OBJECTIVES: Advanced basal cell carcinoma (BCC) can cause severe disfigurement and morbidity, resulting in reduced quality of life. Patient-reported change in fatigue and associations with clinical outcome in patients treated with the hedgehog pathway inhibitor sonidegib in BOLT (NCT01327053) were investigated.  METHODS: Fatigue was assessed in 226 patients with locally advanced (n=191) or metastatic (n=35) BCC treated with sonidegib 200 or 800 mg daily using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (scale, 0-100; higher scores indicate greater fatigue). Data were analyzed with 2 longitudinal techniques that use individual-level data at all observed time points (baseline to week 73): growth mixture modeling (GMM) investigated the presence of subgroups of differential responders via model-identified heterogeneity in fatigue scores, and latent growth modeling (LGM) investigated differential change in fatigue as a function of response (partial response [PR] or stable disease [SD]). RESULTS: Two subgroups were identified with GMM. Subgroup 1 (32% of trial sample) had lower mean levels of fatigue than subgroup 2 (68%) at baseline (6.0 vs 29.1) and week 73 (33.3 vs 76.0). Patients in subgroup 1 vs subgroup 2 were significantly more likely to reside in Europe, be fully active per ECOG, have fewer metastatic sites, and achieve overall survival, and were significantly less likely to reside in North America; regional differences may be confounded by the number of patients with metastases. LGM showed that the increase in fatigue was lower among patients with PR vs SD (change from baseline to week 61: 16.7 vs 39.1). CONCLUSIONS: Differential change in fatigue in patients treated with sonidegib in BOLT correlated with geographic region, performance status, metastatic burden, and treatment response. Increase in fatigue was lower in patients responding to treatment. These data support the clinical benefit observed with sonidegib in patients with advanced BCC.