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Heppt, M.V.;  Gebhardt, C.;  Hassel, J.C.;  Alter, M.;  Gutzmer, R.;  Leiter, U.;  Berking, C. Long-Term Management of Advanced Basal Cell Carcinoma. Encyclopedia. Available online: https://encyclopedia.pub/entry/37317 (accessed on 18 April 2024).
Heppt MV,  Gebhardt C,  Hassel JC,  Alter M,  Gutzmer R,  Leiter U, et al. Long-Term Management of Advanced Basal Cell Carcinoma. Encyclopedia. Available at: https://encyclopedia.pub/entry/37317. Accessed April 18, 2024.
Heppt, Markus V., Christoffer Gebhardt, Jessica C. Hassel, Mareike Alter, Ralf Gutzmer, Ulrike Leiter, Carola Berking. "Long-Term Management of Advanced Basal Cell Carcinoma" Encyclopedia, https://encyclopedia.pub/entry/37317 (accessed April 18, 2024).
Heppt, M.V.,  Gebhardt, C.,  Hassel, J.C.,  Alter, M.,  Gutzmer, R.,  Leiter, U., & Berking, C. (2022, November 30). Long-Term Management of Advanced Basal Cell Carcinoma. In Encyclopedia. https://encyclopedia.pub/entry/37317
Heppt, Markus V., et al. "Long-Term Management of Advanced Basal Cell Carcinoma." Encyclopedia. Web. 30 November, 2022.
Long-Term Management of Advanced Basal Cell Carcinoma
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The first-line therapy for locally advanced basal cell carcinoma (laBCC) is Hedgehog pathway inhibitors (HHIs), as they achieve good efficacy and duration of response. However, toxicity in the course of long-term treatment may lead to a decrease in the quality of life, and consequently to interruption or even discontinuation of therapy. As HHI therapy is a balancing act between effectiveness, adverse events, quality of life, and adherence, numerous successful treatment strategies have evolved, such as dose reduction and dose interruptions with on-off treatment schedules or interruptions with re-challenge after progression. As a small percentage of patients show primary or acquired resistance to HHIs, the inhibition of programmed cell death protein 1 (PD-1) has been approved as a second-line therapy, which may also be accompanied by immune-related toxicities and non-response. Thus, optimization of current treatment schedules, novel agents, and combination strategies are urgently needed for laBCC. 

basal cell carcinoma Hedgehog pathway inhibitors immunotherapy

1. Introduction

Basal cell carcinoma (BCC) is the most commonly diagnosed human cancer in the Caucasian population [1]. Age and ultraviolet (UV) light exposure are among the most important risk factors for the development of BCC [2]. Patients with the rare heritable basal cell nevus syndrome (BCNS, also known as Gorlin–Goltz syndrome) have a genetic predisposition to develop BCCs [1]. Most cases of BCC can be treated surgically or less frequently with radiotherapy, topical, or physical treatments [3][4]. However, in some cases the disease may progress to advanced BCC (aBCC), including locally advanced BCC (laBCC) and metastatic BCC (mBCC), for which local therapies are no longer an option [5].
Aberrant activation of the Hedgehog (HH) pathway is a key pathophysiological event in the development of BCC. In 80–90% of tumors, loss-of-function mutations in the gene encoding the twelve-pass transmembrane receptor Patched 1 (PTCH1) can be identified. Approximately 10% of tumors arise due to activating mutations in the gene Smoothened (SMO) [6][7][8][9]. The HH signaling pathway results in the activation of transcription factors of the GLI family and controls cell differentiation and proliferation in keratinocytes [1]. The HH pathway therefore maintains cutaneous stem cell populations and regulates sebaceous gland and hair follicle development. Aberrant activation results in uncontrolled tumor growth and survival. Since the HH signaling pathway is the most important factor in the pathogenesis and progression of BCC, it is an important therapeutic target.
HH pathway inhibitors (HHIs), such as vismodegib and sonidegib, are small molecule antagonists that bind and inhibit SMO; thereby preventing downstream signaling [10][11]. Vismodegib has been approved as first-in-class HHI for the treatment of adults with laBCC or mBCC that is unsuitable for surgery or radiotherapy [12]. More recently, sonidegib was approved as a second HHI for laBCC [13].
Although these drugs are effective and relatively well tolerated, treatment-related toxic effects under long-term treatment can lead to a decrease in patients’ quality of life [14]. The most commonly observed adverse events (AEs) in HHI-treated patients include muscle spasms, ageusia/dysgeusia, alopecia, weight loss, and asthenia (fatigue) [15]. This may result in early treatment interruption and even discontinuation and may thus impact the clinical outcome. For the clinician, this means a balancing act between effectiveness, AEs, quality of life, and adherence. There is, therefore, a high unmet need for the treatment of BCC patients requiring long-term treatment.

2. First-Line Therapy: Hedgehog Inhibitors

The HHI sonidegib (200 mg) was approved for laBCC based on results of the BOLT trial (NCT01327053), a double-blind, two arm (200 mg vs. 800 mg sonidegib once daily [QD]) phase II study that evaluated the long-term efficacy and safety of sonidegib for laBCC (n = 194) and mBCC (n = 36) [16]. Vismodegib (150 mg), another HHI, was approved based on the ERIVANCE trial (NCT00833417), a single-arm, multicenter, 2-cohort phase II study that evaluated the efficacy and safety of vismodegib in patients with aBCC (laBCC n = 71, mBCC n = 33) [17]. The efficacy data of sonidegib and vismodegib from the pivotal studies showed response rates that ranged from 47% to 60% based on comparable evaluation methods (response evaluation criteria in solid tumors, RECIST) [16][17]. Complete response (CR) was observed in slightly more than 20% for both drugs [16][17][18]. The median duration of response (DOR) by central review was 26.1 months for sonidegib [16][19] and 9.5 months for vismodegib [17]. Sonidegib showed a high disease control rate (DCR: CR + partial response [PR] + stable disease [SD]) of 92.3% [16][19].
After approval, subsequent studies investigated the efficacy, safety, and utilization of these two HHIs for the treatment of laBCC in real-world clinical practice. The non-interventional study NIELS assessed the effectiveness and safety of vismodegib for the treatment of laBCC under real-world conditions in Germany [20]. A total of 66 patients were observed at 26 German centers. Complete discontinuation of treatment due to adverse events only occurred in one patient, but 36% of the patients interrupted treatment because of side effects with a median interruption of 7.6 months before re-challenge. This approach of AE management, with interruptions and re-challenge, still led to an objective response rate (ORR) of 74.2% and a median DOR and median progression-free survival (mPFS) of 15.9 months and 19.1 months, respectively. After 42 months, 60% of the patients with an initial CR had a recurrence, which is probably because of the interruption of treatment after the CR until progression.
To evaluate the efficacy of sonidegib under real-world conditions, 21 patients were studied in the retrospective, single-center observational study PaSoS [21]. An ORR of 81% was achieved. Nine patients underwent surgery after discontinuation of sonidegib. None of them experienced disease progression. The median time to first tumor response was 2.3 months. In the study, it was reported for the first time that the time to maximal response was 3.2 months, suggesting that the patients’ response peaked just slightly after their initial response. Leow and Teh recently published a case series of 10 patients with laBCC who were treated with 200 mg sonidegib QD [22]. Eight patients had no residual BCC following sonidegib treatment and two patients experienced sufficient tumor size reduction to allow surgical removal of the tumor. Villani et al. responded to the study by reporting their real-life experience of treating 36 laBCC patients with sonidegib (200 mg daily) [23]. To reduce the degree of AEs, 10 patients received an alternative dosing regimen (200 mg every other day). In total, 47.2% of patients achieved CR, 38.9% had >50% clinical reduction of the laBCC, and 13.9% showed no treatment response (<50% of tumor size reduction).
Overall, real-life data have confirmed the efficacy and tolerability profile of HHIs in laBCC. Remarkably, response rates in real-world studies were even higher than those in pivotal studies. One possible explanation for these differences could be a discrepancy between the populations studied. In the pivotal study, 89% of patients had surgery prior to vismodegib treatment [24]. By contrast, 22.7% of patients in the NIELS study were treatment-naïve for BCC therapy [20].

3. Targeted Treatment with HHIs—How to Balance Efficacy and Toxicity

3.1. On-Off Treatment Schedules

Several studies aimed at improving the tolerability of HHIs while maintaining their efficacy. This should reduce the number of patients who discontinue HHI therapy due to AEs. Thus, some studies have sought to determine whether an intermittent dosing regimen leads to a reduction of AEs, and thus to a prolonged duration of treatment (DOT).

Villani et al. reported a case series of 10 patients with multiple BCCs treated with different vismodegib treatment regimens [25]. Three patients were treated with a regular dosing regimen (150 mg daily), four patients received a modified treatment regimen based on dose adjustment (on-off scheme with eight or twelve weeks interruption) according to the number and severity of reported AEs, and three patients received a prophylactic dose reduction (150 mg every other day) from baseline in order to avoid severe AEs. Patients who received a holiday regimen (during treatment or at baseline) reported a good AE profile characterized by mild adverse events leading to longer treatment durations.

3.2. Dose Reduction

Another approach to improve the tolerability of HHIs and the DOT is to reduce the recommended dose of one capsule daily. The reduction to one capsule every other day in case this is required to reduce side effects is specifically within the label of sonidegib [26].
In a retrospective case series of 20 sonidegib patients, nine patients received dose adjustment to reduce AEs and prevent discontinuation [27]. Patients were switched to an every-other-day dosage after 12–24 weeks. Patients receiving alternative dosage regimens showed comparable clinical responses, with milder AEs (grade 1–2) than patients receiving daily dosage. CR occurred in six patients and PR in three patients.
As the low-grade toxicities associated with long-term HHI treatment may lead to treatment interruption or discontinuation, management of AEs and an increase in tolerability are important to keep patients on treatment. The management of AEs has been well summarized by Lacouture et al. [14]. On-off treatment schedules and dose-reduction regimens are effective methods to reduce the intensity of common AEs and maintain patients on treatment without losing efficacy.

3.3. Re-Challenge after Relapse without Other Intercurrent Treatments

In a retrospective multicenter observational study, 116 patients with laBCC who had CR on vismodegib and subsequently discontinued treatment were studied [28]. The median relapse-free survival (RFS) was 18.4 months (95% CI 13.5–24.8 months). The RFS rate at 36 months was 35.4% (95% CI 22.5–47.9%) for the total population and 40.0% (95% CI 25.7–53.7%) for patients with Gorlin–Goltz syndrome. The median overall survival (OS) was not reached, and the rate at 36 months was 85% (95% CI 74.6–96%). Risk factors associated with RFS were laBCC for limbs and trunk (hazard ratio 2.77; 95% CI 1.23–6.22). A total of 50% of patients who relapsed during follow-up were re-treated with vismodegib, of whom 85% experienced an objective response, 37% a CR, and 48% a PR.

3.4. Maintenance of Remission

Once (complete) remission has been achieved, the goal is to maintain this state for as long as possible. Initial studies have investigated the effect of long-term low-dose HHI treatment after remission. In a multicenter, randomized, double-blind, placebo-controlled phase II study, 41 patients with BCNS treated with vismodegib or placebo were monitored [29]. In patients taking vismodegib continuously for at least 15 months (n = 10), the effect against BCC was maintained (i.e., there was no return to baseline tumor burden) for 18 months after drug discontinuation.

3.5. Resistance Mechanisms of HHIs

Vismodegib and sonidegib are effective drugs for the treatment of laBCC. However, some patients may be resistant to treatment, termed intrinsic resistance, or may develop resistance to treatment after the initial response, termed acquired resistance [30]. Numbers of acquired resistance on HHIs are not known from pivotal studies, but the occurrence of intrinsic and acquired resistance was investigated in a subset of 148 patients of the STEVIE study [31]. In this trial 9 patients (6.1%) discontinued treatment because of intrinsic resistance and 14 patients (9.5%) because of acquired resistance.

4. Immune Checkpoint Blockade with Anti-PD-1-Blocking Antibodies

4.1. Efficacy of PD-1 Inhibitors in BCC

An open-label, multicenter, single-arm phase II study resulted in primary analysis data of the PD-1 antibody cemiplimab from patients with laBCC who had developed resistance while on HHI treatment or were intolerant to previous HHI therapy [32]. Reasons for discontinuation of prior HHI therapy were disease progression (71%), intolerance to previous HHI therapy (38%), or no better than SD after nine months on HHI therapy (8%). A total of 84 patients received cemiplimab 350 mg every three weeks for up to 93 weeks or until progression or unacceptable toxicity. The ORR was 31% (95% CI 21–42), of which 6% had CR, 25% had PR, 49% had SD, and 11% showed PD. The Kaplan–Meier estimate of DOR was 85% of responders at 12 months. Grade 3–4 treatment-emerging AEs occurred in 48% of patients and serious treatment-related AEs occurred in 35% of patients. Latest long-term follow-up data up to 40 months revealed a mPFS of 16.5 months (95% CI 8.6–21.4) [33].

4.2. Rationale for the Use of Immune Checkpoint Blockade in BCC

Since immunotherapy in cutaneous melanoma has proved to be successful, the immunogenicity of non-melanoma skin cancers, such as cutaneous SCC (cSCC), has increasingly become an area of research interest. Pathogenesis occurs via UV-induced DNA damage to epidermal keratinocytes; thereby leading to genetic alterations. Notably, cutaneous neoplasms have the highest TMB of all cancer types (Figure 1) [34]. Accordingly, a high TMB likely causes high expression of neoantigens, leading to high immunogenicity.
Figure 1. Schematic representation of the immunological aspects of the basal cell carcinoma (BCC). (A) The tumor microenvironment is characterized by decreased infiltration of CD4+ and CD8+ T cells and increased presence of regulatory T cells (T reg). Dendritic cells (DC) of an immature phenotype are present in in the tumor microenvironment of laBCC. Increased expression of TH2 cytokines (interleukin [IL]-4, IL-5) and transforming growth factor (TGF)-β, as well as IL-10, supports an immunosuppressive environment surrounding the tumor. In addition to a high mutational load, tumor cells are characterized by the expression of the inhibitory molecules programmed cell death 1 ligand 1 (PD-L1) and PD-L2, which can suppress T cell activity by binding to programmed cell death protein 1 (PD-1) on T cells; (B) loss-of-function mutations in PTCH1 or activating mutations in SMO activate the HH signaling pathway in laBCC cells; (C) decreased expression of the transporter associated with antigen processing-1 (TAP-1) and major histocompatibility complex (MHC)-I lead to decreased recognition of tumor cells by the immune system.

5. Conclusions

The current standard of care of laBCCs that are neither amenable to surgery nor radiation therapy is treatment with HHIs, which show good response rates and DOR. However, toxicities in the course of long-term treatment can lead to a decreased quality of life, and consequently to therapy interruption or even discontinuation. To keep patients on the effective HHI therapy, various strategies are being explored in the clinic to reduce toxicity while maintaining efficacy, such as dose reduction and on-off treatment schedules. After therapy pause and recurrence, a re-challenge with HHI can be performed.
Nevertheless, some patients show primary or acquired resistance to HHI treatment. In these cases, PD-1 inhibitors can be used as second-line therapy. However, they show lower response rates than HHIs and may also be accompanied by significant toxicities. The low response rates to PD-1 inhibitors may be due to the low immunogenicity of BCCs. A key question therefore remains—what follows immunotherapy? The combination of HHIs and itraconazole or PD-1 inhibitors is, therefore, under investigation.

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