Background: Following the pivotal phase II trial BOLT, the Hedgehog (Hh) inhibitor sonidegib was approved in the EU to treat locally advanced basal cell carcinoma (laBCC) in patients not amenable to surgery or radiotherapy. We report safety data from the interim analysis of the real-world NISSO study., Methods: NISSO is an ongoing non-interventional, multinational, post-authorization safety study (NCT04066504). Patients with laBCC are treated with sonidegib 200 mg orally once daily and followed for 3 years. Dose modifications were allowed according to the local prescribing information., Results: Between May 6, 2019, and March 15, 2022, 321 patients with laBCC were enrolled at 46 European sites (data cut-off: June 22, 2023). Treatment was discontinued in 241 (75.1%) patients, with the main reasons being the patient/guardian decision (n = 69, 28.6%), treatment success (n = 40, 16.6%) and the physician decision (n = 35, 14.5%). The median duration of sonidegib exposure was 8.8 months (4.4-13.7 months). Overall, 284 (88.5%) patients had ≥ one treatment-emergent adverse event (TEAE). Most TEAEs were ≤ grade 2 and the most common were muscle spasms (n = 141; 43.9%), dysgeusia (n = 119; 37.1%), and alopecia (n = 97; 30.2%). After 3 months of treatment, the cumulative rates of muscle spasms, dysgeusia, and alopecia were 21.8%, 16.2%, and 3.7%, respectively. TEAEs led to treatment discontinuation in 59 (18.4%) patients, while 149 (46.4%) patients had at least one TEAE leading to dose reduction or interruption. Serious drug-related TEAEs were reported in 13 (4.1%) patients., Conclusions: These results confirm the safety profile previously observed. Most patients experienced the onset of common TEAEs after 3 months of treatment, and the cumulative incidence of most common TEAEs was 10-20% lower compared to the BOLT study, except for dysgeusia and fatigue that had a similar incidence. The percentage of patients experiencing TEAEs requiring interruption or dose reduction was similar to the BOLT study, while the proportion of patients with TEAE leading to discontinuation of sonidegib was lower. This study demonstrates that the tolerability of sonidegib is manageable in routine clinical practice., Trial Registration: NCT04066504., Competing Interests: Declarations Ethics approval and consent to participate This study was performed in line with the principles of the Declaration of Helsinki. The study protocol was approved by ethics committees of participating study centers: Ethics Committee of the MHH Hannover; Ethics Committee of Westphalia-Lippe; Ethics Committee of the Christian-Albrechts-Universität zu Kiel; Ethics Committee of the Saxony-Anhalt Medical Association; Ethics Committee of the Medical Association of Thuringia; Ethics Committee of the Medical Faculty of the University of Duisburg-Essen; Ethics Committee of the University of Tübingen; Ethics Committee of the Albert-Ludwigs-University Freiburg; Ethics Committee of the Medical Association of Lower Saxony; Ethics Committee of the University of Regensburg; Ethics Committee of the University of Lübeck; Ethics Committee of the Rhineland-Palatinate Medical Association; Ethics Committee of the Medical Association of Hesse; Ethics Committee of the North Rhine Medical Association; Ethics Committee of the Medical Faculty of the Ruhr University Bochum; Ethics Committee of the Goethe University Frankfurt; Ethics Committee Hamburg; Ethics Committee of the University of Ulm; Ethics Committee of the Technical University of Munich; Ethics Committee Bad Oeynhausen; Ethics Committee at the Technical University of Dresden; Ethics Committee Berne; Ethics Committee Zurich; Comitato Etico Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale"; Comitato Etico I.R.C.C.S. Istituto Tumori “Giovanni Paolo II”; Comitato Etico Interaziendale Novara; Comitato Etico Università Federico II; Comitato Etico Fondazione Policlinico Universitario Agostino Gemelli IRCCS – Università Cattolica del Sacro Cuore; Comitato Etico ASL Avezzano/Sulmona/L’Aquila Teramo; Comitato Etico Regionale Liguria; Comitato Etico di Area Vasta Centro; Comitato Etico Fondazione IRCCS “Istituto Nazionale dei Tumori”; Comitato Etico Istituto Dermopatico dell’Immacolata – IRCCS; Comitato Etico di Brescia; Comitato Etico della Romagna (CEROM); Ethics Committee for Clinical Research of Hospital Clínic of Barcelona; Ethics Committee of Hospital of Nuestra Señora de la Candelaria; Ethics Committee of Hospital of Ramón y Cajal; Research Ethics Committee / Ethics Committee for Drug Research of the Dr. Negrín University Hospital of Gran Canaria; Ethics Committee of Galicia (SERGAS); Ethics Committee of the Hospital of Vall d'Hebron; Ethics Committee of University Hospital of La Paz; Ethics Committee of Hospital of Santa Creu i Sant Pau; Ethics Committee of Hospital of La Fe; Ethics Committee of University General Hospital of Valencia; Ethics Committee of Hospital of Germans Trias i Pujol; Ethics Committee of University Hospital of Vírgen de la Macarena (site was not initiated). Consent for publication Not applicable. Competing interests RG served as consultant for BristolMyers Squibb, MerckSharpDohme, Novartis, GlaxoSmithKline, Amgen, Almirall-Hermal, Pierre-Fabre, SUN Pharma, Immunocore, Delcath, Merck Healthcare, Sanofi/Regeneron. RG received honoraria for lectures from BristolMyers Squibb, MerckSharpDohme, Novartis, Amgen, Merck Healthcare, Almirall-Hermal, Pierre-Fabre, Sanofi/Regeneron, SUN Pharma. RG received travel support from Pierre-Fabre, SUN Pharma, Boehringer Ingelheim. RG received research grants from Sanofi/Regeneron, Merck Healthcare, Amgen, SUN Pharma, KyowaKirin, Almirall-Hermal. UL served as a consultant to MSD, Novartis, Sanofi, Sun Pharma, received travel support from Sun Pharma and Pierre Fabre, speakers’ fees from Sun Pharma, Sanofi, MSD, Novartis and institutional grants from MSD, outside the submitted work. PM received honoraria for lectures and presentations from MSD, Novartis, BMS, Pierre Fabre, Sanofi Genzyme, Immunocore, Delcath, Almirall Hermal, Sun Pharma, Regeneron. PM received travel support from MSD, BMS, Sun Pharma, Novartis and served as consultant for Novartis, BMS, Pierre Fabre, Sanofi Genzyme, Beiersdorf, MSD, Beiersdorf, Biotech, Regeneron, Sun Pharma. KCK serves as consultant to Philogen, BMS, MSD, Sanofi Aventis, Immunocore and received travel grants and speaker fees from Philogen, Pierre Fabre, BMS, MSD, Sun Pharma, Sanofi Aventis, Novartis, Medac and has received research support from Novartis. PAA has/had a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, Sun Pharma, Sanofi, Sandoz, Immunocore, Italfarmaco, Boehringer-Ingelheim, Regeneron, Pfizer, Nouscom, Lunaphore, Medicenna, Bio-Al Health, ValoTX, Replimmune, Bayer, Erasca, Philogen, Biontech, Anaveon. He also received research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer, Sanofi and travel support from Pfizer, Bio-Al Health, Replimmune, MSD, Pierre Fabre, Philogen. MS declares no conflicts of interest. KP reports grants and personal fees from Sanofi, Novartis, Abbvie, Almirall, Philogen, Leo Pharma, Lilly, Janssen, Pierre Fabre, Sun Pharma, Biogen, Galderma. KP received speaker fees from Lilly, Sanofi, Sun Pharma. GMPP has conflicts of interest with Sun Pharma, Almirall and La Roche-Posay. RFdM has/had a consultant/advisory role for Takeda, Kyowa Kirin, Recordati, Sun Pharma and received travel support from Kyowa Kirin, Sun Pharma, Janssen, UCB. RBE and REH have no conflicts of interest to state. AH reports grants and personal fees from Agenus, Almirall, Amgen, BMS, CureVac, Dermagnostix, Eisai, Highlight Therapeutics, Huya Biosciences, IO Biotech, Immunocore, Incyte, Iovance, Kyowa Kirin, MerckPfizer, MSD/Merck, NeraCare, Novartis Pharma, Philogen, Pierre Fabre, Replimune, Regeneron, Roche, Sanofi-Genzyme, Seagen, Xenthera, and from Sun Pharma outside the submitted work. SM, NG, and RA are employees of Sun Pharmaceuticals Industries and SUN Pharmaceuticals Germany GmbH., (© 2024. The Author(s).)