Efficacy and safety of sonidegib in the treatment of locally advanced basal cell carcinoma: A multicenter retrospective experience in real-world China

To the Editor: Basal cell carcinoma (BCC) is a malignant tumor originating from the basal cells of the epidermis and is the most common form of skin cancer. In China, the incidence of BCC has risen due to socioeconomic advancements and an aging population.[1] While early diagnosis and treatment typically result in favorable outcomes, 0.8–2.0% of patients may progress to locally advanced BCC (laBCC), characterized by lesions ≥10 mm in diameter. Traditional treatments, such as surgery or radiotherapy, may be unsuitable for laBCC due to the risk of morbidity, deformity, incomplete tumor removal, and high recurrence rates.[2] These limitations underscore the need for more effective therapeutic options. The mutations in the Hedgehog (Hh) signaling pathway, particularly in the human homologs of Drosophila patched (PTCH1) and smoothened (SMO), play a crucial role in BCC development by leading to uncontrolled cell proliferation. Sonidegib, a selective SMO receptor antagonist, has demonstrated efficacy in inducing BCC regression by inhibiting Hh pathway and modulating immune responses.[3] It has been approved for treating laBCC in patients ineligible for surgery or radiotherapy. However, real-world data on sonidegib’s effectiveness in China are limited, necessitating further studies to assess its efficacy and safety in this population. This multicenter, retrospective, observational study (www.medicalresearch.org.cn, No. MR31-23-034551) was conducted in compliance with the 1975 Declaration of Helsinki and was approved by the Ethics Committee of Huashan Hospital, affiliated with Fudan University (No. 2023-604). The Medical Ethics Committee of the Dermatology Hospital of Southern Medical University, the Third Affiliated Hospital of Sun Yat-sen University, the Second Affiliated Hospital of Dalian Medical University, and the Dermatology Hospital of Jiangxi Province approved using study data. Written informed consent was obtained from all participants. This study included adults with clinically and histologically confirmed laBCC who were ineligible for traditional treatment modalities. Exclusion criteria included patients who declined to sign the informed consent or were undergoing concurrent antitumor treatments. Data collection included demographic information, medical history, clinical and histopathological findings, laboratory results, and safety events throughout the study. This study was conducted following Good Clinical Practice (GCP) standards, and all the patients were administered 200 mg of sonidegib (Odomzo®, Sun Pharmaceutical Industries Limited, India) daily for up to 48 ± 2 weeks. Medical data from within 4 weeks before the start of treatment was used as a baseline, and posttreatment data collection ranged from a minimum of 24 weeks or until complete remission was achieved, up to a maximum of 48 ± 2 weeks. Efficacy was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.[4] The primary endpoint was the objective response rate (ORR), which included the percentage of patients achieving complete response (CR) and partial response (PR). Secondary endpoints included the disease control rate (DCR), defined as the combined rates of CR, PR, and stable disease (SD). Safety assessments included the occurrence of treatment-emergent adverse events (TEAEs), clinical laboratory tests, and 12-lead electrocardiogram (ECG) monitoring. All adverse events (AEs) were recorded and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0).[4] Statistical analyses were performed using the SAS software package (SAS Institute Inc., USA) with all tests being two-tailed and an α level of 0.05. A P-value of <0.05 was considered statistically significant. A total of 18 patients were enrolled in this study. The most common tumor locations were the perinasal region (7/18, 39%) and the periocular region (5/18, 28%). Four patients (22%) had multiple BCC lesions, and one (6%) was diagnosed with Gorlin–Goltz syndrome. Two patients (11%) had undergone previous surgical excision. Notably, 72% (13/18) of the participants received Sonidegib for at least 24 weeks, with a median treatment duration of 28 weeks (range: 12–48 weeks) [Supplementary Table 1, https://links.lww.com/CM9/C280]. The ORR was 94%, with 78% achieving CR (14/18) and 17% showing PR (3/18). One patient (6%) experienced SD, resulting in a DCR of 100% [Supplementary Figure 1 and Supplementary Table 2, https://links.lww.com/CM9/C280]. A total of 89% (16/18) of patients experienced 67 TEAEs, with the most common being dysgeusia (28%), weight loss (22%), and muscle spasms (22%) [Supplementary Figure 2, https://links.lww.com/CM9/C280]. Most AEs were mild to moderate, with 50% (9/18) of patients experiencing Grade 1 events and 39% (7/18) experiencing Grade 2 events [Supplementary Table 2, https://links.lww.com/CM9/C280]. No serious AEs were reported. Aside from a slight reduction in hemoglobin levels (P = 0.045), no significant deviations from baseline were observed in laboratory assessments [Supplementary Figure 3, https://links.lww.com/CM9/C280]. This first multicenter study of sonidegib in Chinese patients with laBCC demonstrated a 94.44% ORR and 100% DCR, confirming its efficacy in this population. Several factors may have contributed to the higher efficacy observed in this study compared to previous reports, including variations in evaluation criteria, retrospective study design, the subjective nature of response assessments, and potential ethnic differences in treatment response.[4,5] Moreover, the study supports the effectiveness of Sonidegib in a patient with Gorlin–Goltz syndrome, which is consistent with previous reports.[6] The safety profile aligned with earlier studies, although the observed decrease in hemoglobin level warrants further evaluation. Limitations of the study include its retrospective design, small sample size, and lack of a control group. Future prospective, randomized controlled trials are necessary to validate these findings further. In summary, sonidegib exhibited high efficacy and a favorable safety profile in Chinese patients with laBCC. This pioneering multicenter study offers evidence supporting the clinical use of sonidegib for laBCC in China. Acknowledgments We are grateful to the patients who participated in this study and to Huashan Hospital affiliated with Fudan University, Southern Medical University, the Third Affiliated Hospital of Sun Yat-sen University, the Second Affiliated Hospital of Dalian Medical University and Dermatology Hospital of Jiangxi Province for their invaluable support and contributions to the research. Funding This work was supported by the grants from the National Natural Science Foundation of China (Nos. 81703145, 82003351, 82002042, and 82104485), the National Key Research and Development Program of China (No. 2023YFC2509000), the Clinical Research Plan of Shanghai Hospital Development Center (No. SHDC22022302), the Shanghai Key Specialty Research Centre Construction Project (Shanghai Municipal Health Commission, No. 2023ZZ02018), the Leading Talent Project of Shanghai Municipal Health Commission (No. 2022LJ017), and the Shanghai Municipal Key Clinical Specialty (No. shslczdzk01002). Conflicts of interest None.