Managing Advanced Basal Cell Carcinoma: A Guide for the Dermatology Clinician

J Clin Aesthet Dermatol. 2025;18(3):21–27.

by Joshua Burshtein, MD, and Todd Schlesinger, MD

Dr. Burshtein is with the Department of Dermatology at the University of Illinois-Chicago in Chicago, Illinois. Dr. Schlesinger is with the Clinical Research Center of the Carolinas in Charleston, South Carolina.

FUNDING: No funding was provided for this article.

DISCLOSURES: Dr. Burshtein has no conflicts of interest to disclose. Dr. Schlesinger serves as an investigator, consultant and/or speaker for Abbvie, Almirall, Biofrontera, Bristol Myers Squibb, Galderma, Incyte, Novartis, Regeneron, SUN Pharmaceuticals, UCB, and Verrica Pharmaceuticals.

ABSTRACT: Objective: Basal cell carcinoma (BCC) is the most common form of skin cancer. Advanced BCCs include locally advanced BCCs (laBCCs), primary or recurrent tumors that are not amenable to surgery or radiation therapy, and metastatic BCCs (mBCCs). The management of advanced BCC has been revolutionized in recent years by the development of hedgehog inhibitors (HHIs) and immunotherapies (ie, PD-1 inhibitors). We aim to review the current literature on therapeutic options and outline treatment strategies to optimize care for patients with advanced BCC. Methods: A comprehensive literature search was completed using the keywords “advanced basal cell carcinoma,”  “treatment,”  “hedgehog inhibitor,” “vismodegib,”  “sonidegib,”  “PD1-inhibitor,” and “cemiplimab.” The authors reviewed all studies and included those which addressed the topic of the review. Results: Surgery or radiotherapy may not be an option for certain high-risk BCCs due to due to invasion into local tissue, location near anatomically sensitive areas, or metastasis. There is increasing evidence for the efficacy of HHIs, including vismodegib and sonidegib, as the first-line treatment for these advanced BCCs. Despite known efficacy, utility of HHIs can be limited by their adverse event profiles. If patients fail HHIs due to inefficacy or adverse effects, there is evidence for use of the PD-1 inhibitor cemiplimab. Limitations: This is a review article and is limited by the information available in the published literature. In addition, comparison between studies is limited as they utilized varying methodologies. Conclusion: Treatment of advanced BCCs can be complex and poses challenges for clinicians. HHIs are currently the first-line treatments for laBCC and mBCC, while cemiplimab can be used if patients do not respond to or are unable to tolerate HHIs, or for whom HHIs are not appropriate.

Keywords: Advanced basal cell carcinoma, surgery, radiotherapy, hedgehog inhibitors, PD-1inhibitors, guidance

Introduction

Basal cell carcinoma (BCC) is the most common form of skin cancer and has an overall favorable prognosis. While most BCCs are localized and amenable to surgical interventions, a subset of patients develop advanced, inoperable, or metastatic disease, where treatment options are limited. Advanced BCCs include locally advanced BCCs (laBCCs), primary or recurrent tumors that are not amenable to surgery or radiation therapy, and metastatic BCCs.¹ Patients with advanced BCCs can experience significant physical and psychological burden, from infections and limitation of function to depression, anxiety, and increased financial burden.² As these tumors may not be ideal candidates for traditional treatment options (surgery and radiation), systemic targeted therapies may be indicated. The management of advanced BCC has been revolutionized in recent years by the development of hedgehog inhibitors (HHIs) and immunotherapies (ie, PD-1 inhibitors), offering novel treatment modalities for patients.

Due to the complexities in the management of advanced BCCs, it is important to provide guidance for implementation of the various treatment options available. We aim to review the current literature on therapeutic options and outline treatment strategies to optimize care for patients with advanced BCC.

Advanced BCC

Advanced BCCs are a progressive form of difficult-to-treat BCCs, which can be due to invasion into local tissue, location near anatomically sensitive areas, or metastasis. According to the National Comprehensive Cancer Network classifications, there are two types of advanced BCC, laBCC and metastatic (mBCC).³ Incidence of patients with advanced disease ranges from 0.8 percent to 2 percent.^4,5 LaBCC is further defined as “primary or recurrent disease that is not amenable to surgery or radiation therapy.”³ Various groups have attempted more specific definitions for laBCC that include locations, aggressive subtypes, large sizes, number of BCCs, or recurrence penetrating deep in tissue.^6–8 However, there are currently no clinical guidelines for BCC features that determine when it is categorized as laBCC.

Surgical or radiation intervention of these tumors may result in considerable deformities (especially facial BCCs) such as pinnectomy or rhinectomy, loss of function, and elevated morbidity.^6–8 Additionally, patient-related factors such as age, overall health status, comorbid conditions, patient preferences, and quality-of-life effects can all contribute to the difficulty of treated advanced BCCs with surgery or radiation.⁶

Despite increasing literature on the treatment options for advanced BCC, it continues to be difficult for clinicians to determine which therapeutic option is best for patients with advanced BCCs and when to initiate next step treatments.

Treatment Options

Mohs micrographic surgery. Treatment of BCC depends on a variety of clinical and histological characteristics. Small, well-defined tumors, having low risk of recurrence and on low-risk anatomic areas are typically treated with surgical excision.¹ The standard of care for high-risk, recurrent BCCs or those in high-risk anatomic locations is Mohs micrographic surgery (MMS).¹ MMS is associated with the lowest recurrence rates for BCCs.⁹ Specific criteria of BCCs that qualify for MMS are outlined in the MMS Appropriate Use Criteria.^10,11 Certain BCCs advance to the stage where surgical intervention is not a recommended option. In addition, there are some patients who may not be surgical or radiotherapy candidates due to surgical fatigue or presence of numerous tumors. However, it may be difficult for clinicians to determine whether an advanced BCC is fully resectable.¹² If surgery is initiated on these patients, it can result in significant disfigurement, loss of function, and negative impact on quality of life.

Radiotherapy. For high-risk BCCs that are not able to be completely resected (positive margins) or are in anatomically restrictive locations, radiotherapy (RT) may be a feasible option as adjuvant therapy or selected as an alternative to surgery.^9,13 One analysis found that five-year local recurrence occurred in 39 percent of patients with positive microscopic margins, whereas those who received RT had a recurrence probability of nine percent.⁹ Additionally, for advanced BCCs such as stage T3/T4 tumors, treatment with RT resulted in 88 to 93 percent three-year disease-specific survival.¹⁴ RT should also be considered for patients with perineural and/or large-nerve involvement.¹²

One type of RT that has been used for many decades is Superficial Radiation Therapy (SRT). SRT has been clinically proven to effectively treat many types of BCCs.^15,16 BCCs in particular anatomical areas such as the nasal ala, ear, perioral, periorbital, and below the knee are more suitable for SRT.¹⁷ In a study of 175 BCCs (103 nodular, 25 superficial, 47 sclerosing) treated with SRT, 5-year recurrence rates were highest for sclerosing (27.7%) and superficial (26.1%) and lower for nodular (8.2%) subtypes.¹⁵ An expert consensus panel recommended that SRT be considered for primary BCCs while for larger, deeper tumors it may have lower cure rates.¹⁷ SRT is generally contraindicated for aggressive BCCs, deep invasion, and tumors which received prior SRT.¹⁷

Image-guided SRT (IGSRT) uses high-resolution dermal ultrasound to determine tumor depth and lateral extent and can afford more directed radiation administration.^18,19 In a recent large, retrospective cohort study, overall freedom from recurrence rates for non-melanoma skin cancers (NMSCs) treated with IGSRT were 99.68 percent at two years and 99.54 percent at six years.¹⁹ Though there was a significant difference in freedom from recurrence rates based on tumor stage, all tumor stages maintained >99 percent freedom of recurrence, demonstrating the utility of this form of RT in treating high- and low-risk NMSCs.¹⁹

Additionally, external beam RT (electron-beam, orthovoltage, megavoltage photon) can be utilized to treat BCCs.²⁰ Electron-beam RT uses a non-penetrating electron beam to target and destroy cancer cells.²¹ One retrospective analysis found that electron-beam RT is not inferior to superficial x-ray therapy and is superior for larger tumors.²² Another study found that local control was achieved in 88 percent of patients who received electron-beam therapy.²³ Though this can be an effective form of radiation therapy for BCCs, it is most commonly used for superficial BCCs.²¹ Advanced lesions can be treated with megavoltage radiation per the 2023 European consensus-based guidelines.²⁰

Clinicians should be aware that RT should not be administered to patients with connective tissue diseases, tumors recurring after prior RT, and those with certain genodermatoses which predispose to skin cancers, and is not usually recommended for patients younger than 60 years of age unless there are extenuating circumstances.^12,13 Though RT can be a possible alternative to surgery, many advanced BCCs are not amenable this therapy.

Hedgehog inhibitors. As treatment of laBCC with traditional modalities (surgery and RT) is oftentimes not practical, targeted systemic therapies have emerged as a realistic alternative. Hedgehog inhibitors (HHIs) are first-line treatment for laBCCs per the NCCN1. Vismodegib was the first HHI approved by the FDA in 2012 and inhibits the over-activation of this signaling cascade.^24,25 It is indicated for laBCC and mBCC.^24,25 The pivotal trial for vismodegib, ERIVANCE, was an international, two-cohort, single-arm trial with 71 laBCC patients and 33 mBCC patients treated with 150mg dose.^25,26 Objective response rate (ORR) in this trial was 43 percent in patients with laBCC and 21 percent of patients had complete response.²⁵ In the 30-month follow-up, 60.3 percent experienced an ORR and median duration of response was 26.2 months.²⁷ Further, an open-label multicenter-trial (STEVIE) with 1,215 patients reported ORR of 68.5 percent for laBCC with a median duration of response of 23 months.²⁸ A meta-analysis published in 2023 combining data for vismodegib in multiple studies reported 74.2 percent ORR for laBCC and 41.9 percent ORR for mBCC.²⁴

Recently, several international studies have reported favorable efficacy of vismodegib. A retrospective study of 39 patients in Slovenia with laBCC and multiple BCC found ORR of 80 percent with median duration of treatment of 9.9 months.²⁹ Similarly, 53 patients in a German skin cancer registry were found to have ORR of 77.4 percent for vismodegib.³⁰ Another study of 36 patients in Canada with laBCC reported a 50 percent complete response rate (CRR) and 41.3 percent had partial response, with median time to maximum response being 5.3 months.³¹ In this study, 23.9 percent of patients were amenable to surgery after a median of 17.2 months.³¹ A real-world multicenter cohort study further reported that 108 patients with laBCC and 13 with mBCC treated with vismodegib had overall survival rate of 86 percent after one year, 73 percent after two years, and 60 percent after three years and a progression-free survival rate of 61 percent after one year.³² Similar to other studies, a nationwide retrospective study including patients from 15 clinics reported 45.9 percent complete remission rate and 77.5 percent ORR.³³ A study of 61 French patients treated with vismodegib found that though no factors predicted response to vismodegib, multiple BCCs was the only factor related to increased risk of relapse (hazard ratio (HR)13.80) and longer treatment duration decreased risk of relapse (HR 0.95).³⁴

Vismodegib has also been shown to reduce tumor burden in combination with surgery. One study reported a significantly lower rate of new surgically eligible BCCs compared to placebo in those with Basal Cell Nevus Syndrome.³⁵ In another study, 80 percent of patients had downstaging of surgical procedure after vismodegib.³⁶ A group of 15 large BCCs had a 27 percent mean decrease in surgical defect size after vismodegib treatment for up to six months.³⁷ However, there are some reports of patients who develop resistance to vismodegib.¹²

Sonidegib was introduced after vismodegib and garnered FDA approval in 2015 based on results from a randomized, double-blind phase II trial (BOLT).³⁸ Patients were either administered 200mg or 800mg once daily.³⁸ After 42 months, patients with laBCC treated with sonidegib 200mg had 56 percent ORR and those with mBCC had eight percent ORR.³⁹ Median duration of response was 26.1 months for laBCC.³⁹ For laBCC classified as aggressive, 42-month ORR was 59.5 percent while for nonaggressive types it was 51.7 percent.⁴⁰ Of aggressive subtypes, ORR was the highest for infiltrative (200mg, 51.6%) and morpheaform (200mg, 50.0%).⁴⁰

Direct comparisons between vismodegib and sonidegib are limited as there are currently no head-to-head trials. The two pivotal trials also differed in various characteristics including patients’ treatment history, length of follow-up, and type of reporting criteria. The ERIVANCE trial for vismodegib used the investigator-based Response Evaluation Criteria in Solid Tumors (RECIST) for evaluation of response rates while the BOLT study for sonidegib used the modified RECIST (mRECIST) criteria.^26,38 The mRECIST tool has been described as a stricter evaluation, defining response based on composite evidence from magnetic resonance imaging, color photography, and histology.^38,41 This has been discussed as a potential reason for the differences in response rates between vismodegib and sonidegib.^24,41–43 In a study by Gutzmer et al,⁴⁴ applying RECIST criteria to patients with laBCC treated with sonidegib results in higher response rates (ORR per central review 60.6 percent, ORR per investigator review 74.2%) compared to mRECIST criteria (ORR per central review 56.1 percent, ORR per investigator review 71.2%).

A multicenter retrospective analysis of 82 real-world patients treated with sonidegib reported 81.7 percent showed clinical improvement (29.3% CRR, 52.4% partial response).⁴⁵ In this group, median treatment duration was six months, after which time 48.8 percent of patients discontinued the drug.⁴⁵ Interestingly, those having prior treatment with vismodegib and recurrent primary BCCs had a poorer response to sonidegib.⁴⁵ Another recent retrospective analysis reported that 92 percent of patients treated with sonidegib achieved ORR while 82 percent of those treated with vismodegib achieved ORR.⁴⁶ This study also reported a significantly greater rate of dysgeusia with vismodegib compared to sonidegib (p=0.0001) and shorter median time to onset of treatment emergent adverse effects (TEAEs) with vismodegib.⁴⁶

Despite known efficacy, utility of HHIs can be limited by their adverse event profiles. Post-hoc analyses of clinical trials have shown that common adverse effects were alopecia (58.0% vismodegib vs. 49.4% sonidegib), dysgeusia/taste alterations (70.6% vismodegib vs. 44.3% sonidegib, p=0.0003), and muscle spasms (70.6% vismodegib vs. 54.4% sonidegib, p=0.02).⁴³ Gastrointestinal side effects were less common, including diarrhea (25.2% vismodegib vs. 31.6% sonidegib) and nausea (19.3% vismodegib vs. 39.2% sonidegib).⁹ Adverse events related to HHI were the leading reason for treatment discontinuation for both vismodegib and sonidegib,^24,43 and most were reversible after drug cessation.⁴⁷ A recent long-term safety analysis of patients treated with sonidegib reported that the safety profile was consistent with the pivotal BOLT study.⁴⁸ The number of patients experiencing TEAEs leading to dose interruption or reduction was also similar to the BOLT study; however, proportion of those with TEAEs resulting in treatment discontinuation was lower.⁴⁸

Sonidegib has also been associated with longer time to onset of adverse events when compared with vismodegib.^41,43 For muscle spasms, median time to onset with sonidegib was 2.1 months vs. 1.2 months with vismodegib (p=0.0029).⁴³ For taste alterations, median time to onset with sonidegib was 3.7 months vs. 1.4 months with vismodegib (p<0.0001). For alopecia, median time to onset with sonidegib was 5.5 months vs. 2.9 months with vismodegib (p=0.001) and for diarrhea median time to onset with sonidegib was 6.5 months vs.1.3 months with vismodegib (p<0.0001).⁴³ These results lead many clinicians to believe that efficacy for sonidegib is on par with, and may even be greater than vismodegib, with the added benefit of an improved adverse event profile (lower incidence and longer mean time to onset), though comparisons are limited by lack of head-to-head trials.

Importantly, dose interruptions have not been associated with reduced efficacy. An intermittent dosing cycle of vismodegib 150mg daily for 12 weeks and drug holiday for 8 weeks has been previously discussed.^13,49 One study found no difference in efficacy between two different dosing regimens (vismodegib daily for 12 weeks, then three rounds of 8 weeks placebo followed by 12 weeks drug daily vs. vismodegib daily for 24 weeks, then three rounds of 8 weeks placebo followed by 8 weeks drug daily).⁵⁰ Another study found that vismodegib daily for seven days followed by a 21-day drug holiday maintained therapeutic benefit while minimizing adverse effects.⁵¹ Further, it is recommended to interrupt sonidegib if experiencing severe or intolerable muscle spasms, first elevated serum creatinine kinase (CK) between 2.5-10x upper limit of normal (ULN), or recurrent CK elevation 2.5-5x ULN.⁵²

Methods to mitigate adverse events include dietary supplements such as oral L-carnitine for muscle spasms,^53,54 food swaps and consultation with a dietician for taste disturbances,⁵⁵ and topical or oral minoxidil for alopecia.⁵⁶ Utilizing medications to treat gastric motility (ie, domperidone) and emesis (ie, dimenhydrinate) can help with nausea or other gastrointestinal adverse effects.⁵⁷

PD-1 inhibitors. Cemiplimab is an immune checkpoint inhibitor FDA approved for laBCCs and mBCCs for whom HHIs do not provide adequate control, for those that do not tolerate HHIs, or for whom an HHI is not appropriate.¹³ It is the first and currently the only immuno-oncology medication approved for these BCC indications. It is an antibody that blocks programmed cell death protein 1 (PD-1) receptors on T cells, allowing them to attack tumor cells.⁵⁸ Approved in 2021, the pivotal phase II clinical trial treated laBCC patients with a 350mg infusion every three weeks for a maximum of 93 weeks or until treatment failure or intolerable side effects.⁵⁸ Of the 84 patients enrolled in this trial, ORR was 31 percent with six percent achieving complete response and 25 percent partial response.⁵⁸ Median time to response was 4.3 months and 62 percent of patients discontinued the therapy.⁵⁸ This study reported an estimated Kaplan-Meier probability of response duration of 85.2 percent at 12 months and estimated progression-free survival was 19.3 months.⁵⁸ The most common cause of treatment discontinuation was due to disease progression (35%), whereas adverse events (16%) and patient decision (6%) were less common reasons.⁵⁸ 

In the extended follow-up analysis, overall ORR rose to 32.1 percent. More specifically, for those intolerant to HHIs ORR was 38.1 percent while for patients resistant to HHIs it was 30.2 percent.⁵⁹ Further, 70.4 percent of responders experienced a greater than 50-percent change in tumor size from baseline.⁵⁹ Patients also experienced durability of response, as 59.5 percent did not have disease progression for at least 182 days.⁵⁹ With regards to mBCC, a Phase II trial with 54 patients reported ORR of 22 percent (two complete responses, 10 partial responses) with a median time to response of three months.⁶⁰ This data demonstrates clinically meaningful improvement for laBCC and mBCC as a result of treatment with cemiplimab.

Cemiplimab is also indicated for patients when HHIs are not appropriate. There is currently limited data on when to classify patients as not appropriate for HHIs. However, as the adverse event profiles are different for cemiplimab and HHIs, patients who have a history of muscle spasms, alopecia, taste disturbances, or others which may be worsened by HHIs could be candidates to proceed directly to cemiplimab. Patients who also have elevated CK and who are at risk for CK elevation may also not be appropriate candidates for HHIs.

Safety of cemiplimab is consistent with other immunotherapies. A variety of grade 3 or 4 adverse events attributed to the treatment were reported in 48 percent of patients, including hypertension (5%), colitis (5%), and fatigue.⁵⁸ Serious treatment-related adverse events occurred in 35 percent of patients.⁵⁸ Further, immune-related adverse events occurred in 25 percent of patients, of which 10 percent were grade 3.⁵⁸ The extended follow-up analysis demonstrated consistent adverse event profile.⁵⁹

Immuno-oncology therapies such as cemiplimab can also cause immune-mediated adverse events (irAEs) due to nonspecific activation of immunity. These can impact almost all organ systems and can occur anytime during the treatment course and occasionally after treatment discontinuation.^61–63 Though most irAEs are mild to moderate that can be reversed, severe events can occur.^61–63 The most commonly affected organ systems by irAEs are the skin, gastrointestinal, endocrine, hepatic, musculoskeletal and respiratory systems.^61,63 Specifically, frequently reported all-grade irAEs with PD-1 inhibitors are inflammatory dermatitis (itch and/or rash), fatigue, diarrhea, colitis, hepatitis, hypothyroidism, pneumonitis, and others.^61,63,64 Time to onset varies by organ system but can begin to arise within several weeks.⁶¹

Timely identification of irAEs is critical to adequate management.⁶⁵ Clinicians should educate patients and caregivers before initiating therapy regarding the potential symptoms of adverse events that they may experience. Office staff should also be educated on the symptoms that patients may report to prevent a delay in diagnosis. It is recommended that staff should consider any new symptom in a patient receiving immuno-oncologic therapy with high suspicion as it could be the onset of an irAE. When a patient is recognized to be experiencing an irAE, treatment with systemic corticosteroids (ie, prednisone, methylprednisolone, or equivalents) should be initiated immediately.^63,64 For severe reactions or toxicity, immunotherapy should be paused or stopped.^63,64 Additionally, a potential cause of similar symptoms could be development of metastatic disease or progressive disease and clinicians should be mindful to initiate proper evaluation if metastasis or progressive disease is suspected. Diagnosis of metastatic BCC is challenging, but imaging with MRI, CT, or PET/CT can be used to assess for perineural invasion and systemic metastasis.⁶⁶

Characteristics of BCC that affect Management and Prognosis

It is important for clinicians to understand the characteristics of BCCs that would indicate whether to treat with surgery, radiation, or move to an HHI or PD-1 inhibitor. Though there is no consensus in the literature on specific criteria for laBCC, clinical, histological, and other features may indicate when BCCs may be at risk for worse prognosis.

Anatomic location of BCC is a commonly identified risk factor for recurrence. As such, current guidelines stratify anatomic regions into three categories:

• Highest risk—Area H: central face, eyelids, eyebrows, periorbital area, nose, lips, chin, mandible, preauricular and postauricular regions, temple, and ear (collectively known as the “mask area” of the face), genitalia, hands, and feet^10,11
• Area L: trunk and extremities (excluding pretibia, hands, feet, nail units, and ankles)^10,11
• Area M: cheeks, forehead, scalp, neck, and pretibial^10,11
  

Other risk factors for recurrence of BCC include greater size, poorly demarcated borders, and if a lesion is primary or recurrent.^9,67–69 Features of aggressive BCCs often include ulceration, induration, and adherence.⁶⁷ History of organ transplantation, chemotherapy, radiation or long-term phototherapy with UVA are additional patient-related risk factors for development of BCC.^{9,67,68,70,71}

In addition to anatomic location, risk of recurrence is greater for specific histological subtypes of BCC. These subtypes include micronodular, infiltrative and morpheaform.^1,9 Because there can be a mix of BCC subtypes in many tumors, it is important for clinicians to take an adequate biopsy of the target lesion as clinical subtyping has been reported to be correct in only 22 percent of aggressive BCCs.⁶⁷ Nodular subtypes of BCCs have been found to be most likely to reoccur in secondary tumors (53.3%) and most BCCs tend to reoccur in the same anatomic location as the primary tumor.⁷²

The presence of perineural invasion is also a histological feature associated with higher risk.^1,9 Though perineural invasion is infrequent for BCCs, rates range from 0.18 to 10 percent.^9,73,74 A systematic review found that mean incidence of perineural invasion with BCCs was similar between conventional histopathology and MMS (0.85% vs 2.51%, p=0.82).⁷⁴ BCCs found to have perineural or large nerve invasion may require radiologic imaging with magnetic resonance imaging with or without contrast to assess degree of spread.¹ Further imaging should be considered for any high-risk BCC for which clinical exam in unable to determine extent of growth and when bone (CT scan preferred) or soft tissue involvement is suspected.¹

Checklist for Clinicians in Treatment of Advanced BCC

Given the complexity of treating patients with advanced BCC, it is vital for patients to be treated with a multidisciplinary team approach. Incorporating oncologists, plastic surgeons, otolaryngologists, psychologists, physical and occupational therapists, and others can enhance clinical outcomes and is crucial in the management paradigm of advanced BCC.

High-risk BCC

• Meets criteria for high-risk features
  • Based on clinical appearance, size, location, histology, depth of invasion
• Attempt surgery with MMS if possible
• If surgery is not possible, consider radiotherapy
• If radiotherapy is not feasible, start HHI (vismodegib or sonidegib)
  • Consider various dosing regimen, dose interruptions, and other supplements to minimize adverse effects
• If patient fails HHI due to lack of efficacy or no better than stable disease response or adverse effects, start PD-1 inhibitor (cemiplimab)

Locally advanced BCC

• Meets criteria for locally advanced
  • Tumors not amenable to surgery due to size, location, and depth of invasion
  • Tumors not amenable to radiotherapy
• When surgery and/or radiotherapy are not feasible, start HHI (vismodegib or sonidegib)
• If patient fails HHI due to lack of efficacy or no better than stable disease response or adverse effects, start PD-1 inhibitor (cemiplimab)

Metastatic BCC

• Distant spread to other organs or tissues
• Start HHI (vismodegib or sonidegib)
• If patient fails HHI due to lack of efficacy or no better than stable disease response or adverse effects, start PD-1 inhibitor (cemiplimab)

Conclusion

Treatment of advanced BCCs can be complex and poses challenges for clinicians. If not amenable to surgery or radiation therapy, use of systemic therapy may be warranted. HHIs, including vismodegib and sonidegib, are currently the first-line treatments for laBCC and mBCC, while PD-1 inhibitor cemiplimab can be used if patients do not respond to or are unable to tolerate HHIs or for whom HHIs are not appropriate. Considering the fact that results of these systemic therapies take time to manifest, it is crucial for clinicians to understand the various strategies to minimize adverse effects such that therapies can be maintained. In this review, we analyze currently available data to develop a checklist for clinicians to utilize in the treatment of advanced BCC. 

References 

1. Schmults CD, Blitzblau R, Aasi SZ, et al. Basal Cell Skin Cancer, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2023;21(11):1181–1203. 
2. Mohan SV, Chang AL. Advanced Basal Cell Carcinoma: Epidemiology and Therapeutic Innovations. Curr Dermatol Rep. 2014;3(1):40–45.
3. Basal Cell Skin Cancer (version 2.2021). National Comprehensive Cancer Network. 
4. Goldenberg G, Karagiannis T, Palmer JB, et al. Incidence and prevalence of basal cell carcinoma (BCC) and locally advanced BCC (LABCC) in a large commercially insured population in the United States: A retrospective cohort study. J Am Acad Dermatol. 2016;75(5):957–966.e2. 
5. Dreier J, Cheng PF, Bogdan Alleman I, et al. Basal cell carcinomas in a tertiary referral centre: a systematic analysis. Br J Dermatol. 2014;171(5):1066–1072. 
6. Lear JT, Corner C, Dziewulski P, et al. Challenges and new horizons in the management of advanced basal cell carcinoma: a UK perspective. Br J Cancer. 2014;111(8):1476–1481. 
7. Peris K, Licitra L, Ascierto PA, et al. Identifying Locally Advanced Basal Cell Carcinoma Eligible for Treatment with Vismodegib: An Expert Panel Consensus. Future Oncol. 2015;11(4):703–712. 
8. Amici JM, Battistella M, Beylot-Barry M, et al. Defining and recognising locally advanced basal cell carcinoma. Eur J Dermatol. 2015;25(6):586–594. 
9. Cameron MC, Lee E, Hibler BP, et al. Basal cell carcinoma: Contemporary approaches to diagnosis, treatment, and prevention. J Am Acad Dermatol. 2019;80(2):321–339. 
10. Siddiqui FS, Leavitt A. Mohs Micrographic Surgery Appropriate Use Criteria (AUC) Guidelines. 2024 May 5. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan– PMID: 38753911.
11. Connolly SM, Baker DR, Coldiron BM, et al. AAD/ACMS/ASDSA/ASMS 2012 appropriate use criteria for Mohs micrographic surgery: a report of the American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery. J Am Acad Dermatol. 2012;67(4):531–550. 
12. Migden MR, Chang ALS, Dirix L, et al. Emerging trends in the treatment of advanced basal cell carcinoma. Cancer Treat Rev. 2018;64:1–10. 
13. Wilson M, Johnson RP, Senft SC, et al. Advanced basal cell carcinoma: What dermatologists need to know about treatment. J Am Acad Dermatol. 2022;86(6S):S14–S24. 
14. Kim SK, Barker CA. Outcomes of radiation therapy for advanced T3/T4 nonmelanoma cutaneous squamous cell and basal cell carcinoma. Br J Dermatol. 2018;178(1):e30–e32. 
15. Zagrodnik B, Kempf W, Seifert B, et al. Superficial radiotherapy for patients with basal cell carcinoma: Recurrence rates, histologic subtypes, and expression of p53 and Bcl‐2. Cancer. 2003;98(12):2708–2714. 
16. Childers BJ, Goldwyn RM, Ramos D, et al. Long-term results of irradiation for basal cell carcinoma of the skin of the nose. Plast Reconstr Surg. 1994;93(6):1169–1173. 
17. Nestor MS, Berman B, Goldberg D, et al. Consensus Guidelines on the Use of Superficial Radiation Therapy for Treating Nonmelanoma Skin Cancers and Keloids. J Clin Aesthetic Dermatol. 2019;12(2):12–18.
18. Yu L, Oh C, Shea CR. The treatment of non-melanoma skin cancer with image-guided superficial radiation therapy: an analysis of 2917 invasive and in situ keratinocytic carcinoma lesions. Oncol Ther. 2021;9(1):153–166. 
19. Agha R, Heysek RV, Vasily DB, et al. Image-guided superficial radiation therapy for basal and squamous cell carcinomas produces excellent freedom from recurrence independent of risk factors. J Clin Med. 2024;13(19):5835. 
20. Peris K, Fargnoli MC, Kaufmann R, et al. European consensus-based interdisciplinary guideline for diagnosis and treatment of basal cell carcinoma-update 2023. Eur J Cancer. 2023;192:113254. 
21. Yan F, Schmalbach CE. Updates in the management of advanced nonmelanoma skin cancer. Surg Oncol Clin N Am. 2024;33(4):723–733. 
22. Griep C, Davelaar J, Scholten AN, et al. Electron beam therapy is not inferior to superficial x-ray therapy in the treatment of skin carcinoma. Int J Radiat Oncol Biol Phys. 1995;32(5):1347–1350. 
23. Zablow AI, Eanelli TR, Sanfilippo LJ. Electron beam therapy for skin cancer of the head and neck. Head Neck. 1992;14(3):188–195. 
24. Nguyen A, Xie P, Litvinov IV, et al. Efficacy and safety of sonic hedgehog inhibitors in basal cell carcinomas: an updated systematic review and meta-analysis (2009–2022). Am J Clin Dermatol. 2023;24(3):359–374. 
25. Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366(23):2171–2179. 
26. Sekulic A, Migden MR, Lewis K, et al. Pivotal ERIVANCE basal cell carcinoma (BCC) study: 12-month update of efficacy and safety of vismodegib in advanced BCC. J Am Acad Dermatol. 2015;72(6):1021–1026.e8.
27. Sekulic A, Migden MR, Basset-Seguin N, et al. Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study. BMC Cancer. 2017;17(1):332. Erratum in: BMC Cancer. 2019;19(1):366.
28. Basset-Séguin N, Hauschild A, Kunstfeld R, et al. Vismodegib in patients with advanced basal cell carcinoma: primary analysis of STEVIE, an international, open-label trial. Eur J Cancer. 2017;86:334–348. 
29. Mesti T, Sever M, Ocvirk J. Vismodegib in locally advanced basal cell carcinoma in Slovenia. Dermatology. 2023;239(1):158–164. 
30. Kaatz M, Mohr P, Livingstone E, et al. Effectiveness, safety and utilization of vismodegib for locally advanced basal cell carcinoma under real-world conditions: non-interventional Cohort Study JONAS. Acta Derm Venereol. 2022;102:adv00695. 
31. Tong J, Mitchell B, Roth K, et al. Real-world experience of vismodegib in advanced basal cell carcinoma at a Canadian cancer center. J Cutan Med Surg. 2022;26(2):143–148. 
32. Słowińska M, Dudzisz‐Śledź M, Sobczuk P, et al. Analysis of efficacy and safety of vismodegib therapy in patients with advanced basal cell carcinoma – real world multicenter cohort study. J Eur Acad Dermatol Venereol. 2022;36(8):1219–1228. 
33. Ruiz-Salas V, Podlipnik S, Sandoval-Clavijo A, et al. Real-world experience with vismodegib on advanced and multiple BCCs: data from the RELIVIS Study. Dermatology. 2023;239(5):685–693. 
34. Juzot C, Isvy-Joubert A, Khammari A, et al. Predictive factors of response to vismodegib: a French study of 61 patients with multiple or locally advanced basal cell carcinoma. Eur J Dermatol. 2022;32(3):401–407. 
35. Tang JY, Ally MS, Chanana AM, et al. Inhibition of the hedgehog pathway in patients with basal-cell nevus syndrome: final results from the multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2016;17(12):1720–1731. 
36. Bertrand N, Guerreschi P, Basset-Seguin N, et al. Vismodegib in neoadjuvant treatment of locally advanced basal cell carcinoma: First results of a multicenter, open-label, phase 2 trial (VISMONEO study): Neoadjuvant Vismodegib in Locally Advanced Basal Cell Carcinoma. EClinicalMedicine. 2021;35:100844. 
37. Ally MS, Aasi S, Wysong A, et al. An investigator-initiated open-label clinical trial of vismodegib as a neoadjuvant to surgery for high-risk basal cell carcinoma. J Am Acad Dermatol. 2014;71(5):904–911.e1. 
38. Migden MR, Guminski A, Gutzmer R, et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. Lancet Oncol. 2015;16(6):716–728. 
39. Dummer R, Guminksi A, Gutzmer R, et al. Long‐term efficacy and safety of sonidegib in patients with advanced basal cell carcinoma: 42‐month analysis of the phase II randomized, double‐blind BOLT study. Br J Dermatol. 2020;182(6):1369–1378. 
40. Dummer R, Lear JT, Guminski A, et al. Efficacy of sonidegib in histologic subtypes of advanced basal cell carcinoma: results from the final analysis of the randomized phase 2 Basal Cell Carcinoma Outcomes With LDE225 Treatment (BOLT) trial at 42 months. J Am Acad Dermatol. 2021;84(4):1162–1164. 
41. Odom D, Mladsi D, Purser M, et al. A matching adjusted indirect comparison of sonidegib and vismodegib in advanced basal cell carcinoma. J Skin Cancer. 2017;2017:6121760.
42. Villani A, Fabbrocini G, Costa C, et al. Sonidegib: safety and efficacy in treatment of advanced basal cell carcinoma. Dermatol Ther (Heidelb). 2020;10(3):401–412.
43. Gutzmer R, Loquai C, Robert C, et al. Key clinical adverse events in patients with advanced basal cell carcinoma treated with sonidegib or vismodegib: a post hoc analysis. Dermatol Ther (Heidelb). 2021;11(5):1839–1849. 
44. Gutzmer R, Robert C, Loquai C, et al. Assessment of various efficacy outcomes using ERIVANCE-like criteria in patients with locally advanced basal cell carcinoma receiving sonidegib: results from a preplanned sensitivity analysis. BMC Cancer. 2021;21(1):1244. 
45. Moreno-Arrones OM, Béa-Ardebol S, Mayo-Martinez F, et al. Sonidegib as a locally advanced basal cell carcinoma therapy in real-life clinical setting: a national multicentre study. Actas Dermo-Sifiliográficas. 2023;114(7): T565–T571.
46. Truong K, Peera M, Liu R, et al. Real‐world data on the efficacy and safety of hedgehog pathway inhibitors in patients with basal cell carcinoma: Experience of a tertiary Australian centre. Australas J Dermatol. 2024;65(8):e248–e254.
47. Xie P, Lefrançois P. Efficacy, safety, and comparison of sonic hedgehog inhibitors in basal cell carcinomas: A systematic review and meta-analysis. J Am Acad Dermatol. 2018;79(6):1089–1100.e17. 
48. Gutzmer R, Leiter U, Mohr P, et al. Interim analysis of the multinational, post-authorization safety study (NISSO) to assess the long-term safety of sonidegib in patients with locally advanced basal cell carcinoma. BMC Cancer. 2024;24(1):1401. 
49. Woltsche N, Pichler N, Wolf I, et al. Managing adverse effects by dose reduction during routine treatment of locally advanced basal cell carcinoma with the hedgehog inhibitor vismodegib: a single centre experience. J Eur Acad Dermatol Venereol. 2019;33(4): e144–e145.
50. Dréno B, Kunstfeld R, Hauschild A, et al. Two intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas (MIKIE): a randomised, regimen-controlled, double-blind, phase 2 trial. Lancet Oncol. 2017;18(3):404–412. 
51. Orlowski TJ, Hill C, Garcia N, et al. Alternative vismodegib dosing regimen for patients with basal cell carcinoma. SKIN J Cutan Med. 2023;7(5):1001-1004.
52. ODOMZO (sonidegib) Prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/205266s004lbl.pdf
53. Dinehart MS, McMurray S, Dinehart SM, et al. L-Carnitine reduces muscle cramps in   patients taking vismodegib. SKIN J Cutan Med. 2018;2(2):90–95.
54. Cannon JGD, Tran DC, Li S, et al. Levocarnitine for vismodegib‐associated muscle spasms: a pilot randomized, double‐blind, placebo‐controlled, investigator‐initiated trial. J Eur Acad Dermatol Venereol. 2018;32(7): e298–e299.
55. Fife K, Herd R, Lalondrelle S, et al. Managing adverse events associated with vismodegib in the treatment of basal cell carcinoma. Future Oncol. 2017;13(2):175–184. 
56. Villani A, Fabbrocini G, Costa C, et al. Hair loss in patients treated with vismodegib: a single-center retrospective study. Skin Appendage Disord. 2020;6(5):280–282. 
57. Lacouture ME, Dréno B, Ascierto PA, et al. Characterization and management of hedgehog pathway inhibitor-related adverse events in patients with advanced basal cell carcinoma. Oncologist. 2016;21(10):1218–1229. 
58. Stratigos AJ, Sekulic A, Peris K, et al. Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an open-label, multi-centre, single-arm, phase 2 trial. Lancet Oncol. 2021;22(6):848–857. 
59. Stratigos AJ, Sekulic A, Peris K, et al. Phase 2 open-label, multicenter, single-arm study of cemiplimab in patients with locally advanced basal cell carcinoma after hedgehog inhibitor therapy: extended follow-up. J Am Acad Dermatol. 2024;90(2):414–418. 
60. Lewis KD, Peris K, Sekulic A, et al. Final analysis of phase II results with cemiplimab in metastatic basal cell carcinoma after hedgehog pathway inhibitors. Ann Oncol. 2024;35(2):221–228.
61. Aggarwal S. Adverse effects of immuno-oncology drugs—awareness, diagnosis, and management: a literature review of immune-mediated adverse events. Indian J Cancer. 2019;56(Supplement):S10–S22.
62. Kichloo A, Albosta M, Dahiya D, et al. Systemic adverse effects and toxicities associated with immunotherapy: a review. World J Clin Oncol. 2021;12(3):150–163. 
63. Yin Q, Wu L, Han L, et al. Immune-related adverse events of immune checkpoint inhibitors: a review. Front Immunol. 2023;14:1167975. 
64. Morgado M, Plácido A, Morgado S, et al. Management of the adverse effects of immune checkpoint inhibitors. Vaccines (Basel). 2020;8(4):575. 
65. Schneider BJ, Naidoo J, Santomasso BD, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol. 2021;39(36):4073–4126. 
66. Baheti AD, Tirumani SH, Giardino A, et al. Basal cell carcinoma: a comprehensive review for the radiologist. AJR Am J Roentgenol. 2015;204(2):W132–140.
67. Amici JM, Dousset L, Battistella M, et al. Clinical factors predictive for histological aggressiveness of basal cell carcinoma: A prospective study of 2274 cases. Ann Dermatol Venereol. 2021;148(1):23–27.
68. Bøgelund F, Philipsen P, Gniadecki R. Factors affecting the recurrence rate of basal cell carcinoma. Acta Derm Venereol. 2007;87(4):330–334. 
69. Cameron MC, Lee E, Hibler BP, et al. Basal cell carcinoma: epidemiology; pathophysiology; clinical and histological subtypes; and disease associations. J Am Acad Dermatol. 2019;80(2):303–317. Erratum in: J Am Acad Dermatol. 2021;85(2):535.
70. Archier E, Devaux S, Castela E, et al. Carcinogenic risks of psoralen UV‐A therapy and narrowband UV‐B therapy in chronic plaque psoriasis: a systematic literature review. J Eur Acad Dermatol Venereol. 2012;26 Suppl 3:22–31.
71. Mittal A, Colegio OR. Skin cancers in organ transplant recipients. Am J Transplant. 2017;17(10):2509–2530. 
72. Turner LD, Zarkovic A, Lee Siew Hua J, et al. Does the histopathological subtype of primary basal cell carcinoma predict the subtype of secondary tumours? What role do genetic mutations play? Skin Health Dis. 2022;18;3(2):e123.
73. Ratner D, Lowe L, Johnson TM, et al. Perineural spread of basal cell carcinomas treated with Mohs micrographic surgery. Cancer. 2000;88(7):1605–1613. 
74. Hill MJ, Hoegler KM, Zhou AE, et al. A systematic review of the incidence of basal cell carcinoma with perineural invasion: conventional pathology versus Mohs micrographic surgery. Arch Dermatol Res. 2023;315(2):127–132.