On July 24, 2015, the U. S. Food and Drug Administration approved sonidegib (Odomzo Capsules, Novartis Pharmaceuticals Corporation) for the treatment of patients with locally advanced basal cell carcinoma (BCC) 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 (ORR) in an international, multi-center, double-blind, randomized, two-arm, non-comparative trial in patients with locally advanced basal cell carcinoma (laBCC) not amenable to local therapy or metastatic basal cell carcinoma (mBCC).
The clinical trial enrolled 230 patients who were randomized (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 laBCC randomized to receive sonidegib 200 mg daily, the median age was 67 years; 58% were male, 89% were white, 67% had an ECOG performance status of 0, and 3 patients had nevoid basal cell carcinoma syndrome. Most (76%) had received prior therapy for treatment of BCC and approximately half of these patients (56%) had aggressive histology.
Approval was based on demonstration of durable objective responses in patients with laBCC as determined by central independent review according to a modification of RECIST. The ORR for the 66 patients with laBCC randomized to 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 pre-specified sensitivity analysis using an alternative definition for complete response, defined as at least a PR according to MRI and/or photography and no evidence of tumor on biopsy of the residual lesion, yielded a CR rate of 20%. A similar response rate was noted in the 128 patients with laBCC randomized to the sonidegib 800 mg arm [44% (95% CI: 35, 53)]. Among the 38 responding patients with laBCC 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 (CK) elevations.
The most serious risks of sonidegib are rhabdomyolysis and embryofetal toxicity. Across 571 patients receiving sonidegib at total daily doses ranging from 100 mg to 3000 mg, the incidence of rhabdomyolysis (defined as serum CK increase of more than ten times the baseline value with a concurrent 1.5 fold or greater increase in serum creatinine above baseline) was 0.2%, occurring in one patient who received sonidegib 800 mg daily. In the 79 patients who received sonidegib 200 mg daily in the major efficacy study, the incidence of musculoskeletal adverse reactions was 68%; 29% of patients experienced musculoskeletal adverse reactions requiring medical intervention, and 8% required treatment discontinuation for musculoskeletal adverse reactions.
Reproductive toxicology studies in rabbits demonstrated that sonidegib exposure during organogenesis at doses below the recommended human dose of 200 mg resulted in embryotoxicity, fetotoxicity, and teratogenicity. Healthcare professionals should verify pregnancy status prior to the initiation of sonidegib, counsel pregnant women on the potential risks to the embryo and fetus, and advise non-pregnant 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. To avoid the potential risk of exposure to sonidegib that may be contained in semen, male patients should use condoms during treatment with sonidegib, and for at least 8 months after the last dose. Healthcare providers should report to Novartis any cases of exposure during pregnancy (either direct exposure in female patients or through seminal fluid from male patients), and should encourage pregnant women to participate in the Odomzo pregnancy pharmacovigilance program to collect information on pregnancy outcomes.
The recommended dose and schedule for sonidegib is 200 mg orally once daily taken on an empty stomach, at least 1 hour before or 2 hours after a meal.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting