An Investigator-Initiated Open-Label Trial of Sonidegib in Advanced Basal Cell Carcinoma Patients Resistant to Vismodegib

Abstract

Purpose: To assess the tumor response to the smoothened (SMO) inhibitor, sonidegib (LDE225), in patients with an advanced basal cell carcinoma (BCC) resistant to treatment with vismodegib (GDC0449).

Experimental design: Nine patients with an advanced BCC that was previously resistant to treatment with vismodegib were given sonidegib in this investigational, open-label study. Tumor response was determined using the response evaluation criteria in solid tumors. SMO mutations were identified using biopsy samples from the target BCC location.

Results: The median duration of treatment with sonidegib was 6 weeks (range, 3-58 weeks). Five patients experienced progressive disease with sonidegib. Three patients experienced stable disease and discontinued sonidegib either due to adverse events (n = 1) or due to election for surgery (n = 2). The response of one patient was not evaluable. SMO mutations with in vitro data suggesting resistance to Hh pathway inhibition were identified in 5 patients, and none of these patients experienced responses while on sonidegib.

Conclusions: Patients with advanced BCCs that were previously resistant to treatment with vismodegib similarly demonstrated treatment resistance with sonidegib. Patients who have developed treatment resistance to an SMO inhibitor may continue to experience tumor progression in response to other SMO inhibitors.

Figure 1

Target BCC size determination of clinically visible lesions, and overall responses of enrolled subjects. Color photographs were taken of all clinically visible lesions with a ruler in the plane of the lesion. A, in cases where the tumor borders are complex, clean plastic grids were placed over the lesions and traced to document the longest diameter. B, photograph of target lesion in a subject before study start. C, photograph of same target lesion after 6 weeks of sonidegib. Arrows indicate areas of tumor growth. D, change in target tumor diameter from baseline (%) after sonidegib. None of the patients met the 30% partial response (top gray dotted line) per RECIST, version 1.1. SMO mutations that are known to lead to functional resistance in vitro found in individual tumors are annotated for each patient.

Figure 2

Locations of the SMO mutations known to confer resistance through in vitro studies were identified in the BCCs of the study patients. The locations of these mutations within the SMO protein are shown on the left. Mutations Q476 and D473 are within the drug-binding pocket of sonidegib. Mutations S533 and W535 likely cause conformational change in SMO rendering the drug-binding pocket inaccessible to the sonidegib. The chemical structures of sonidegib and vismodegib are shown on the right for comparison.