Transforming Outcomes in Advanced Basal Cell Carcinoma: The Evolving Role of Systemic Therapy

Abstract

Advanced basal cell carcinoma (aBCC) is an uncommon but severe presentation of basal cell carcinoma, including those with extensive local invasion and metastasis. Curative local treatments are often not feasible for patients with aBCC and the introduction of Hedgehog pathway inhibitors (HHIs) expanded the therapeutic landscape. First-line therapy with the HHIs, vismodegib and sonidegib, provides effective disease control, and may enable the preservation of function in locally complex cases. Also, it offers the possibility to simultaneously treat multiple tumors, such as in patients with basal cell nevus syndrome. However, long-term HHI therapy is limited by toxicity, heterogeneous responses and the emergence of resistance or tolerance. For selected patients with progression or limited tolerability under HHIs, immune checkpoint inhibition has emerged as an established second-line option, offering durable responses in a subset of patients. However, immune-related adverse events remain a concern. To address the shortcomings of systemic therapy and improve the long-term disease control of patients with aBCC, ongoing research focuses on alternative dosing strategies, integration of combination or novel systemic agents and the development of predictive biomarkers. This review provides a comprehensive, clinically oriented overview of the evidence on systemic treatment for aBCC, emphasizing efficacy, safety, resistance mechanisms, and therapeutic strategies.

Key Points

Hedgehog pathway inhibitors (HHIs) are established systemic therapies for advanced basal cell carcinoma (aBCC), enabling disease control and function preservation in selected patients who are not candidates for curative surgery or radiotherapy. Long-term use is limited by toxicity, heterogeneous responses and resistance.

Immune checkpoint inhibitors are second-line systemic options for patients with aBCC and a high disease burden. While disease control can be achieved, the occurrence of immune-mediated adverse events remains a key point of attention in patient selection and follow-up.

Management of aBCC requires individualized strategies, including treatment interruptions, alternative dosing and retreatment, while recognizing the safety concerns of neo-adjuvant HHIs use. Ongoing research into resistance mechanisms, novel therapies and systemic combination strategies is expected to further refine systemic treatment and improve long-term disease control for patients with aBCC.

Introduction

Basal cell carcinoma (BCC) is the most prevalent type of cancer and represents about 70% of all skin cancers [1]. Its global age standardized incidence rate is 371 per 100,000 and is expected to continue increasing in the coming years [2, 3]. Although most BCCs are associated with an indolent growth pattern and carry a low risk of metastasis, a small fraction (<1%) progress in a severe form [4, 5]. These cases represent a significant clinical challenge, as conventional treatment options may be insufficient. Consequently, the term ‘advanced BCC’ (aBCC) was originally used to designate complicated forms of BCC that are not considered amenable to surgery or radiotherapy [6, 7].

BCCs arise from an interplay between genotype, phenotype and environment. Genetic mutations affecting the Sonic-Hedgehog (SHH) pathway, most commonly patched 1 (PTCH-1), along with alterations in TP53 and other cancer-related genes, drive the formation of BCCs [8, 9]. PTCH-1, a tumor-suppressor gene in the SHH pathway, inhibits Smoothened (SMO); loss of PTCH-1 function leads to SMO activation and downstream increased cell proliferation [10]. Data on the molecular base for the development of severe cases is limited, although distinct methylation and transcriptomic profiles can be involved in the formation of BCCs and development of more invasive behavior [11, 12].

Beyond molecular events, phenotypic factors such as advanced age, male sex and fair complexion modulate the risk for BCC, as well as environmental factors, such as (childhood) sunburns, intense exposure to ultra-violet or other types of radiation and immunosuppression [13]. Progression to severe disease is typically caused by significant treatment delays or recurrent disease. Aggressive histological subtypes and anatomical sites predisposed to invasion, previous exposure to radiotherapy and inadequate previous treatment lead more frequently to recurrence and are consequently associated with difficult-to-treat BCCs [14]. Psychosocial aspects such as patient vulnerability, denial or self-neglect may play a role in delayed patient presentation [15–17].

There is no clear definition for aBCC. According to the National Comprehensive Cancer Network (NCCN), advanced disease, with an indication for systemic treatment, includes locally advanced BCC (laBCC), metastatic BCC (mBCC), and nodal disease, not amendable for surgery and/or radiotherapy [6]. The European Academy of Dermato-oncology (EADO) guidelines shift the paradigm, introducing the term ‘difficult-to-treat’ BCCs, defined as tumors that can be no longer cured though surgery or radiotherapy, typically corresponding to laBCC (stage III) or mBCC (stage IV) disease. Certain EADO stage II BCCs can also fall within this category when located in critical or functionally sensitive areas, when with poorly defined margins, when the subtype is aggressive or if there are multiple lesions, as in basal cell nevus syndrome (BCNS) [7]. In all guidelines, systemic therapy is recommended when local, curative approaches are no longer feasible.

Consequently, aBCC is a complex condition influenced by both tumor- and patient-related factors. The clinical interpretation of ‘locally advanced’ or unacceptable morbidity can depend on individual clinical judgement. Furthermore, treatment of aBCC often requires a combination of different treatment modalities. If possible, it is recommended to determine the optimal management strategy in a multidisciplinary tumor board [6, 7].

Historically, when surgery and/or radiotherapy were no longer viable treatment options, choices for further intervention were extremely limited, and the prognosis was often poor [17]. Over the past two decades, however, innovations on systemic therapy emerged, offering a more promising outcome for these patients. In 2012, vismodegib, the first Sonic Hedgehog inhibitor (HHI) pathway, was approved by the US Food and Drug Administration (FDA), followed by sonidegib In 2015. These drugs have shown objective response rates (ORRs) of 43–69% for laBCC and 8–39% for mBCC [18, 19]. More recently, In 2018, cemiplimab, an immune checkpoint inhibitor (ICI), was approved for the treatment of aBCC in HHI refractory cases, with ORRs of 31% for laBCC and 22% for mBCC [20, 21]. The implementation of both HHIs and ICIs is challenged by the development of resistance and frequent discontinuation, commonly due to toxicity, which affects at least 30% of patients [22, 23]. Nonetheless, current guidelines now recommend systemic therapies as the standard approach for aBCCs not amendable to surgery or radiotherapy [6, 7].

In response to the resistance and toxicity issues, alternative dosing strategies, combination regimens and the neoadjuvant use of systemic medication prior to surgery or radiotherapy are being investigated, reflecting the evolving treatment patterns observed in clinical practice. Moreover, several investigational therapies are under evaluation, targeting SMO or other components of the SHH pathway, including glioma-associated oncogene (GLI), as well as non-SHH pathway–targeted strategies such as different immunotherapy agents [24].

These ongoing developments highlight the need to critically evaluate the outcomes of systemic treatments periodically, to position them within a comprehensive, stepwise management approach for patients with aBCC. The present review aims to summarize the most current evidence regarding efficacy, safety, and patient-reported outcomes of available systemic therapies for aBCC and to provide an evidence-based practical approach for the management of aBCC.

Methods

This narrative review provides an overview of the evolving systemic treatment landscape for aBCC and includes approved therapies and novel agents under development. Furthermore, future directions are discussed including strategies aimed at overcoming resistance, the management of drug toxicity, and improving long-term disease control through dosing strategies, treatment combinations and retreatment.

A literature search strategy was developed by a PhD candidate, A.P., with the support of a scientific information specialist. Searches were conducted in PubMed, Embase, and Web of Science for primary research articles published in English between January 2012 and October 21, 2025, using combinations of relevant MeSH terms and free-text keywords: ‘Carcinoma, Basal Cell’ [MeSH], ‘basal cell carcinoma*’, BCC, basalioma, aBCC, mBCC, laBCC) AND (advanced, aBCC, laBCC, mBCC, ‘metasta*’, disseminated, unresectable, inoperable, aggressive, progressive, ‘stage III’, ‘stage IV’, ‘stage 3’, ‘stage 4’, ‘stage three’, ‘stage four’, ‘Neoplasm Metastasis’ [MeSH]) AND (‘Drug Therapy’ [MeSH], ‘Therapeutics’ [MeSH], ‘Antineoplastic Agents, Immunological’ [MeSH], ‘Drug Therapy’ [MeSH Subheading], ‘Immune Checkpoint Inhibitors’ [MeSH], therap*, treat*, drug*, management, systemic, intervention*, Immunotherap*, ‘Hedgehog Inhibitor*’, ‘SHH Inhibitor*’, Cemiplimab, Sonidegib, Vismodegib, ‘Antineoplastic Agent*’, ‘Anti-neoplastic Agent*’, ‘SMO inhibitor*’, ‘smoothened inhibitor*’, ‘checkpoint inhibitor*’. In addition, ClinicalTrials.gov was searched to identify relevant registered ongoing or planned clinical trials.

Reviews, case reports and series, conference abstracts, editorials and clinical guidelines were excluded. Case reports and small case series were not systematically searched for and were generally excluded, but were selectively included if illustrative or meaningful, when identified during screening and reference checking. Screening and study selection were performed using the ASReview software and following the modified SAFE criteria [25]. Screening and data extraction were independently carried out by two researchers (A.P and B.V.), who contributed to manuscript development. The principal investigator (K.M.) provided expert guidance throughout the review, contributing to study selection, data interpretation, and manuscript drafting.

Results

The search yielded 3316 articles, of which, after screening, 214 were considered relevant. Of the identified studies, 132 studies evaluated SHH inhibitors (or Hedgehog inhibitors, HHIs), 21 investigated immune checkpoint inhibitors, 19 examined (electro)chemotherapy and 42 focused on emerging agents against aBCC. The following subsections summarize key efficacy and safety data, explore mechanisms of resistance and possible response biomarkers and highlight emerging therapeutic strategies.

Sonic-Hedgehog Pathway Inhibitors

To date, two HHIs have been approved for the treatment of aBCC, vismodegib (ERIVEDGE^®; Genentech, Inc.) and sonidegib (ODOMOZO^®; Sun Pharmaceutical Industries, Inc.). Both inhibitors prevent SMO activation and downstream transcription of genes that drive uncontrolled cell proliferation by targeting the SMO receptor, a key transducer in the SHH pathway.

Efficacy

The pioneering trials of these agents led to the approval of vismodegib for both laBCC and mBCC and of sonidegib for laBCC. In the ERIVANCE study, vismodegib showed an ORR of 60% for laBCC and 48% for mBCC at 39 months’ follow-up, with median response durations of 26 and 15 months, respectively [19, 26]. In the phase II BOLT trial, sonidegib 200 mg/day demonstrated an ORR of 56% for laBCC and 8% for mBCC at 42-month follow-up, with a median response duration of 26 months for laBCC [27]. Direct comparison between the two drugs is limited by the absence of head-to-head trials and methodological differences across pivotal trials. Treatment response criteria differ between studies. Vismodegib trials used the Response Evaluation Criteria in Solid Tumors (RECIST) for mBCC, and combined clinical or radiological assessments for laBCC, with histological confirmation of complete response, whereas BOLT applied a modified RECIST, integrating clinical, radiological and histological parameters. Although direct comparison between the two drugs is limited, both agents have demonstrated consistent efficacy across studies and are now established treatment options for aBCC, with multiple real-world analyses further supporting their applicability [22, 28–34].

To guide clinical decision making, a few studies have performed indirect comparative analyses of the ERIVANCE and BOLT trials. These analyses indicated that vismodegib and sonidegib offer similar clinical benefits and a similar tolerability profile. However, according to these post-hoc analyses, sonidegib could exhibit some favorable characteristics, including a slightly lower incidence and delayed onset of adverse events (AEs) [35]. These differences could be attributed to study differences in methodology and heterogeneous baseline patient characteristics, which cannot be fully corrected for, or to the dosing flexibility of sonidegib that allowed every-other-day dose reductions. Also, the higher tissue penetration of sonidegib compared with vismodegib could also explain the differences in delayed onset and lower incidence of AEs [35].

Drug Toxicity

The most characteristic AEs observed during HHI treatment are muscle spasms, alopecia, fatigue, dysgeusia, nausea and weight loss [26, 27]. Additionally, elevated creatine kinase (CK) has been reported, more frequently during sonidegib treatment [27]. Although severity of AEs was generally mild to moderate, the pivotal trials reported grade ≥3 AEs in approximately half of the patients, occurring in 55.8% of those receiving vismodegib (150 mg) and 43% of those receiving sonidegib (200 mg) [27]. Subsequent trials and real-world studies, including the STEVIE trial, suggested lower incidences of severe toxicity for both drugs [36–39]. Several management strategies have been suggested to mitigate AEs, but supporting evidence is limited and the effect of most of these interventions has not been confirmed in clinical trials [40–44]. Figure 1 presents some of the management strategies from clinical practice against commonly encountered AEs [40–44].

Fig. 1.

Practical adverse event management during Hedgehog pathway inhibitor therapy. Adverse event grading according to the Common Terminology Criteria of Adverse Events [45]. BMI body mass index, CK creatine phosphokinase, EMG electromyography

Besides the most common AEs, other early concerns on HHIs involved liver and kidney toxicity, as well as the formation of cutaneous squamous cell carcinomas (SCCs). Hepatotoxicity was reported in vismodegib and sonidegib in a small subset of patients, and was mostly related with premorbid hepatic impairment or concomitant medication, such as paracetamol [36, 46–48]. Renal complications have been reported rarely, most commonly for sonidegib [49]. The growing body of evidence on HHIs indicates that frequent monitoring of liver and kidney function could be reserved for patients with a clinical indication. The early concern on the association between vismodegib and the development of SCCs arose from several descriptive studies [35, 36, 50, 51], raising speculation that SHH pathway inhibition might activate alternative oncogenic pathways. However, robust comparative studies did not confirm an increased SCC risk among vismodegib-treated patients, suggesting that the reported SCC likely reflected coincidental field carcinogenesis or increased detection rather than a true drug-related effect [39, 52].

The high prevalence of AEs may negatively affect quality of life during HHI therapy, to the point where treatment-related complaints could outweigh those related to the disease itself. Questionnaire-based quality-of-life assessments show domain-specific but inconsistent benefits [53–55]. Interviews conducted with patients after HHI discontinuation indicated that patients may experience considerable quality-of-life challenges and unmet needs, highlighting the need to explore new treatment strategies [56].

Drug toxicity is a major limiting factor in HHI therapy and frequently leads to treatment discontinuation, reported in approximately 20–30% of patients in clinical trials [26, 36, 48, 57]. Even low-grade AEs can limit treatment persistence, as demonstrated in the STEVIE trial, where most discontinuations were triggered by grade 1–2 AEs [36].

Alternative Dosing Schedules

To further improve tolerability, and thereby treatment persistence, dose reductions and short treatment interruptions (‘drug holidays’) are commonly used during HHI therapy. In the vismodegib ERIVANCE trial, 4-week treatment interruptions were allowed [19], and in the sonidegib BOLT trial, dose reductions and treatment interruptions of maximally 21 days were allowed, without apparent loss of efficacy in that study [58]. Based on reports suggesting that disease control may be sustained even when continuous daily dosing is interrupted for toxicity management, several other treatment algorithms for HHIs have been proposed incorporating dose reductions and treatment interruptions [59–61]. Along similar lines, a pulsed sonidegib schedule, 14 days on/14 days off, adjusted based on patient-specific tolerance, is being investigated in the ongoing SONIBEC trial [62].

Strategies to investigate the effect of lower maintenance dosages have also been explored. In a retrospective cohort of 27 patients, a stable maintenance dose of vismodegib 150 mg per week was administered after complete response, and no disease recurrence was observed during the 1-year follow-up. In contrast, in the same period recurrence occurred in 27% (4/15) of patients who decided not to follow the maintenance regimen [63]. Although the mean time to clinical response is reported to be approximately 3–4 months, the optimal duration of the induction period before dose reduction or interruption remains unclear [22, 36, 48, 61, 64–66]. Robust evidence supporting treatment strategies is scarce and difficult to generate due to patient, physician and healthcare variability in real-world clinical decision making.

Specific Cases

Basal Cell Nevus Syndrome and the Chronic Use of Hedgehog Inhibitors (HHIs)

Systemic treatment with HHIs may have major benefits for patients with BCNS (Gorlin-Goltz syndrome), who may accumulate hundreds of BCCs throughout their lifetime because of a heterozygous mutation in the PTCH1 gene [67]. As radiotherapy is contraindicated in BCNS, due to its mutagenic potential, HHIs offer a valuable alternative for patients with extensive tumor burden where repeated surgery would be undesirable or morbid. By targeting the pathway disrupted in BCNS and treating multiple BCCs simultaneously, HHIs are very effective in this population. However, continuous use is limited by toxicity, making treatment pauses necessary [66].

Intermittent dosing schedules are therefore an important tool for the long-term management of these patients with multiple and continuously developing BCCs. In the MIKIE trial, vismodegib treatment was continued intermittently after a 12 or 24-week induction period in patients with BCNS or high-frequency BCC without BCNS. Alternating cycles of 12 or 8 weeks of vismodegib, respectively, and 8 weeks of placebo appeared effective in patients with multiple BCCs. After 73 weeks, both regimens showed a similar efficacy, with a reduction in number of BCCs of 54–63% [57].

Although HHIs have been shown to be highly effective in patients clinically diagnosed with BCNS [66], a small subgroup of patients may not respond. Those harboring a Suppressor of fused (SUFU) gene mutation as the underlying genetic cause of BCNS instead of a PTHC1 mutation may be intrinsically resistant to HHI therapy, as SUFU acts downstream of SMO, the molecular target of vismodegib and sonidegib [68].

Periocular Basal Cell Carcinomas (BCCs)

Periocular BCCs are a distinct subgroup, since curative surgery may carry the risk of impairment of the eye function, or even orbital exenteration. HHIs are particularly valuable in this setting, offering the possibility of eye function preservation and enabling patients to be self-supportive and therefore substantially impacting their independence. A subset analysis of 244 patients of the STEVIE study with periocular involvement showed an ORR of 67.2%, leading to the proposal of a response-guided protocol [69].

Several smaller real-world studies investigated the use of HHIs for periocular BCC, supporting their use as an eye-sparing strategy [47, 70–73]. However, despite clinical complete response, recurrence rates are high, underscoring the palliative nature of this strategy and the need for adequate long-term follow-up [47, 71, 74]. In the VISORB trial, for example, 33% of patients undergoing surgery after HHI downstaging had histologically detectable residual disease, sometimes in clinically occult areas [75]. Because occult residual tumor growth in this precarious area may progress to an incurable disease, the long-term benefit of HHI treatment remains debatable.

Resistance and Tolerance

Incomplete tumor eradication can stem from primary or secondary resistance, and drug tolerance. Primary (intrinsic) resistance, showing a lack of clinical response from the start of treatment, was found in only 9/148 (6%) tumors in a STEVIE sub-analysis and occurred more often in previously chemotherapy or radiotherapy-treated patients [76]. Genomic analyses suggested that intrinsic resistance is heterogeneous, involving genomic instability and baseline SHH alterations, such as SMO or GLI mutations [11, 77], as well as activation of alternative signaling pathways, such as HIPPO-YAP or WNT [76].

Acquired resistance (i.e. progression after an initial response) results from the clonal expansion of tumor cells with SMO mutations conferring a growth advantage under treatment pressure [76–80]. Beyond resistance based on SMO mutations, resistance can also be caused by concomitant activation of alternative survival pathways [80]. For instance, Wnt/β-catenin signaling, regulating survival, has been found to be upregulated in vismodegib-resistant BCCs, suggesting that Wnt activation may support BCC survival under SHH blockade [81]. Such resistance may be overcome by using therapies acting downstream of SMO, such as GLI inhibitors [77, 79]. Finally, treatment pressure may select cells with other active signaling routes, after which BCC growth becomes entirely independent of SHH pathway activity, and therefore resistant to both SMO inhibitors and to downstream agents [82].

Beyond primary and acquired resistance, drug tolerance may appear in clinically and histologically cleared tumors. Preclinical studies have identified a distinct mechanism in which a small subset of drug-tolerant BCC cells survive HHI therapy. Either pre-existing or treatment-induced Wnt-dependent cell populations remain clinically inactive during treatment but reactivate and drive tumor regrowth after HHI withdrawal. In animal models, co-targeting SHH and Wnt signaling effectively suppressed these persistent populations, suggesting a potential future therapeutic strategy [83, 84]. A summary of resistance and tolerance mechanisms is depicted in Figure 2.

Fig. 2.

Mechanisms of resistance and tolerance to Hedgehog inhibitors. HHIs Hedgehog inhibitors, SHH Sonic Hedgehog pathway, SMO Smoothened

Biomarkers for HHI Response

An established predictive biomarker panel of HHI response is lacking. However, in selected cases, defining the tumoral molecular profile can aid treatment decision making. In a case of laBCC with secondary resistance, sequencing of pretreatment and recurrent tumor tissue revealed newly acquired SMO mutations, absent before treatment. This clinical study demonstrated the concept of SMO mutations causing treatment resistance during HHI treatment [78]. Similarly, in resistant mBCCs, targeted next-generation sequencing demonstrated that resistance-associated SMO variants were present in a subset of cases developing clinical disease progression under vismodegib [85]. The findings of both studies suggest that determining the molecular profile of the aBCC pretreatment and during progression can provide additional value in guiding the treatment process. Despite its potential value in terms of cost-effective use of resources and limiting unnecessary toxicity, biomarker assessment is currently confined to research settings.

Immune Checkpoint Inhibitors (ICIs)

Cemiplimab is currently the only FDA-approved ICI for treatment of aBCC [86]. This immunoglobulin G4 antibody targets Programmed Death-1 (PD-1), a receptor that downregulates T-cell activation. By blocking PD-1, cemiplimab reestablishes T-cell effector function, enabling a T-cell mediated antitumor response. This immune-mediated mechanism also underlies the activity of cemiplimab in several other tumor types, including melanoma, advanced cutaneous SCC, non-small cell lung cancer and cervical cancer [87]. Tumors with a high mutational burden, such as BCC, generate numerous neoantigens that can elicit T-cell responses and are associated with high response rates [9]. Despite their immunogenicity, BCCs may evade immune detection via inhibitory checkpoint pathways, which immune checkpoint inhibitors can block to restore antitumor immunity.

Efficacy

The pivotal first phase II trial on cemiplimab, which led to its approval In 2021, included patients who discontinued HHI treatment due to lack of efficacy or toxicity. In the laBCC cohort, the ORR was 32% [21], while in the mBCC cohort, the ORR was 22%, suggesting that mBCCs are more refractory to treatment [20].

While cemiplimab remains the PD-1 inhibitor for which efficacy and safety are best established in aBCC, exploratory studies suggest that two other PD-1 inhibitors, nivolumab and pembrolizumab, are also effective. In an exploratory study, nivolumab demonstrated a broadly comparable efficacy profile to that of cemiplimab, with ORRs ranging from 22% to 31% [88]. Pembrolizumab has been evaluated in a small, proof-of concept study in which an ORR of 44% was achieved [89]. Real-world data from a retrospective cohort including 29 patients with laBCC and mBCC in any line of therapy further supports the clinical activity of cemiplimab, pembrolizumab and nivolumab in patients with aBCC [90].

Drug Toxicity

ICI-related AEs differ from those seen after HHI treatment, reflecting the distinct mechanism of action. In addition to common AEs such as fatigue and diarrhea, ICIs are associated with a wide spectrum of immune-related toxicities. Colitis and, less frequently, endocrinopathies such as adrenal insufficiency or hypothyroidism are of special relevance, as they account for a substantial proportion of AE-driven discontinuation [20, 21]. Immune-mediated AEs may be treated with immunosuppressives, usually systemic corticosteroids, but a subset may persist or result in permanent tissue damage, such as endocrine dysfunction, requiring long-term hormone replacement [91].

In the pivotal cemiplimab study, treatment-related AEs occurred in nearly all patients, and grade ≥ 3 AEs were reported in 43–52% of cases, with hypertension and colitis being the most reported high-grade toxicities [20, 21]. Although the type of toxicity differs, the proportion of grade ≥ 3 AEs and subsequent discontinuation rates associated with ICIs are comparable to those observed with HHIs. No treatment-related fatalities were observed in either laBCC or mBCC cemiplimab cohorts [20, 86].

Positioning of ICIs Within the Treatment Guidelines

Cemiplimab is currently placed as a second-line therapy for aBCC, largely because responses in the pivotal trial were lower than the efficacy reported for HHIs [86]. However, whether this reflects true inferiority or patient selection has been questioned, since the pivotal trial recruited only patients that previously had been treated with HHIs. In a real-world analysis, patients treated with first-line cemiplimab had a higher ORR than those with second-line treatment (62% vs 31%), suggesting that ICI efficacy may be reduced in more aggressive, treatment-refractory tumors compared with treatment-naïve tumors [92]. Two ongoing trials are evaluating the use of cemiplimab without previous HHIs: CEMIfirst (NCT06981325) and IMPACT (IRAS 1006482).

Biomarkers for ICI Response

Several studies have explored biomarkers to predict response in ICIs; however, no validated predictive biomarker has been identified for BCCs. Promising candidates such as tumor mutational burden and PD-L1 expression assessed by immunohistochemistry on a tumor biopsy failed to reliably predict clinical response in BCCs [86, 93]. This likely reflects the importance of factors in the tumor immune microenvironment, beyond tumor-intrinsic factors. BCCs display a comparatively ‘cold’ immune microenvironment, characterized by stromal-driven immune exclusion and impaired antigen presentation [20, 86]. Immunological studies suggest that the response to ICI depends on coordinated immune activity, including B and T-cell interactions, while non-response is associated with stromal factors such as activin A, which promotes immune exclusion by reducing T-cell infiltration [94, 95]. Consistent with these analyses, results of a real-world cohort study supported the importance of host immune competence; none of the immuno-compromised patients achieved an objective response, whereas the development of immune-related AEs was associated with improved disease control [90].

Re-induction of HHIs

When second-line treatment with ICIs fails, subsequent treatment options become limited and re-induction with HHIs has therefore been explored as a salvage approach. In a retrospective cohort of 12 patients who received HHI re-induction after sequential HHI and ICI treatment, re-induction with HHIs resulted in an objective response in four patients. All patients had initially achieved disease control with HHIs, discontinued HHIs due to disease progression, toxicity or personal preference and subsequently progressed under PD-1 inhibition. Response to the initial HHI course did not predict response upon re-induction [96]. Other reports on HHI rechallenge after initial HHI discontinuation show that disease control can occur [34, 97], although efficacy could be reduced compared with the initial course [98]. These studies highlight that HHI re-use remains feasible after first and/or second-line therapies.

Combination Therapies Involving Systemic Agents

Combination Therapy Employing HHIs and Surgery

Beyond alternating schemes employing HHI monotherapy, the use of HHIs in a neoadjuvant role has been increasingly emphasized. Planned neoadjuvant HHI treatment prior to surgery has been investigated in several studies but remains controversial due to concerns regarding undertreatment. In the VISMONEO study, 55 patients with facial BCCs were evaluated in whom surgery was either impossible or of major impact. After vismodegib therapy for 4–10 months, once the best expected response was achieved, the clinically remaining lesion was excised. Although 44 patients achieved a better surgical stage, with a smaller defect than predicted before HHI treatment, 16 (35.4%) patients had recurrences in the 3-year follow up, of whom nine were considered to have had compete responses after vismodegib therapy [99]. Inherent to aBCC literature, studies combining HHIs with surgery are limited by small sample sizes, have yielded inconsistent results and often lacked sufficient follow-up to evaluate long-term disease control [100–102]. Undertreatment remains a key concern, as clinical remission is not always associated with pathological clearance. Residual tumor foci have been detected on biopsy, despite apparent clinical remission, and a pathologic complete response after neoadjuvant therapy does not guarantee cure [75, 102]. In clinical practice, unplanned neoadjuvant HHI treatment is probably more common. In this situation, HHI treatment is initiated in patients who initially decline or are deemed unsuitable for complex surgery, but surgery is reconsidered after HHI discontinuation because of HHI intolerability or resistance [78]. In such cases, patients and clinicians must be aware that surgical margins must include all previously affected tumor tissue in case of curative intent. Beyond neoadjuvant use, no trial data are yet available on adjuvant HHIs.

Combination Therapy Employing HHIs and Radiotherapy

Combination treatment of HHIs and radiotherapy have been described in multiple case reports and case series [103–106]. In a phase II trial with 24 patients, vismodegib was used as induction therapy for 12–14 weeks followed by 7 weeks of combined vismodegib and radiotherapy (66–70 Gy in 33–35 fractions). This trial demonstrated a progression-free survival of 78% at 5 years’ follow-up and quality-of-life improvement. It is speculated that a synergistic effect between HHI and radiotherapy takes place, where the drugs select cancer cells prone to radio-sensitivity [107]. The RADIOSONIC (NCT05561634) non-randomized trial is currently investigating the effects of consolidation radiotherapy in laBCCs with complete response after HHIs, with a planned follow-up time of 3 years. As the slow growth of BCCs makes early detection of recurrences challenging, long-term follow-up is essential.

Combination Treatment Employing Immunotherapy

It has been hypothesized that combining HHIs and ICIs would improve response compared with monotherapy. However, no added benefit was observed in a small proof-of-concept study, where pembrolizumab was administered alone or in combination with vismodegib [89]. Combining two different immunotherapies has also been proposed to overcome resistance to PD-1 blockade but to date no clear improvement in efficacy could be demonstrated. Combining nivolumab with ipilimumab, targeting CTLA-4 as a complementary checkpoint pathway blockade, led to an ORR of 31% in a cohort of 16 patients who had progressed on or were intolerant to HHIs. This response rate was similar to the reported ORR after nivolumab monotherapy, revealing no added efficacy from dual blockade [108]. Beyond systemic combinations, perioperative immunotherapy is also under exploration. The underlying hypothesis for neoadjuvant immunotherapy is that PD-1 blockade will activate an anti-tumoral immune response, inducing clinical regression and facilitating function-preserving surgery. Preliminary data on neoadjuvant pembrolizumab for resectable head and neck laBCC have demonstrated clinical and pathological responses. In addition, cemiplimab is being studied in a phase II trial with unresectable head and neck laBCCs, with the aim of enabling subsequent surgery. The trial is currently recruiting, with an estimated completion in July 2027 (NCT05929664). No studies yet have evaluated the role of adjuvant ICIs in this setting.

Chemotherapy and Electrochemotherapy

The role of chemotherapy for the treatment of aBCCs has been largely reduced since the introduction of HHIs and ICIs. As the evidence for traditional chemotherapy is limited to case reports and case series, mostly employing platin-based combinations, chemotherapy is only recommended when first- or second-line treatment options and combination therapies fail or are not possible [6, 7, 109]. Recent evidence suggests combining systemic or intratumorally injected chemotherapy with the subsequent induction of short, pulsed electrical stimulation inside the tumor, so-called electrochemotherapy (ECT). The aim of this technique is to permeabilize the cell membrane to improve drug uptake. In clinical practice, electrical pulses are applied locally with a needle electrode shortly after drug administration, typically during a single treatment session. ECT may be an effective approach for laBCC when other treatment options are not feasible [7]. Most clinical evidence on ECT in BCCs derives from heterogeneous cohorts, primarily with small BCCs. A retrospective study including 41 laBCCs showed an ORR of 78% 1–2 months after the first ECT cycle, with a 5-year recurrence rate of 38% [110]. In a small cohort of 19 patients with periocular laBCC and recurrent BCCs, an ORR of 100% was achieved after 6 months with 15.8% recurrences after 79 months’ follow-up time [111]. Generally, smaller tumors had higher odds of achieving complete and durable disease control, whereas large or extensive lesions showed lower complete response rates and higher long-term recurrence risk. These variations in efficacy might reflect the variability in tumor size, subtype, location, and depth that may be associated with the coverage of the full tumor volume by the electric pulses induced by needles [110, 112, 113].

ECT is generally well tolerated, with a low frequency of AEs mostly limited to local skin toxicity, such as ulceration and hyperpigmentation. Systemic toxicity is seldom reported [111–113]. This toxicity profile makes ECT appropriate for the elderly and those with multiple comorbidities. Although ECT could potentially be a good treatment alternative for aBCC, randomized trials are needed to compare its efficacy in aBCC to other treatments in order to position this relatively new modality. Furthermore, the combination of HHIs and electric pulse stimulation is a potential direction for future research.

New Drugs

Strategies targeting the SHH pathway beyond the approved SMO inhibitors are currently under investigation, with the aim of overcoming resistance. These include agents that directly inhibit GLI activation, such as atypical protein kinase C and casein kinase 1 isoforms [114–117], epigenetic modulators of GLI-driven transcription, such as class I HDAC inhibitors that prevent GLI binding to DNA, [114, 118] and dual approaches that act both on GLI and SMO [119].

Finally, beyond strict systemic options, intralesional immunotherapies are being explored to reduce the risk of systemic AEs, while inducing local and possibly regional tumor regression [120]. For instance, intralesional cemiplimab, the cytokine combination L19IL2/L19TNF (Daromun) and oncolytic virotherapy with talimogene laherparepvec (T-vec) are under investigation.

Conclusion

In the last decades, systemic therapy with HHIs and ICIs substantially improved the management options for aBCC patients not amenable to surgery or radiotherapy. Both vismodegib and sonidegib have proven to be effective drugs that can be safely administered, and ICIs are now consolidated second-line therapy for aBCC. These drugs may be integrated more flexibly in the treatment algorithm in the future, as evidence from first-line and combination strategies evolve. Outcomes remain, however, heterogeneous, highlighting the need for real-life evaluation. (Inter)national registries are essential to collect robust evidence on patients who progress under HHIs and ICIs, given the low prevalence of advanced disease. Furthermore, there is a need to further develop biomarkers to predict response to both HHIs and ICIs in order to personalize treatment and to manage the burden of these relatively costly drugs on healthcare budgets. Finally, multidisciplinary tumor boards and active patient participation in shared decision making and multidisciplinary treatment will provide the best patient-tailored treatment. Patient perspectives represent a key parameter in determining treatment goals, weighing toxicity against tumor control, and determining the timing of treatment pauses or transitions.

Funding

No external funding was used in the preparation of this manuscript.

Declarations

Conflicts of interest

Klara Mosterd received consulting or speaker fees from Pierre Fabre, Janssen-Cilag, and Almirall, and a research grant from Sun Pharma, outside the submitted work. Anna A. L. Massella Patsea and Babette J. A. Verkouteren declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

Ethics Approval, Consent to Participate, Consent for Publication, Code Availability

Not applicable.

Availability of Data and Material

The literature extraction file underlying this article will be shared on reasonable request to the corresponding author.

Authors’ Contributions

All authors contributed to the study conception and design. Anna Massella Patsea developed the search strategy. Anna Massella Patsea and Babette Verkouteren independently performed screening and data extraction. Anna Massella Patsea wrote the first draft of the manuscript. Babette Verkouteren and Klara Mosterd contributed to study selection, data interpretation, critical revision of the manuscript, and supervision. All authors read and approved the final manuscript.