# Locally advanced and metastatic basal cell carcinoma

Source: https://onco.cc/cancers/locally-advanced-bcc/  
OnCo record `locally-advanced-bcc` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Locally advanced basal cell carcinoma is a skin cancer that has grown so large or deep, usually on the face, that surgery or radiotherapy can no longer remove it without unacceptable damage. Almost all these tumours depend on the hedgehog growth pathway, and the pills vismodegib and sonidegib shrink about four in ten of them; cemiplimab is used when the pills fail or cannot be tolerated.

## Summary

Nearly every basal cell carcinoma is driven by the hedgehog pathway, through loss of the receptor PTCH1 in most tumours or activating mutations of SMO in about one in ten; germline PTCH1 mutations cause Gorlin syndrome with dozens to hundreds of tumours. Locally advanced disease means a tumour that is not amenable to surgery or radiotherapy because of size, depth, invasion of bone, orbit or nerves, or because repeated recurrence has exhausted local options; metastatic disease, to nodes, lung or bone, is very rare. Surgery with margin control, radiotherapy and, for superficial tumours, topical or photodynamic therapy cure the vast majority before this point.

Vismodegib, the first inhibitor of SMO, produced responses in 43 percent of locally advanced and 30 percent of metastatic tumours in ERIVANCE (2012) and was approved in January 2012 as the first systemic drug for the disease; sonidegib produced responses in 43 percent of locally advanced tumours at 200 mg in BOLT (2015). Responses are often deep and durable, but muscle cramps, hair loss, loss of taste and weight loss affect nearly everyone and lead many to stop within a year; intermittent dosing (MIKIE) keeps much of the benefit with fewer side effects, and neoadjuvant use to shrink tumours before surgery is established. Both drugs are teratogenic. Resistance arises through SMO mutations that block drug binding.

Cemiplimab, tested in patients whose disease had progressed on or could not tolerate hedgehog inhibitors, produced responses in 31 percent of locally advanced tumours and was approved in February 2021, giving the disease a second line. Because basal cell carcinoma carries a very high ultraviolet mutation burden, PD-1 blockade may be more active than the modest response rate suggests in patients not selected for hedgehog-inhibitor failure, and first-line immunotherapy and intratumoural agents are in trials; topical patidegib is being tested to prevent new tumours in Gorlin syndrome.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: Advanced basal cell carcinoma; Unresectable basal cell carcinoma; Metastatic basal cell carcinoma; Hedgehog inhibitor-treated basal cell carcinoma
- Tags: subtype-page
- Group: skin
- Burden: Basal cell carcinoma is the commonest human cancer, with millions of cases a year, but fewer than one in a hundred becomes locally advanced beyond surgery and radiotherapy and metastasis is rarer still; most advanced cases are neglected or repeatedly recurrent tumours of the head and neck, or arise in Gorlin syndrome.
- Subtypes: Locally advanced basal cell carcinoma (unresectable or not suitable for radiotherapy); Metastatic basal cell carcinoma (nodes, lung, bone); Hedgehog inhibitor-resistant basal cell carcinoma (cemiplimab candidates); Infiltrative and morphoeic basal cell carcinoma with perineural invasion; Basosquamous carcinoma (behaves like squamous cell carcinoma); Gorlin syndrome with multiple basal cell carcinomas (germline PTCH1)
- Biomarkers: PTCH1 loss or SMO activation (nearly universal; testing not needed for treatment); Germline PTCH1 or SUFU (Gorlin syndrome); SMO resistance mutations after hedgehog inhibitors (research); Perineural invasion and bone or orbital involvement on imaging; High ultraviolet-signature tumour mutational burden

## Standard of care

- Locally advanced, first line: Vismodegib (ERIVANCE) or sonidegib (BOLT); intermittent dosing to limit cramps, hair loss and taste loss; surgery or radiotherapy after response where feasible. ([ERIVANCE BCC](https://onco.cc/trials/erivance/), [BOLT](https://onco.cc/trials/bolt/), [Vismodegib](https://onco.cc/drugs/vismodegib/), [Sonidegib](https://onco.cc/drugs/sonidegib/), [Hedgehog pathway inhibitors](https://onco.cc/technologies/hedgehog-inhibitors/))
- Neoadjuvant: Vismodegib for several months to shrink large facial tumours before surgery and reduce the defect. ([Vismodegib](https://onco.cc/drugs/vismodegib/), [Mohs surgery](https://onco.cc/terms/mohs-surgery/))
- After hedgehog inhibitor failure or intolerance: Cemiplimab (approved 2021); clinical trials of intratumoural agents and immunotherapy combinations. ([Cemiplimab](https://onco.cc/drugs/cemiplimab/), [Clinical Trial to Evaluate BO-112 in Patients With Basal Cell Carcinoma (BCC)](https://onco.cc/trials/nct06422936/), [Study to Investigate the Efficacy and Safety of RP1 in Adult Patients With Organ Transplants and Advanced Skin Malignancies](https://onco.cc/trials/nct04349436/))
- Metastatic disease: Vismodegib or sonidegib; cemiplimab after progression; platinum chemotherapy has only case-series support. ([Vismodegib](https://onco.cc/drugs/vismodegib/), [Sonidegib](https://onco.cc/drugs/sonidegib/), [Cemiplimab](https://onco.cc/drugs/cemiplimab/))
- Radiotherapy and local options: Radiotherapy for tumours not resectable but still confined; electron beam and superficial radiotherapy for suitable sites; multidisciplinary review of all advanced cases. ([IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [Superficial and orthovoltage radiotherapy for skin cancer](https://onco.cc/technologies/superficial-radiotherapy/), [Electron beam therapy systems (linac electrons, total skin electron units, mobile electron IORT)](https://onco.cc/technologies/electron-beam-therapy-systems/))
- Gorlin syndrome: Surveillance and surgery, avoidance of radiotherapy, hedgehog inhibitors for multiple advanced tumours, topical patidegib in trials. ([Vismodegib](https://onco.cc/drugs/vismodegib/), [Efficacy and Safety of Patidegib Gel 2% for Preventing Basal Cell Carcinomas on the Face of Adults With Gorlin Syndrome](https://onco.cc/trials/nct06050122/))

## State of the art

- Hedgehog inhibitors shrink about four in ten locally advanced tumours, many for years, in a disease that had no systemic drug before 2012.
- Cemiplimab gives a second line after hedgehog inhibitor failure.
- Intermittent dosing and neoadjuvant use have made the pills more tolerable and more useful.

## Open problems

- Hedgehog inhibitor side effects lead many patients to stop before the tumour is controlled.
- Only about a third of patients respond to cemiplimab after hedgehog inhibitor failure and there is no third line.
- Advanced disease is largely a failure of access and neglect, since almost every tumour is curable when small.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Basal-cell_carcinoma
- ERIVANCE (NEJM 2012): https://www.nejm.org/doi/full/10.1056/NEJMoa1113713
- Cemiplimab after hedgehog inhibitors (Lancet Oncology 2021): https://doi.org/10.1016/S1470-2045(21)00126-1
- Wikipedia: https://en.wikipedia.org/wiki/Basal-cell_carcinoma

## Connected records

- cancers: [Basal cell carcinoma](https://onco.cc/cancers/basal-cell-carcinoma/)
- technologies: [Electron beam therapy systems (linac electrons, total skin electron units, mobile electron IORT)](https://onco.cc/technologies/electron-beam-therapy-systems/), [Hedgehog pathway inhibitors](https://onco.cc/technologies/hedgehog-inhibitors/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [Superficial and orthovoltage radiotherapy for skin cancer](https://onco.cc/technologies/superficial-radiotherapy/)
- terms: [Mohs surgery](https://onco.cc/terms/mohs-surgery/)
- targets: [PD-1](https://onco.cc/targets/pd1/), [Smoothened (hedgehog pathway)](https://onco.cc/targets/smoothened/)
- drugs: [Cemiplimab](https://onco.cc/drugs/cemiplimab/), [Sonidegib](https://onco.cc/drugs/sonidegib/), [Vismodegib](https://onco.cc/drugs/vismodegib/)
- pathways: [Basal cell carcinoma (KEGG map)](https://onco.cc/pathways/basal-cell-carcinoma-signalling/), [Hedgehog signalling](https://onco.cc/pathways/hedgehog/)
- trials: [BOLT](https://onco.cc/trials/bolt/), [Clinical Trial to Evaluate BO-112 in Patients With Basal Cell Carcinoma (BCC)](https://onco.cc/trials/nct06422936/), [Efficacy and Safety of Patidegib Gel 2% for Preventing Basal Cell Carcinomas on the Face of Adults With Gorlin Syndrome](https://onco.cc/trials/nct06050122/), [ERIVANCE BCC](https://onco.cc/trials/erivance/), [Study to Investigate the Efficacy and Safety of RP1 in Adult Patients With Organ Transplants and Advanced Skin Malignancies](https://onco.cc/trials/nct04349436/), [To Assess the Safety and Efficacy of SP-002 with Vismodegib for the Treatment of Locally Advanced Basal Cell Carcinoma](https://onco.cc/trials/nct06344052/)

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