patients reported to the Swedish Cancer Registry were >61 000, compared to 36 500 in 2008 [1]. The most common reason for BCC is chronic or in- termittent exposure of UV-radiation, where the disease development is driven by an abnormal activation of the Hedgehog signaling pathway [2-6]. The majority of BCCs occur sporadically, but a rare autosomal dominant inherited condition, Gorlin syndrome, also exists [7-9]. Vismodegib (Erivedge®, Hoffmann-La Roche Ltd, Basel, Switzerland) is a first-in-class, oral small molecule inhibitor of the Hedge- hog signaling pathway, developed to treat hedgehog mutated tumors. The European approval of vismodegib was based on the pivotal study ERIVANCE, an international, phase-2, open-label, non-comparative clinical trial that showed high efficacy and acceptable tolerability in patients with met- astatic or locally advanced BCC with or without Gorlin syndrome [10, 11]. The results were confirmed in a larger multicenter safety study, STEVIE [12]. Both trials included continuous treatment with vismodegib 150 mg once daily, until disease progression or intolerable toxicity. Thirty-one percent of the patients discontinued treatment due to toxic- ity, although treatment interruptions/pauses up to 4-8 weeks were allowed. To overcome the toxicity with maintained efficacy, the dosing regimen has been further evaluated in several trials, as intermittent dosing, or reduced dosing [13- 16]. However, there is no established guideline for optimal treatment duration with vismodegib. At the time of initiation of this non-interventional study (NIS), data on treatment in a real-life setting was lacking in Sweden as well as world-wide. Implementing a systematic data collection was encouraged by the necessity to increase knowledge of current treatment patterns, effectiveness and safety. Since then, three similar European studies with data collected both retrospectively and prospectively have been published: one from Greece with 67 patients and two from Germany with 66 and 53 patients, respectively, have been published [17-19]. The current study intends to add more data to the growing collection of evidence on real-life treat- ment with vismodegib. Methods Study Population, Cohorts and Data Collection This study was a non-interventional, prospective cohort study in adult patients with aBCC. All patients were planned for vismodegib treatment within normal routine practice according to the current product label. Following non- interventional study guidelines, study assessments and tim- ing of visits were not mandatory, but performed according to routine care at each participating clinic (www.encepp. eu 2011). Guidelines for Good Pharmaco-epidemiological Practice (GPP) were followed and approval by the Swedish Ethical Review Authority was obtained prior to study start in December 2014 (www.pharmacoepi.org). An overview of the study details is published on www.clinicaltrials.gov, NCT 02371967. The study enrolled 50 patients at four university hospitals in Sweden between April 2015 and September 2017, with a follow-up period of 3 years. The trial sites were two derma- tology clinics (Skåne University Hospital and Sahlgrenska University Hospital) and two oncology clinics (Karolinska University Hospital and Norrland University Hospital). Patients included were ≥18 years old, with a diagnosed aBCC, defined as metastatic or locally advanced (where other therapy such as surgery or radiotherapy were not an option), or Gorlin syndrome requiring systemic treatment and planned for treatment with vismodegib. A signed in- formed consent for collection of data was obtained from all patients before enrolment. All patients were divided into three cohorts: cohort 1 included patients with aBCC without Gorlin syndrome and not previously exposed to a hedgehog pathway inhibitor (HPI), cohort 2 included patients with aBCC without Gorlin syndrome that previously had been exposed to an HPI and cohort 3 included patients with Gor- lin syndrome independent of previous exposure to an HPI. Patients previously included in other clinical trials within 90 days were excluded, with exceptions for patients in cohort 2. The aim of the study was to assess effectiveness, safety and treatment patterns of vismodegib treatment in a re- al-life setting. Clinical outcomes included: clinical response, time to response, duration of response, recurrence rate, progression-free survival and overall survival. Safety objec- tives included: incidence, severity, and relationship of adverse and serious adverse events (SAEs) including pregnancies, and adverse events leading to treatment interruption or 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. Original article | Dermatol Pract Concept. 2023;13(2):e2023211 3 discontinuation. Toxicity was graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4. Adverse events of special interest (AESI) included: muscle spasms, alopecia, dysgeusia/ageusia, weight loss, fatigue of grade ≥2, amenorrhea, gastrointes- tinal events grade ≥2, cardiovascular events and secondary malignancies. Patient data were collected from the patient’s medical re- cords into an electronic case report form (CRF) (Viedoc™, Viedoc Technologies, Uppsala, Sweden) and data quality was checked by on-site and remote monitoring. Analysis of data was done after a clean file report and database lock. Statistical Analysis The statistical analysis was done according to the ICH E9 guideline for Statistical Principles of Clinical Trials using SAS® (version 9.4 or higher). The intention-to-treat (ITT) population used for the effectiveness analysis was defined as all patients enrolled in the study. The safety population was defined as all patients who received at least one dose of vismodegib during the study. MedDRA terminology was used for adverse events and NCI CTCAE version 4 was used for toxicity grading. Tumor assessments were done by radio- logical assessment using RECIST v 1.1. and/or by clinical assessment. The analysis of the study was exploratory and descriptive methods were used, presenting data by cohort and in total. No pre-specified hypotheses were defined, the sample size of 50 patients was regarded as sufficient to characterize the treatment pattern considering the rare indication of aBCC. Continuous data were summarized as the number of subjects with evaluable observations and missing observations, arith- metic mean and standard deviation, median with first and third quartiles, minimum and maximum. Categorical data were presented using frequency and percentage. Confidence intervals were 2-sided with a 95% confidence interval. Drug exposure was summarized with number and per- centage of patients for the total exposure, maximum treat- ment duration, including breakdowns for treatment pauses and dose modifications. More than one treatment discon- tinuation or dose modification could be reported for each patient. Results In total, 50 patients were enrolled. One patient was found non-eligible prior to drug intake and excluded from the study. The remaining 49 patients comprised the ITT pop- ulation. One of these patients withdrew consent prior to first administration of vismodegib. Thus, the remaining 48  patients constituted the safety population. In total, 40 patients were diagnosed with aBCC without Gorlin syndrome. The majority of these, 37 patients, were not previously exposed to an HPI and allocated to cohort 1. Thus, three patients were allocated to cohort 2. Nine pa- tients with Gorlin syndrome were allocated to cohort 3 in- dependent of previous exposure to an HPI. Baseline patient characteristics can be found in Table 1. One patient of child- bearing potential was included and followed with monthly pregnancy tests up to 1 year after treatment completion. All tests were negative. All patients had an ongoing locally advanced or meta- 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- sarcoma, lymphoma, melanoma, nasopharyngeal cancer, prostate cancer and squamous cell carcinoma). The most fre- quent non-cancer condition was hypertension. Six patients (12.2%) were reported to have received vismodegib previ- ously, all patients in cohort 2 and three patients in cohort 3. At baseline, the extent of the disease was clinically assessed in 34 patients whereas 14 patients also required radiological assessment. More than half of the study population, 28 patients (57.1%) completed the study with a 3-year follow-up pe- riod. The remaining study population (21 patients, 42.9%) withdrew prematurely from the study. The most common reasons were death (not related to treatment) or progressive disease. Treatment discontinuations and pauses were frequent and reported at least once by 45 patients (93.8%) during the study. The most common reasons were complete remis- sions (22 patients) and adverse events (14 patients). Median duration of exposure (including days off treatment) was 5.7 months (range 1-35.9 months) and 5.2 months (range 1-35.5 months) excluding days off treatment (Table 2). The over- all treatment pattern with number of days of treatment and pauses from treatment per patient showed high variability (Table 3). Of the 49 included patients, 43 (87.8%) achieved a clin- ical response (95% CI; 75.2-95.4%). Clinical response was observed in 34 patients (91.9%) in cohort 1, two patients (66.7%) in cohort 2 and seven patients (77.8%) in cohort 3. Approximately half of the responses were complete remis- sions as best response. At 2 months of treatment (60 days), approximately half of the study population had achieved a clinical response, and at 3.3 months (100 days), 80% of the patients had achieved a clinical response. Median duration of response was approximately 14.3 months (430 days). Recurrence during the study occurred in 14 patients (28.6%), 11 of these patients were in cohort 1 and three patients were in cohort 3. The median time to recurrence was 4 Original article | Dermatol Pract Concept. 2023;13(2):e2023211 events (77.3%) were regarded to be at least possibly related to vismodegib treatment. Most adverse events were mild or moderate and commonly reported as muscle spasms, dys- geusia and alopecia. Severe adverse events were reported on 17 occasions, where three events (ageusia, dysgeusia and fatigue) were deemed as related to vismodegib treatment. The frequencies of predefined AESIs can be found in Table 4. A total of 19 SAEs were reported during the entire study period by 16 patients (33.3%). Of these, 11 SAEs had a fatal outcome. Causes of death included natural causes (3 patients), cardiac failure (2 patients), stroke, complications after brain surgery, gastrointestinal bleeding, metastatic dis- ease and in two patients the cause was unknown. One pa- tient died while on treatment due to natural causes and 10 approximately 20 months (600 days) and there was a 20% probability of an early recurrence at 6.7 months (200 days). Ten patients were re-challenged due to progression after an initially achieved response. Eight reached new remissions, five with partial remissions and three with complete remis- sions. Both complete and partial responses were achieved. Two patients were even re-challenged twice with repeated partial remissions as response. The median progression-free survival (PFS) was estimated to be 16.6 months (500 days). The 80% overall survival rate was 2.7 years and the 90% overall survival rate (OS) was 13 months. A median overall survival was not reached within the study period (Figure I). There were 45 patients (93.8%) that experienced at least one adverse event, with a total of 194 events. Of these, 150 Table 1. Baseline characteristics. Cohort 1 (N=37) Cohort 2 (N=3) Cohort 3 (N=9) Total (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) Previous medical treatments, n (%)a Imiquimod 1 (3) 0 0 1 (2) Vismodegib 0 3 (100) 3 (33) 4 Previous surgical procedures, n (%)b 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) Previous radiotherapy and photodynamic therapy n (%)b Radiotherapy 5 (13.5) 0 0 5 (10.2) Photodynamic therapy 1 (2.7) 0 0 1 (2.0) areflect at least 14 days prior to study start blast 10 years prior to study start Original article | Dermatol Pract Concept. 2023;13(2):e2023211 5 dysgeusia, upper limb fracture, loss of effect and weight loss (Table 4). Conclusions The aim of the current study was to systematically collect data on effect, safety and treatment patterns of vismode- gib in a real-world setting. The resulting study population correlates well in general to other studies on the use of patients died during the follow-up period. None of the fatal events were assessed as related to vismodegib. 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- sea, pruritus and back pain. There were 12 adverse events reported by seven patients (14.6%) that resulted in an interruption or discontinuation of vismodegib. The reasons were gastro- intestinal disorders, nausea, vomiting, diarrhoea, fatigue, 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, n (%) 35 (94.6) 3 (100.0) 7 (87.5) 45 (93.8) 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. 6 Original article | Dermatol Pract Concept. 2023;13(2):e2023211 in the pivotal study [11] and comparable or slightly shorter than the median time to response of 2.7 months in the Ger- man real-world study [18]. Again, the differences between a controlled and a real-world setting is probably the main rea- son for the shorter time to response reported in the non-in- terventional studies. The results illustrate the relatively short time to a clinically relevant effect when used in everyday healthcare. Interestingly, ten patients were re-challenged with vismo- degib resulting in five partial remissions and three complete remissions. Two patients were even re-challenged twice with repeated remissions. These data are in line with the Greek study that reported responses after re-challenging in 8 pa- tients [17]. Of the predefined AESIs, the frequencies of alopecia, fatigue, nausea and weight-loss were lower or much lower compared to those reported in the ERIVANCE and STEVIE studies. Other adverse events were as expected in frequency and most events were mild to moderate [11, 12]. Ten patients (20.8%) discontinued treatment due to adverse events, while seven patients (14.6%) interrupted or discontinued treat- ment but could remain on treatment regimen. Compared to previously reported trials, this is a low frequency. There were more SAEs reported in this study (33.3%) compared to the German studies that reported 22.7% and 17.0%, re- spectively. Nevertheless, the majority of the SAEs were not related to vismodegib in any of the studies [18, 19]. Of the vismodegib for aBCC, including the pivotal study ERIVANCE [10, 11], the safety study STEVIE [12, 20] and the more re- cently published non-interventional studies from Germany [18, 19] and Greece [17]. In the current study, the group with Gorlin syndrome were markedly younger than the overall populations, as could be expected with the greater severity and earlier onset of disease for these patients [7, 8]. The pre- dominance of men compared to women in the current study is similar to most studies [11-13, 17-19, 21] and the base- line comorbidity and concomitant treatments as could be expected with respect to the ages and the disease indication. The obtained study data support previous knowledge of vismodegib as highly effective; the PFS and OS levels are in line with the pivotal ERIVANCE and STEVIE trials [18, 12] whereas the clinical response of 95.4% in this trial is high compared to other studies, where 50-77% clinical respond- ers were observed [11, 13, 18, 19] and similar to the Greek study that reported 95.6% responders [17]. The variability in clinical response rate between studies is most likely due to differences in response evaluation methods. The current study pragmatically allowed for physician assessment to de- termine clinical response in order to reflect the real-world practice and thus a resulting higher response rate than when using strict radiologic criteria is to be expected. Approximately half of the patients had reached a clin- ical response after 2 months (60 days), and 80% after 3.3 months (100 days) of treatment. This is a shorter time to response, compared to the median time of 5.5-6.7 months Table 3. Extent of exposure including duration of treatment and pauses from treatment. Cohort 1 n=37 Cohort 2 n=3 Cohort 3 n=8 Total 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. Original article | Dermatol Pract Concept. 2023;13(2):e2023211 7 1.0 A 0.9 0.8 0.7 0.6 0.5 P ro p o rt io n o f s u b je ct s 0.4 0.3 0.2 0.1 0.0 0 50 100 150 200 250 Time (days) Cohort 1 Cohort 2 Cohort 3 Total 300 350 400 450 500 Censored Time to clinical response 1.0 B 0.9 0.8 0.7 0.6 0.5 P ro p o rt io n o f s u b je ct s 0.4 0.3 0.2 0.1 0.0 0 100 200 300 400 500 600 Time (days) Cohort 1 Cohort 2 Cohort 3 Total 700 800 900 1000 1100 1200 1300 Censored Duration of Response 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. 8 Original article | Dermatol Pract Concept. 2023;13(2):e2023211 Table 4. Adverse events, safety population. Cohort 1 (n=37) Cohort 2 (n=3) Cohort 3 (n=8) Total (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 treatmentb, n (%) 8 (21.6) 0 2 (25.0) 10 (20.8) 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 treatment, n 5 (13.5) 1 (33.3) 1 (12.5) 7 (14.6) Number of adverse events leading to interruption of study treatment 9 2 1 12 Nausea 1 (2.7) 1 (33.3) 0 2 (4.2) 1.0 C 0.9 0.8 0.7 0.6 0.5 P ro p o rt io n o f s u b je ct s 0.4 0.3 0.2 0.1 0.0 0 100 200 300 400 500 600 Time (days) Cohort 1 Cohort 2 Cohort 3 Total 700 800 900 1000 1100 1200 1300 Censored Time to recurrence - All applicable patients 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) Original article | Dermatol Pract Concept. 2023;13(2):e2023211 9 The journal of investigative dermatology Symposium proceed- ings, 1999; 4: 41-45. doi:10.1038/sj.jidsp.5640179 3. Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nature reviews Cancer, 2008; 8: 743-754. doi:10.1038/nrc2503 4. Von Hoff DD, LoRusso PM, Rudin CM, et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. The New England journal of medicine, 2009; 361: 1164-1172. doi:10.1056 /NEJMoa0905360 5. Caro I, Low JA. The role of the hedgehog signaling pathway in the development of basal cell carcinoma and opportunities for treat- ment. Clinical cancer research : an official journal of the Amer- ican Association for Cancer Research, 2010; 16: 3335-3339. doi:10.1158/1078-0432.ccr-09-2570 6. Lindelöf B, Lapins J, Dal H. Shift in Occupational Risk for Basal Cell Carcinoma from Outdoor to Indoor Workers: A Large Population-based Case-control Register Study from Sweden. Acta dermato-venereologica, 2017; 97: 830-833. doi:10.2340 /00015555-2660 7. Gorlin RJ. Nevoid basal-cell carcinoma syndrome. Medicine, 1987; 66: 98-113. doi:10.1097/00005792-198703000-00002 8. Tang JY, Mackay-Wiggan JM, Aszterbaum M, et al. Inhibit- ing the hedgehog pathway in patients with the basal-cell nevus syndrome. The New England journal of medicine, 2012; 366: 2180-2188. doi:10.1056/NEJMoa1113538 9. Spiker AM, Troxell T, Ramsey ML. Gorlin Syndrome. StatPearls. Treasure Island (FL): StatPearls Publishing Copyright © 2021, StatPearls Publishing LLC., 2021. 10. Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. The New En- gland journal of medicine, 2012; 366: 2171-2179. doi:10.1056 /NEJMoa1113713 11. Sekulic A, Migden MR, Basset-Seguin N, et al. Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study. BMC cancer, 2017; 17: 332. doi:10.1186/s12885-017 -3286-5 12. Basset-Séguin N, Hauschild A, Kunstfeld R, et al. Vismodegib in patients with advanced basal cell carcinoma: Primary anal- ysis of STEVIE, an international, open-label trial. European life-threatening or fatal events, none were judged to be re- lated to vismodegib treatment. In all, a non-interventional study design cannot be com- pared to the strength of a controlled clinical trial. The data collection follows the standard care at each study site and obviously varies between clinics. Treatment durations were not standardized but adjusted to each patient and frequent treatment pauses were allowed; all which might influence the response outcome. The patient demographics show some imbalances between the cohorts, but with exception of the younger age in cohort 3, these differences do not appear rel- evant. Comparison of the cohorts must be done with great caution, due to the big differences in number of patients be- tween them. However, in general the collected data mirror the standard of care of the patient population at each clinic and reflect the real-life treatment of patients with aBCC, which was the purpose of the study. To conclude, this study is the largest study performed in Sweden with aBCC patients treated with vismodegib and mirrors the routine clinical care of aBCC. Vismodegib treat- ment resulted in a high number of patients with a clinical response and PFS and OS in the same range as in other trials despite a shorter and more intermittent treatment duration. The close monitoring of patient safety, tolerability and ad- aptation of treatment, including re-challenge of treatment in some cases, may be a step towards optimizing the treatment schedule of aBCC patients. References 1. Stegmayer B. Basal cell carcinoma in Sweden 2004-2008. Socialstyrelsen; 2009 2009-12-12. 2. Aszterbaum M, Beech J, Epstein EH, Jr. Ultraviolet radiation mu- tagenesis of hedgehog pathway genes in basal cell carcinomas. Cohort 1 (n=37) Cohort 2 (n=3) Cohort 3 (n=8) Total (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) Table 4. Adverse events, safety population. (Continued) 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. 10 Original article | Dermatol Pract Concept. 2023;13(2):e2023211 18. Gutzmer R, Schulze HJ, Hauschild A, et al. Effectiveness, safety and utilization of vismodegib in locally advanced basal cell carcinoma under real-world conditions in Germany - The non- interventional study NIELS. Journal of the European Academy of Dermatology and Venereology : JEADV, 2021; 35: 1678-1685. doi:10.1111/jdv.17332 19. Kaatz M, Mohr P, Livingstone E, et al. Effectiveness, Safety and Utilization of Vismodegib for Locally Advanced Basal Cell Carcinoma Under Real-world Conditions: Non-interventional Cohort Study JONAS. Acta dermato-venereologica, 2022; 102: adv00695. doi:10.2340/actadv.v102.293 20. Dummer R, Basset-Seguin N, Hansson J, et al. Impact of treatment breaks on vismodegib patient outcomes: Exploratory analysis of the STEVIE study. Journal of Clinical Oncology, 2015; 33: 9024-9024. doi:10.1200/jco.2015.33.15_suppl.9024 21. Frampton JE, Basset-Séguin N. Vismodegib: A Review in Advanced Basal Cell Carcinoma. Drugs, 2018; 78: 1145-1156. doi:10.1007 /s40265-018-0948-9 22. Lacouture ME, Dréno B, Ascierto PA, et al. Characterization and Management of Hedgehog Pathway Inhibitor-Related Adverse Events in Patients With Advanced Basal Cell Carcinoma. The oncologist, 2016; 21: 1218-1229. doi:10.1634/theoncologist .2016-0186 23. Peris K, Fargnoli MC, Garbe C, et al. Diagnosis and treatment of basal cell carcinoma: European consensus-based interdis- ciplinary guidelines. European journal of cancer (Oxford, England: 1990), 2019; 118: 10-34. doi:10.1016/j.ejca.2019 .06.003 journal of cancer (Oxford, England : 1990), 2017; 86: 334-348. doi:10.1016/j.ejca.2017.08.022 13. Dréno B, Kunstfeld R, Hauschild A, et al. Two intermittent vismo- degib dosing regimens in patients with multiple basal-cell carcino- mas (MIKIE): a randomised, regimen-controlled, double-blind, phase 2 trial. The Lancet Oncology, 2017; 18: 404-412. doi:10.1016/s1470-2045(17)30072-4 14. Woltsche N, Pichler N, Wolf I, Di Meo N, Zalaudek I. Manag- ing adverse effects by dose reduction during routine treatment of locally advanced basal cell carcinoma with the hedgehog inhib- itor vismodegib: a single centre experience. Journal of the Euro- pean Academy of Dermatology and Venereology : JEADV, 2019; 33: e144-e145. doi:10.1111/jdv.15367 15. Routt E, Ratner D. Outcomes for Basal Cell Carcinoma Treated With Vismodegib Extended Alternate Day Dosing. Dermatologic surgery : official publication for American Society for Derma- tologic Surgery [et al], 2020; 46: 1109-1112. doi:10.1097/dss .0000000000001985 16. Wong C, Poblete-Lopez C, Vidimos A. Comparison of daily dosing versus Monday through Friday dosing of vismodegib for locally advanced basal cell carcinoma and basal cell nevus syndrome: A retrospective case series. Journal of the American Academy of Der- matology, 2020; 82: 1539-1542. doi:10.1016/j.jaad.2020.02.050 17. Apalla Z, Spyridis I, Kyrgidis A, et al. Vismodegib in real-life clinical settings: A multicenter, longitudinal cohort providing long-term data on efficacy and safety. Journal of the American Academy of Dermatology, 2021; 85: 1589-1592. doi:10.1016 /j.jaad.2020.11.036