The U.S. Food and Drug Administration (FDA) approved sonidegib (Odomzo) for the treatment of patients with locally advanced basal cell carcinoma that has recurred following surgery or radiation therapy or those who are not candidates for surgery or radiation therapy.
The approval was based on demonstration of a durable objective response rate in an international, multicenter, double-blind, randomized, two-arm, noncomparative trial in patients with locally advanced basal cell carcinoma not amenable to local therapy or metastatic basal cell carcinoma.
The clinical trial enrolled 230 patients who were randomly assigned (2:1) to receive sonidegib 800 mg (n = 151) or 200 mg (n = 79) daily until disease progression or unacceptable toxicity. Randomization was stratified by disease stage (locally advanced or metastatic), histologic subtype (aggressive or nonaggressive), and geographic region.
The majority (84%) of those enrolled had locally advanced disease. Among patients with locally advanced basal cell carcinoma randomly assigned to receive sonidegib 200 mg daily, the median age was 67 years; 58% were male, 89% were white, 67% had an Eastern Cooperative Oncology Group performance status of 0, and three patients had nevoid basal cell carcinoma syndrome. Most (76%) had received prior therapy for basal cell carcinoma, and approximately half of these patients (56%) had an aggressive histology.
Approval was based on demonstration of durable objective responses in patients with locally advanced basal cell carcinoma, as determined by central independent review according to a modification of Response Evaluation Criteria in Solid Tumors (RECIST).
The objective response rate for the 66 patients in the sonidegib 200-mg arm was 58% (95% confidence interval [CI] = 45%–70%], consisting of 3 (5%) complete responses and 35 (53%) partial responses. A prespecified sensitivity analysis using an alternative definition for complete response, defined as at least a partial response according to magnetic resonance imaging and/or photography and no evidence of tumor on biopsy of the residual lesion, yielded a complete response rate of 20%. A similar response rate was noted in the 128 patients in the sonidegib 800-mg arm (44% [95% CI = 35%–53%]).
Among the 38 responding patients in the 200-mg arm, 7 patients (18%) experienced subsequent disease progression, and 4 of these 7 patients had maintained a response of 6 months or longer. The remaining 31 patients (82%) continue to respond, with ongoing responses ranging from 1.9+ to 18.6+ months; 16 patients have ongoing responses of 6 months or longer, and the median duration of response has not been reached.
Serious and common adverse reactions and discontinuation of sonidegib for adverse reactions occurred more frequently in the 800-mg treatment arm. Adverse reactions occurring in more than 10% of patients treated in the 200-mg arm were muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, and pruritus. The most frequent grade 3 and 4 laboratory abnormalities occurring in at least 5% of patients in the 200-mg arm were serum lipase and creatine kinase elevations.
The most serious risks of sonidegib are rhabdomyolysis and embryofetal toxicity. Sonidegib carries a boxed warning alerting health-care professionals that the drug may cause death or severe birth defects in a developing fetus when administered to a pregnant woman.
Health-care professionals should verify pregnancy status prior to the initiation of sonidegib, counsel pregnant women on the potential risks of sonidegib to the embryo and fetus, and advise nonpregnant women to use effective contraception during treatment with sonidegib and for at least 20 months after the last dose based on the 28-day half-life of sonidegib. ■