The Efficacy of Sonidegib in Treating Locally Advanced Basal Cell Carcinoma Involving the Periocular Area

Abstract

Introduction

Basal cell carcinoma (BCC) is the most common skin malignancy in Caucasians. Globally, about 20% of BCCs involve the periocular region. The treatment of periocular BCC may be very challenging because of its proximity to the intracranial structures. Thus, early diagnosis and early treatment is mandatory. Recently, the introduction of Hedgehog pathway inhibitor therapy revolutionized the management of unresectable BCCs. The aim of our study was to evaluate the outcome of sonidegib treatment in patients affected by periocular locally advanced (la) BCC at our skin cancer center.

Methods

A 3-year retrospective study was carried out enrolling patients with periocular laBCC treated with sonidegib. Therapeutic response was defined as complete remission (CR) in case of complete regression of the tumor, partial remission (PR) in case of tumor regression not achieving complete remission, and stable disease (SD).

Results

A total 16 patients (11 men and 5 women; medium age 71.6 ± 11.5 years) with periocular laBCCs undergoing treatment with 200 mg/day of sonidegib were included in our study. Patients included in the study were treated for at least 6 months for a median duration of 9 months. Overall, CR was reported in 9/16 (56.2%) patients, PR was reported in 4/16 patients (25%), and tumor remained stable in 3 patients (18.8%). No cases of disease progression were collected. Fourteen out of 16 patients experienced multiple adverse events (AEs): dysgeusia was reported in 12 (75%) patients, muscle spasms in 13 (81%) patients, and 7 (43.7%) patients presented with alopecia. However, all of the AEs were mild and none required treatment discontinuation.

Conclusion

To the best of our knowledge, this is the first study investigating the effectiveness and safety of sonidegib in the management of BCC localized at the periocular region. Even if limited, our study suggests this drug as a valuable and safe option in periocular BCC management.

Key Summary Points

Why carry out this study?

Basal cell carcinoma (BCC) is the most common skin malignancy in Caucasians. Globally, about 20% of BCCs involve the periocular region.

The treatment of periocular BCC may be very challenging because of its proximity to the intracranial structures. Thus, early diagnosis and early treatment is mandatory.

The aim of our study was to evaluate the outcome of sonidegib treatment in patients affected by periocular locally advanced BCC at our skin cancer center.

What was learned from the study?

Sonidegib showed promising results in terms of efficacy and safety for the management of periocular BCC, suggesting this drug as a valuable and safe option in periocular BCC management.

Introduction

Basal cell carcinoma (BCC) is the most common skin malignancy in Caucasians, frequently involving sun-exposed areas such as the head and neck region [1]. Globally, more than 75% of BCCs appear in the head and neck region, and about 20% of BCCs involve the periocular area [2]. When localized on the periocular region, the treatment of BCC may be very challenging because of its proximity to the intracranial structures [3]. Thus, early diagnosis and early treatment is mandatory for periocular BCCs both for functional and cosmetic outcomes [2, 3]. Although surgical excision still represents the gold standard treatment for the majority of BCCs, a small subset are not eligible for surgery or radiotherapy because of their size or location [4]. Recently, new knowledge on BCC pathogenesis led to the development of new selective drugs [5]. In particular, the introduction of Hedgehog pathway inhibitor (Hhi) therapy revolutionized the management of unresectable BCCs [5, 6]. To date, vismodegib and sonidegib are the two Smoothened (Smo) inhibitors approved for the treatment of advanced BCCs, and trials on other Hhi are ongoing [5, 6]. Currently, there are several studies reporting the effectiveness of Hhi in BCC management [7, 8]. However, data on the efficacy and safety of vismodegib and sonidegib in treating advanced BCCs located on the ocular-periocular site or their use as neoadjuvant treatment before surgery are scant [9–12]. In this scenario, we performed a retrospective study to evaluate the outcome of sonidegib treatment in patients affected by periocular locally advanced (la) BCC at our skin cancer center.

Material and Methods

A retrospective study was carried out enrolling patients with periocular laBCC undergoing treatment with sonidegib from February 2020 to February 2023. All of the BCCs were histologically confirmed. Informed consent was obtained from each patient and the study was approved by the Local Ethics Committee of the University of Naples Federico II. Demographic data including age, sex, tumor site, and presence of orbital involvement were retrospectively reviewed. Other data included dose, duration, and related adverse events (AEs). Concomitant BCCs located at other areas of the body were excluded in our analysis. Therapeutic response was defined as complete remission (CR) in case of complete regression of the tumor, partial remission (PR) in case of tumor regression not achieving complete remission, and stable disease (SD). Patients were visited every month and all AEs were collected and evaluated according to the Common Terminology Criteria for Adverse Events version 5.0 from the National Cancer Institute [13]. Sonidegib was administered at standard dosage of 200 mg once a day. This study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments.

Results

Sixteen patients (11 men and 5 women; medium age 71.6 ± 11.5 years) with periocular laBCCs undergoing treatment with 200 mg/day of sonidegib were included in our study. Patients’ features at baseline are reported in Table 1. In particular, 43.8% (7/16) of the BCCs were localized on the lateral canthus, 4 out of 16 (25.0%) were localized on the lower eyelid, and 5 out of 16 (31.2%) were localized on the superior orbit extending to the forehead. Of note, orbital involvement was confirmed with magnetic resonance imaging in 5 patients. No one presented with metastatic disease. Features of the periocular BCCs are reported in Table 1. Patients included in the study were treated for at least 6 months (range 6–14 months) for a median duration of 9 months. Moreover, all of the patients were followed up monthly for at least 3 months (range 3–6 months) after treatment interruption to assess the persistence of CR. Overall, CR was reported in 9/16 (56.2%) patients, PR was reported in 4/16 patients (25%), while tumor remained stable in 3 patients (18.8%) (Table 1). PR on sonidegib treatment was followed by complete surgical excision of BCC in 3 patients (Fig. 1). No cases of disease progression were collected. Fourteen out of 16 patients experienced multiple AEs: dysgeusia was reported in 12 (75%) patients, muscle spasms in 13 (81.3%) patients, and 7 (43.8%) patients presented with alopecia (Table 1). However, all of the AEs were mild and none required treatment discontinuation.

Table 1.

Characteristics of patients and clinical features of periocular BCCs at baseline and following treatment with sonidegib

Patients	16
Men, n (%)	11 (68.8)
Mean age (years)	71.6 ± 11.5
Patients with BCCs
Only periocular BCC	8 (50.0)
Multiple BCC	8 (50.0)
Periocular BCC: periocular location, n (%)
Lateral canthus	7 (43.8)
Lower eyelid	4 (25.0)
Superior orbit	5 (31.2)
Periocular BCC: tumor size
< 1 cm	5 (31.2)
1–2 cm	8 (50.0)
> 2 cm	3 (18.8)
Periocular BCC: histological subtype, n (%)
Nodular	6 (37.5)
Infiltrative, morpheaform, or micronodular	3 (18.8)
Superficial	2 (12.5)
Mixed	3 (18.8)
Basosquamous	1 (6.3)
Periocular BCC: previous treatments, n (%)
Excisional surgery	7 (43.8)
Topical medications	3 (18.8)
Photodynamic therapy	1 (6.3)
Radiation therapy	1 (6.3)
None	4 (25.0)
Treatment with sonidegib outcomes, n (%)
Complete response	9 (56.2)
Partial response	4 (25.0)
Stable disease	3 (18.8)
Disease progression	0 (0)
Treatment with sonidegib adverse events, n (%)
At least 1 adverse event	16 (100)
Dysgeusia	12 (75.0)
Muscle spasms	13 (81.3)
Alopecia	7 (43.8)

Fig. 1.

Basal cell carcinoma regression following sonidegib treatment. a An 84-year old woman with locally advanced BCC of superior orbit extending to the forehead at presentation and b after 10-month treatment with 200 mg/day sonidegib showing complete remission

Discussion

Surgical treatment is the mainstay of advanced BCCs management [5–7]. However, tumor size, tumor location, and patients’ comorbidities may limit this approach [5–7]. In particular, the periocular area has always represented a challenge in terms of the functional aspect and because of the difficulty of ensuring disease-free margins of excision, requiring new treatment strategies [3]. Recently, the introduction of Hhi therapy opened a new era of treatment for these forms of BCCs. However, there are still few data on the effectiveness and safety of Hhi therapy in the management of periocular BCCs. In particular, data on the use of sonidegib in periocular BCC are scant [9–12]. Also, the effectiveness results of the BOLT trial did not focus on periocular BCC [14].

De Giorgi et al. reported a single-center study investigating the effectiveness and safety of Hhi for the management of periocular BCC [9]. Among the 15 patients included in their cohort, two received sonidegib. Both patients achieved a satisfactory response, experiencing only mild AEs [9].

Hou et al. described the case of a 73-year-old man affected by multiple BCCs, including a morphea-like BCC of the left lower eyelid successfully treated with sonidegib, without requiring a surgical approach [10]. Similarly, Rokohl et al. reported the case of a patient with periocular BCC successfully treated with sonidegib, noting the promising safety profile of the drug [11].

Finally, Tchernev et al. reported the case of a 103-year-old patient affected by periocular BCC with intraocular invasion, suggesting Hhi as a valuable weapon in this type of patient [12].

Here, we reported the results of a retrospective study investigating the effectiveness and safety of sonidegib treatment in patients affected by periocular laBCC at our skin cancer center. Sixteen patients were included in our cohort. Among these, 9 (56.2%) and 4 (25%) patients reported CR and PR, respectively, while tumor remained stable in the remaining cases (3, 18.8%). Moreover, no cases of tumor progression were collected. Of note, 3 patients who achieved a PR were subsequently treated with complete surgical excision of BCC. As regards the safety, despite 14 (87.5%) patients experiencing at least one AE, no treatment discontinuation was required. The retrospective nature of our study was the main limitation.

In line with other studies [9–12], sonidegib showed promising results in terms of efficacy and safety for the management of periocular BCC.

The management of skin cancer is changing thanks to the recent knowledge of cancer pathogenesis [15, 16] and new medical services [17].

To the best of our knowledge, our study is the largest study investigating the effectiveness and safety of sonidegib in the management of BCC localized at the periocular region, confirming previously promising results. Even if limited, our study suggests this drug as a valuable and safe option in periocular BCC management.

Conclusion

The management of periocular BCC is challenging. Our study highlighted that sonidegib seems to offer a valuable therapeutic opportunity in patients with unresectable periocular BCC. However, further studies are required to confirm our data.