Locally advanced and metastatic basal cell carcinoma

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.