30 | Sonidegib for nevoid basal cell carcinoma (Gorlin) syndrome and EADO stage IIb sporadic basal cell carcinomas: a phase II study (SIBLINGS trial)

Sara Farinatti^1|2, Giuseppe Agenziano³, Emi Dika^4|5, Emanuela Passoni⁶, Ketty Peris⁷, Pietro Quaglino⁸, Paola Queirolo⁹, Massimiliano Scalvenzi¹⁰, Iris Zalaudek¹¹, Luigi Lorini¹¹, Cristina Gurizzan¹, Monica Variolo^1|2, Paolo Bossi*^1|2, Carlo Resteghini*^1|2 | ¹Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Rozzano, Milano; ²Department of Biomedical Sciences, Humanitas University, Rozzano ^MI; ³Unit of Dermatology, Luigi Vanvitelli University of Campania, Naples; ⁴Oncologic Dermatology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna; ⁵Department of Medical and Surgical Sciences, DIMEC, University of Bologna, Bologna; ⁶Dermatology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan; ⁷Institute of Dermatology, Catholic University of the Sacred Heart, Rome; Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome; ⁸Dermatologic Clinic, University of Turin Medical School, Turin; ⁹Medical Oncology Unit; ¹⁰Section of Dermatology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples; ¹¹Department of Dermatology and Venereology, University of Trieste, Ospedale Maggiore, Trieste, Italy. *Contributed equally.

Background: Nevoid Basal Cell Carcinoma Syndrome (NBCCS), or Gorlin syndrome, is a rare genetic condition characterized by multiple basal cell carcinomas (BCCs). Some sporadic BCC patients present multiple lesions, classified as difficult-to-treat (EADO stage IIb). In this population, surgery and radiotherapy are often unfeasible. Hedgehog-inhibitors (HHIs), such as vismodegib and sonidegib, demonstrated efficacy in advanced BCCs, including NBCCS. Class-specific adverse events (AEs) often lead to treatment discontinuation, limiting long-term benefits. Pulsed treatment schedules mitigate toxicity and improve compliance.

Methods: This is a phase II, single-arm, open-label study evaluating a tailored sonidegib schedule in adults with NBCCS or sporadic EADO stage IIb BCC patients. Eligible participants are aged 18–50, ECOG PS 0–1, HHI-naïve, not candidates for surgery or radiotherapy. Following a 16-week induction phase with daily sonidegib (200 mg), responders enter a 24-week maintenance phase using a pulsed 2:2 schedule (2 weeks on, 2 weeks off - Figure 1). Temporary suspensions (≤3 weeks) and dose reductions are permitted for grade ≥3 AEs. Response is assessed via RECIST at clinical visits, focusing on objective response rate , duration of response, and emergence of new lesions. The primary endpoint is treatment compliance, defined by the discontinuation rate. Secondary outcomes include safety, quality of life, and BCC control. A sample size of 15 patients provides 80% power to detect a reduction in discontinuation from 54% (from literature) to 20%.

Discussion: This study explores whether a planned pulsed dosing strategy can improve tolerability, reducing discontinuation while maintaining clinical benefit. This approach may extend treatment duration, improve quality of life, reduce relapse rates and emergence of new lesions. Limitations include small sample size and slow recruitment, inherent to the rarity of NBCCS and stringent eligibility criteria. Nevertheless, the study could provide valuable insights for optimizing long-term management in these high-need populations. Protocol number: EU CT n. 2024-515989-14-00.

---

Figure 1.