Richard Pazdur, MD
The approval is based on the phase II BOLT study in which sonidegib had an objective response rate (ORR) of 58% (95% CI, 0.45-0.70) in patients with laBCC. The responses were durable.
"Our increasing understanding of molecular pathways involved in cancer has led to approvals of many oncology drugs in difficult-to-treat diseases for which few therapeutic options previously existed,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Thanks to a better understanding of the hedgehog pathway, the FDA has now approved two drugs for the treatment of basal cell carcinoma just in the last 3 years.”
The FDA approved the hedgehog inhibitor vismodegib (Erivedge) in 2012 for the treatment of patients with locally advanced and metastatic basal cell carcinoma.
The BOLT trial was an international, double-blind, noncomparative study that randomized 230 patients with metastatic basal cell carcinoma or laBCC not amenable to local therapy in a 2:1 ratio to either 800 mg (n = 151) or 200 mg (n = 79) of sonidegib until disease progression or unacceptable toxicity. Patients were stratified by disease stage, histology, and geographic region. Eighty-four percent of patients had locally advanced disease. In the 200-mg laBCC cohort, two-thirds of patients had an ECOG performance status of 0, 58% were male, 89% were white, the median age was 67 years, and three patients had nevoid basal cell carcinoma syndrome. Three-fourths of patients had been previously treated for BCC and 56% had aggressive histology.
The 58% ORR on which the FDA based its approval was observed in a cohort of 66 patients with laBCC treated at the 200-mg dose. The ORR comprised three complete responses (CR; 5%) and 35 partial responses (PR; 53%). The CR rate was 20% in a prespecified sensitivity analysis which used a varying definition of CR—PR based on MRI and/or photography and no evidence of tumor on biopsy of the residual lesion.
Thirty-one of the 38 patients (82%) who achieved an objective response have ongoing responses (range, 1.9-18+ months). Ongoing responses of ≥6 months have occurred in 16 patients and the median duration of response has not been reached. Seven patients (18%) had disease progression after initially responding to treatment, with four of these individuals having had a response of ≥6 months.
Treatment with the higher dose did not significantly improve clinical outcomes. The ORR was 44% (95% CI, 0.35-0.53) among 128 patients with laBCC who received 800 mg of sonidegib.
As expected, there was a higher incidence of adverse events (AEs) in patients receiving the 800-mg dose. The most frequently reported AEs (10% of patients) in the 200-mg cohort were muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, and pruritus. Creatine kinase elevation and lipase elevation were the most common grade 3/4 laboratory abnormalities (≥5% of patients). Sixty-eight percent of patients in the 200-mg arm had musculoskeletal AEs, including grade 3/4 toxicities in 9%.
According to the FDA, the most serious risks associated with sonidegib treatment are rhabdomyolysis and embryofetal toxicity. Accordingly, sonidegib was approved along with a Boxed Warning indicating that treatment with the drug may cause severe birth defects or the death of a developing fetus when administered to a pregnant woman.
Commenting on the approval, Bruno Strigini, president of Novartis Oncology, said, "The FDA approval of Odomzo offers a new and noninvasive treatment option for a potentially devastating disease that is hard to treat and can be disfiguring. Odomzo is an important addition to our growing portfolio of targeted treatments for advanced skin cancers and underscores our commitment to developing and bringing to market new options for patients."