Hedgehog Inhibitors Show Significant Benefit in Advanced Basal Cell Carcinoma

Ryan J. Sullivan, MD

Ryan J. Sullivan, MD

For patients with locally advanced basal cell carcinoma that has recurred following surgery or radiation therapy, the hedgehog/smoothened inhibitors sonidegib (Odomzo) and vismodegib (Erivedge) have both shown significant benefit.

Sonidegib was approved in 2015 based on the phase II BOLT study, in which the drug had an objective response rate (ORR) of 58% (95% CI, 0.45-0.70). The ORR included 3 complete responses (5%) and 35 partial responses (53%).

Vismodegib, the first hedgehog inhibitor approved for locally advanced basal cell carcinoma, was approved in 2012 based on results of the ERIVANCE study. In the trial, the agent demonstrated an ORR of 43% in patients with locally advanced disease and 30% in patients with metastatic basal cell carcinoma. The median duration of response was 7.6 months.

To learn more about advanced basal cell carcinoma,Targeted Oncologyspoke with Ryan J. Sullivan, MD, instructor of Medicine, Harvard Medical School, assistant in medicine, MGH Cancer Center, Massachusetts General Hospital. Sullivan discusses which patients are at risk for the disease, the current standard therapies available, and what options exist for those who relapse after treatment with hedgehog/smoothened inhibitors.

TARGETED ONCOLOGY:How common is it for basal cell carcinoma to advance?

Sullivan:It is not all that common. It is a disease that is mostly a local problem, and one that typically affects the elderly. It is, often, a very locally destructive disease for patients who, for whatever reason, don’t bring themselves to the attention of physicians.

It is also relatively common in patients who have solid organ transplantation and are chronically on immunosuppression. Those patients tend to be younger, and the element of immunosuppression becomes a little more challenging, particularly when you are thinking about using immunotherapies. It is hard to think about how to use immunotherapies in the context of immunosuppression, and in the context of solid organ transplant.

TARGETED ONCOLOGY:What is the current standard treatment for advanced basal cell carcinoma?

Sullivan:The majority of basal cell carcinomas have a mutation that predicts activity of a pathway that is blocked by a couple of agents that have now been approved. These drugs are called smoothened inhibitors. Typically, we give a smoothened inhibitor to patients with basal cell carcinoma and it usually works. Their tumors shrink and there is control of the disease. The [treatments] are usually well tolerated.

TARGETED ONCOLOGY:Why is hedgehog pathway inhibition effective in basal cell carcinoma?

Sullivan:The smoothened gene, when mutated, leads to hyperactivation of the hedgehog pathway, and smoothened is one of the mediators of that pathway. When you have smoothened mutations, you block the hedgehog pathway.

TARGETED ONCOLOGY:What options are there for patients who relapse after receiving smoothened inhibitors?

Sullivan:For some patients, these therapies do not work forever. Therefore, we get into a scenario where we have to try and understand what the next line of therapy is for patients. There is no amazing data that suggest that we should be doing this therapy versus another treatment after the failure of these smoothened inhibitors.

We are thinking more and more about using immunotherapy. We don’t have large sets of data with basal cell carcinoma, but what we do have is the knowledge that basal cell carcinoma is obviously a skin cancer. Also, we know that its genesis is through UV damage and mutational events in the skin—particularly in the basal layer of skin.