Dear Editors, Basal cell carcinomas (BCCs) are the most frequent malignant tumors in humans, accounting for 75–80 % of non-melanoma skin cancers (NMSC), and typically involve chronically sun-exposed areas in elderly patients.1, 2 In the elderly population, age-related immune system impairment (immunosenescence) may play a significant role in promoting the development of more aggressive, giant or difficult-to-treat BCCS, potentially influencing both tumor behavior and therapeutic response.3 According to the EADO guidelines, BCCs can be classified as easy-to-treat or difficult-to-treat tumors. Difficult-to-treat BCCs include both common BCCs with specific management challenges and locally advanced BCCs (laBCCs), which by definition are not amenable to curative surgery or radiotherapy. The management of difficult-to-treat BCCs includes palliative surgery or surgery as part of a neoadjuvant approach, radiotherapy for patients who refuse or have contraindications to surgery, and systemic therapy with Hedgehog signaling pathway inhibitors (HHIs), such as Vismodegib and Sonidegib.1 This work describes five real-life cases of laBCC in ultra-nonagenarian patients treated with Sonidegib using dose-reduction strategies at the Dermato-Oncology Unit of Trieste (Maggiore Hospital, University of Trieste). The cohort included three women aged 93 years, one woman aged 91 years, and one 93-year-old man, all characterized by significant comorbidities and limited eligibility for standard surgical or radiotherapeutic approaches. In all cases, advanced age and frailty strongly influenced therapeutic decision-making, leading to the adoption of reduced regimen aimed at improving tolerability while maintaining clinical efficacy. Across the series, Sonidegib was administered from treatment initiation at 200 mg every other day, corresponding to a 50 % dose reduction compared with the dosing regimen indicated in the summary of product characteristics, and in one case was further reduced to once-weekly administration. Despite the advanced age of the patients and the presence of multiple comorbidities (including cardiovascular disease, diabetes, renal impairment, anemia, and pacemaker implantation) treatment was generally well tolerated. Three patients experienced no adverse events, one patient reported an increase in serum creatinine level, stated unrelated to Sonidegib by a nephrology consultation and one patient reported clinically significant myalgias that required a drug holiday of three weeks; those who reported side effects showed complete resolution following further dose reduction or short drug holidays, without the need for permanent treatment discontinuation. Clinically meaningful responses were observed in all patients, including reduction in tumor size, cessation of bleeding, pain relief, and healing of ulcerated lesions, with complete clinical remission of individual lesions in several cases (Figure 1, Figure 2) and partial but still meaningful responses in another case (Figure 3). The mean time to clinical response was approximately seven months, compared with the median time to response of 2.3 months reported in the literature.4 These responses were maintained over prolonged treatment periods, even under reduced dosing schedules. Importantly, laboratory parameters remained within normal limits in the majority of patients, and no severe or life-threatening adverse events were reported. In one patient, transient renal function impairment prompted dose reduction; however, subsequent evaluation excluded a causal relationship with Sonidegib, allowing continued therapy. In another case, rechallenge with Sonidegib at a markedly reduced dose (200 mg once a week) after disease recurrence resulted in renewed disease control with improved tolerability. The safety and efficacy of Sonidegib in the treatment of laBCC have been well established in both clinical trials and real-world settings. The favorable safety profile observed in the pivotal BOLT trial was subsequently confirmed by the 3-year non-interventional, multinational post-authorization safety study NISSO, supporting the overall benefit–risk balance of this hedgehog pathway inhibitor.5 To reduce treatment-related toxicities associated with HHIs and minimize the risk of early treatment discontinuation, alternative dosing strategies, such as treatment interruptions or dose reductions from the standard Sonidegib regimen of 200 mg daily, have been proposed.6 In this context, retrospective data have shown that patients treated with Sonidegib 200 mg every other day achieved clinical responses comparable to those receiving daily dosing, while experiencing a more favorable tolerability profile.7 Our case series further explores the use of reduced and intermittent Sonidegib dosing schedules (200 mg every other day or once weekly) in an extremely elderly population of ultra-nonagenarian patients with laBCCs. The findings of this series are consistent with and expand upon existing literature, with a specific focus on the oldest segment of the population, which is often underrepresented or excluded from clinical trials due to advanced age and frailty.7, 8 Notably, no severe adverse events were observed, underscoring the safety of Sonidegib in a particularly vulnerable population characterized by multiple comorbidities and increased susceptibility to treatment-related toxicities. This aspect is especially relevant in clinical practice, as treatment tolerability often represents a major limiting factor in elderly patients, in whom even mild adverse effects may be perceived as unacceptable and lead to early treatment discontinuation in order to preserve quality of life. Sonidegib demonstrated encouraging efficacy in our cohort, with consistent tumor regression, including significant lesion shrinkage and improvement of associated symptoms such as pain, ulceration, bleeding, and functional impairment. Although the onset of clinical benefit appeared slower than that reported in younger populations, this aspect remains clinically relevant in very elderly patients, for whom rapid tumor response often comes at the expense of treatment-related toxicity and reduced quality of life. In this frail population, Sonidegib may be better conceptualized as a chronic therapy, in which patient compliance and long-term adherence are more critical than rapidity of response. A further key observation emerging from our series is the effectiveness of administering Sonidegib at half of the standard recommended dose from the beginning of treatment. Dose reduction to 200 mg every other day did not appear to compromise therapeutic efficacy, while clearly improving tolerability and facilitating prolonged treatment duration. This observation is supported by recent case reports demonstrating maintained efficacy and improved safety profiles with alternate-day dosing in elderly patients.9 Importantly, in our series, reduced or intermittent dosing allowed sustained disease control over extended periods and, in one case, enabled successful rechallenge after disease recurrence with minimal toxicity. Although controlled prospective studies are needed to better define the optimal dosing regimen of Sonidegib in elderly and frail patients, our real-world experience suggests that reduced-frequency administration, such as every-other-day dosing, may represent a valuable therapeutic strategy. This approach appears to preserve clinical efficacy while minimizing adverse events, potentially offering a more favorable balance between efficacy and safety in this fragile population. In conclusion, this case series highlights the potential role of Sonidegib 200 mg every other day as a safe and effective treatment option for ultra-nonagenarian patients, a population that is rarely represented in literature. Our findings suggest that Sonidegib, even when administered at reduced doses, can induce tumor regression and symptom improvement without severe adverse events. These results suggest that less frequent dosing schedules may mitigate treatment-related toxicity without compromising therapeutic benefit. On this basis, consideration of treatment initiation with reduced Sonidegib dosing may be warranted in elderly patients with laBCC to optimize the risk-benefit ratio, improve long-term adherence, and ultimately enhance quality of life in this vulnerable patient population. None. Open access publishing facilitated by Universita degli Studi di Trieste, as part of the Wiley - CRUI-CARE agreement. Dr. Meo received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events (Almirall, Sunpharma, MSD, Sanofi, and Pfizer). Dr. Zalaudek received data safety monitoring board (Philogen), payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events (Sanofi Genzyme, Sunpharma, Novartis, MSD, BMS, Philogen, Biogena, La Roche Posay, Kyowara Kirin, Fotofinder, Mall.inckrodt, Cieffe Derma, Pierre Fabre, Regeneron, Canova, Almirall, Beiersdorf), support for attending meetings and/or travel (Difa Cooper); Dr. Caposiena Caro has received honoraria for participation in speaker bureaus from Novartis, Eli Lilly, Sanofi, and Pfizer. Drs. Brunello, Corio and Zanette have no conflicts of interest to declare.
Brunello et al. (2026) studied this question.