PracticalDermatology

The FDA last month approved the oral agent sonidegib (Odomzo, Novartis Pharmaceuticals) for the treatment of patients with locally advanced basal cell carcinoma (BCC). Specifically, sonidegib is an oral, selective smoothened (SMO) inhibitor that is indicated for patients whose BCC has advanced following surgery or radiation therapy, or for patients who are not candidates for either modality. The approval comes on the heels of impressive data both in terms of efficacy and adverse event profile, representing a potentially significant addition to the BCC treatment armamentarium.

The Data

The FDA’s decision was based on the results of a non-comparative randomized trial of 230 patients with metastatic basal cell carcinoma or locally advanced basal cell carcinoma not amenable to local therapies. Patients were randomly assigned to receive 800mg or 200mg doses of daily sonidegib, with the latter group including 66 patients with locally advanced disease. Of these patients, 76 percent had been previously treated and 56 percent had aggressive histology. All patients were followed for at least 12 months unless discontinued earlier. (Note: At press time, it was unclear why some patients dropped out of the study.)

Overall response rate (ORR) among the 200mg group was 58 percent, with five percent of patients achieving complete response and 53 percent achieving partial response. Of note, seven of the 38 responding patients in the 200mg group subsequently experienced disease progression, four of which had maintained a response for six or more months; responses were ongoing in the other 31 patients. Some patients’ ongoing responses have lasted up to 18 months. In the 800mg group, ORR among 128 patients with locally advanced basal cell carcinoma was considerably lower, at 44 percent. In the 800mg group common and serious AEs occurred more frequently.

In the 200mg group, adverse events occurring in 10 percent or more of patients included muscle spasms, alopecia, dysgeusia, fatigue, nausea, diarrhea, decreased weight and appetite, headache, and vomiting. Among all patients assigned the 200mg group, 68 percent experienced musculoskeletal adverse reactions, 29 percent of which required medical intervention and eight percent of which warranted treatment discontinuation.

Based on the results, the investigators suggested that the recommended dose and schedule for sonidegib be 200mg once daily on an empty stomach. They also indicated that the optimal time to take the drug is at least one hour prior to or two hours following a meal.

Relevance

Topical and oral treatment of BCCs have remained suspect due to poor long-term outcomes. However, in high-risk patients, these agents can be an important treatment modality. Also, as tumor debaulking agents, they can have a role. This new treatment adds to the available options and appears to have a favorable side effect profile. However, it bears mentioning that this agent comes with a boxed warning, and the myositis side effect deserves consideration before treatment, as well.

As researchers continue to make gains in the understanding of the genetic mechanisms of BCCs, more therapeutic changes are likely to follow, which is a positive development for patients. Arguably the most fascinating aspect of the data for sonidegib, specifically, is the duration of response, which is ongoing in some patients but has been documented to be up to 18 months in others. For sonidegib and other agents, continued inquiry and long-term follow-up will ultimately answer whether these agents will be first line treatment options. Only time will tell. n

Jonathan Wolfe, MD is an Associate Professor of Dermatology at the University of Pennsylvania.