Odomzo, a New Treatment for Basal Cell Carcinoma, Approved by FDA

Patients with locally advanced basal cell carcinoma (laBCC) have a new treatment option. The U.S. Food & Drug Administration has approved Odomzo (sonidegib) for the treatment of patients who have experienced a recurrence of this condition after surgery or radiation, or who weren’t eligible for those therapies.

Odomzo is inhibits the activity of the hedgehog cell signaling pathway, which has been shown to be involved in the development of basal cell carcinoma.

The drug’s approval is based on the phase 2 BOLT study, in which Odomzo demonstrated an objective response rate (ORR) of 58 percent 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,” says Richard Pazdur, 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 three years.”

The FDA approved the hedgehog inhibitor Erivedge (vismodegib) 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 Odomzo 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, meaning they were healthy enough to remain fully active. Fifty-eight percent were male, 89 percent were white, the median age was 67 years, and three patients had nevoid basal cell carcinoma syndrome, which affects many body areas and increases cancer risk. Three-fourths of patients had been previously treated for BCC and 56 percent had aggressive histology.

The 58 percent 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 percent) and 35 partial responses (PR; 53 percent). The CR rate was 20 percent 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 percent) who achieved an objective response have experienced ongoing responses (range, 1.9-18+ months). Ongoing responses of six or more months have occurred in 16 patients and the median duration of response has not been reached. Seven patients (18 percent) had disease progression after initially responding to treatment, with four of these individuals having had a response of six months or longer.

Treatment with the higher dose did not significantly improve clinical outcomes. The ORR was 44 percent among 128 patients with laBCC who received 800 mg of Odomzo.

As expected, there was a higher incidence of adverse events in patients receiving the 800-mg dose. The most frequently reported side effects (10 percent of patients) in the 200-mg cohort were muscle spasms, hair loss, a distortion in the ability to perceive tastes, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, muscle pain, abdominal pain, headache, pain, vomiting and itching. Creatine kinase elevation, which signals muscle problems, and lipase elevation, which can signal pancreas inflammation, were the most common severe laboratory abnormalities (5 percent of patients or more). Sixty-eight percent of patients in the 200-mg arm had musculoskeletal side effects, including severe toxicities in 9 percent.

According to the FDA, the most serious risks associated with Odomzo treatment are rhabdomyolysis, or muscle destruction, and embryofetal toxicity. Accordingly, Odomzo 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."