The European Commission (EC) has approved the hedgehog inhibitor sonidegib (Odomzo) for the treatment of patients with locally advanced basal cell carcinoma (laBCC) who are not amenable to curative surgery or radiation therapy.
The approval is based on the phase II BOLT study in which sonidegib had an objective response rate (ORR) of 56% (95% CI, 0.43-0.68) and a median progression-free survival (PFS) of 22 months among patients with laBCC who received the hedgehog inhibitor at a 200-mg dose.
"We are pleased to have a new treatment option for European patients living with advanced basal cell carcinoma," said Bruno Strigini, president, Novartis Oncology. "This milestone follows the recent approval of Odomzo in the US and is the latest example of our commitment to precision oncology and developing targeted treatments to address unmet needs."
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 56% ORR on which the EC based its approval was observed by an independent panel in a cohort of 66 patients with laBCC treated at the 200-mg dose who were followed for at least 18 months. The ORR comprised three complete responses (CR; 5%) and 34 partial responses (PR; 52%). The CR rate was 23% 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. The median duration of response has not been reached.
ORR per investigator review was 71% (95% CI, 0.59-0.82) and included 6 CRs (9%) and 41 PRs (62%). PFS rates per independent and investigator review were 22 and 19 months, respectively.
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%.
The most serious risks associated with sonidegib treatment are rhabdomyolysis and embryofetal toxicity.
Commenting on the EC approval, Reinhard Dummer, MD, professor and vice chairman, Department of Dermatology at the University of Zurich, said, “I have seen first-hand the devastating impact advanced basal cell carcinoma can have on those living with the disease. As the lesions are usually highly visible and located predominantly on the face, they can impact patients both physically and emotionally. The approval of Odomzo brings new hope in the form of a non-invasive option to help treat this disfiguring and potentially life-threatening disease.”
Sonidegib was recently approved in the United States and also has approvals in Australia and Switerzland. Additional regulatory filings are ongoing, according to Novartis, the manufacturer of the drug.