Hedgehog pathway inhibitors

FDA approval was supported by an international, multicenter, open-label, two-cohort trial enrolling 104 patients: 33 with metastatic BCC and 71 with locally advanced BCC with inoperable disease or for whom surgery was inappropriate. Patients received vismodegib 150 mg daily.[50][Level of evidence C3] Objective response rate (RR) assessed by an independent review committee was the primary end point. The study was sized to test whether the RR was higher than 10% in patients with metastatic BCC and higher than 20% in patients with locally advanced BCC by exact binomial 1-sided tests. Of the 104 patients, 96 were evaluable for RR, with 8 patients who had locally advanced BCC excluded from analysis after the independent pathologist did not identify BCC in the biopsy specimens. In both cohorts, the median duration of treatment was 10.2 months (range, 0.7–18.7 months).

FDA approval was supported by an international, multicenter, open-label, two-cohort trial enrolling 104 patients: 33 with metastatic BCC and 71 with locally advanced BCC with inoperable disease or for whom surgery was inappropriate. Patients received vismodegib 150 mg daily.[50][Level of evidence C3] Objective response rate (RR) assessed by an independent review committee was the primary end point. The study was sized to test whether the RR was higher than 10% in patients with metastatic BCC and higher than 20% in patients with locally advanced BCC by exact binomial 1-sided tests. Of the 104 patients, 96 were evaluable for RR, with 8 patients who had locally advanced BCC excluded from analysis after the independent pathologist did not identify BCC in the biopsy specimens. In both cohorts, the median duration of treatment was 10.2 months (range, 0.7–18.7 months).

In 33 patients with metastatic BCC, the RR was 30% (95% CI, 16%–48%; P = .001). In 63 patients with locally advanced BCC, the RR was 43% (95% CI, 31%–56%; P < .001), with complete responses in 13 patients (21%). In both cohorts, the median duration of response was 7.6 months.[50][Level of evidence C3]

FDA approval was supported by an international, multicenter, open-label, two-cohort trial enrolling 104 patients: 33 with metastatic BCC and 71 with locally advanced BCC with inoperable disease or for whom surgery was inappropriate. Patients received vismodegib 150 mg daily.[50][Level of evidence C3] Objective response rate (RR) assessed by an independent review committee was the primary end point. The study was sized to test whether the RR was higher than 10% in patients with metastatic BCC and higher than 20% in patients with locally advanced BCC by exact binomial 1-sided tests. Of the 104 patients, 96 were evaluable for RR, with 8 patients who had locally advanced BCC excluded from analysis after the independent pathologist did not identify BCC in the biopsy specimens. In both cohorts, the median duration of treatment was 10.2 months (range, 0.7–18.7 months).

The most common adverse events were muscle spasms, alopecia, dysgeusia, weight loss, and fatigue. Adverse events led to the discontinuation of vismodegib in 12% of patients.

FDA approval was supported by an international, multicenter, open-label, two-cohort trial enrolling 104 patients: 33 with metastatic BCC and 71 with locally advanced BCC with inoperable disease or for whom surgery was inappropriate. Patients received vismodegib 150 mg daily.[50][Level of evidence C3] Objective response rate (RR) assessed by an independent review committee was the primary end point. The study was sized to test whether the RR was higher than 10% in patients with metastatic BCC and higher than 20% in patients with locally advanced BCC by exact binomial 1-sided tests. Of the 104 patients, 96 were evaluable for RR, with 8 patients who had locally advanced BCC excluded from analysis after the independent pathologist did not identify BCC in the biopsy specimens. In both cohorts, the median duration of treatment was 10.2 months (range, 0.7–18.7 months).

There were fatal adverse events in seven patients: three deaths from unknown causes; and one death each from hypovolemic shock, myocardial infarction, meningeal disease, and ischemic stroke. The relationship between the study drug and the deaths is unknown.

Sonidegib was evaluated at two doses in a multinational, double-blind, multiple-cohort trial conducted in patients with metastatic BCC (n = 36) or locally advanced BCC (n = 194).[51]Level of evidence B3] Patients were randomly assigned (in a 2:1 fashion) to receive either 200 mg or 800 mg orally, once a day. The primary end point was RR, with data collected up to 6 months after randomization of the last patient and determined by blinded central review. A sample size of 210 patients was targeted to ensure 150 patients for the primary efficacy analysis, which required locally advanced disease to be assessable by modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Success was prespecified as a 30% RR.

Sonidegib was evaluated at two doses in a multinational, double-blind, multiple-cohort trial conducted in patients with metastatic BCC (n = 36) or locally advanced BCC (n = 194).[51]Level of evidence B3] Patients were randomly assigned (in a 2:1 fashion) to receive either 200 mg or 800 mg orally, once a day. The primary end point was RR, with data collected up to 6 months after randomization of the last patient and determined by blinded central review. A sample size of 210 patients was targeted to ensure 150 patients for the primary efficacy analysis, which required locally advanced disease to be assessable by modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Success was prespecified as a 30% RR.

In the 200-mg cohort, a central review identified 18 of 42 patients with locally advanced BCC (43%; 95% CI, 28%–59%) and 2 of 13 patients with metastatic BCC (15%; 95% CI, 2%–45%) who had an objective response and qualified for the primary efficacy analysis. The median duration of response was not reached. RR was similar in the two-dose cohorts, with fewer adverse events at the lower dose, leading to FDA approval of the 200-mg once-daily dose.[51][Level of evidence B3]

Sonidegib was evaluated at two doses in a multinational, double-blind, multiple-cohort trial conducted in patients with metastatic BCC (n = 36) or locally advanced BCC (n = 194).[51]Level of evidence B3] Patients were randomly assigned (in a 2:1 fashion) to receive either 200 mg or 800 mg orally, once a day. The primary end point was RR, with data collected up to 6 months after randomization of the last patient and determined by blinded central review. A sample size of 210 patients was targeted to ensure 150 patients for the primary efficacy analysis, which required locally advanced disease to be assessable by modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Success was prespecified as a 30% RR.

Frequent adverse events included muscle spasms, alopecia, dysgeusia, fatigue, nausea, vomiting, decreased appetite, decreased weight, myalgia, and pain.

Sonidegib was evaluated at two doses in a multinational, double-blind, multiple-cohort trial conducted in patients with metastatic BCC (n = 36) or locally advanced BCC (n = 194).[51]Level of evidence B3] Patients were randomly assigned (in a 2:1 fashion) to receive either 200 mg or 800 mg orally, once a day. The primary end point was RR, with data collected up to 6 months after randomization of the last patient and determined by blinded central review. A sample size of 210 patients was targeted to ensure 150 patients for the primary efficacy analysis, which required locally advanced disease to be assessable by modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Success was prespecified as a 30% RR.

Four patients in the 800-mg cohort died during the study: two from cardiac death and two from metastatic disease progression.