339 An open-label investigator initiated study to evaluate the efficacy and safety of sonidegib and buparlisib in advanced basal cell carcinomas (NCT02303041)

Abstract

Smoothened inhibitors (SI) are FDA approved for advanced basal cell carcinomas (BCCs), but chemo-resistance is a clinical challenge. One mechanism of chemo-resistance involves upregulation of phosphoinositide 3-kinase pathway (PI3K). Hypothesis: Combination treatment with sonidegib, an SI, and buparlisib, a pan-PI3K inhibitor, has efficacy in advanced BCC patients (pts). Methods: After IRB approval, pts. who met all enrollment criteria at Stanford received sonidegib (200 mg/d) and buparlisib (80 mg/d) until disease progression or intolerable toxicity. Primary endpoint: overall response rate (ORR) after 328 days of therapy, by Response Evaluation Criteria for Solid Tumors version 1.1. Secondary endpoints: progression-free survival (PFS), and incidence and severity of adverse events (AEs) (by the Common Terminology Criteria for Adverse Events, version 4.0). Results: Of 10 pts enrolled, 7 were response evaluable, and 8 were AE evaluable. Median follow-up time for response evaluable pts was 14.8 mos.; for AE evaluable pts 12.0 mos. ORR=42.8% for response evaluable pts: RR=40.0% in previously SI-exposed pts (n=6), 50.0% in naïve pts (n=2). Overall, median PFS=13.8 mos. (range 1.9 – 18.6). Grade 3 AEs occurred in 50% of evaluable pts, consisting of n=2 pts with transaminitis, and n=1 with abdominal pain, esophagitis, muscle spasms, anxiety, and elevated creatine phosphokinase. Two pts discontinued the study due to AEs. One pt with response is currently still on the study. Conclusions: Though the sample size is small as advanced BCCs are rare, this pilot study suggests the combination of sonidegib and buparlisib has potential benefit in this patient population with few treatment options. The frequency of grade 3 toxicity at the doses used in this study may limit usage. Larger clinical trials across multiple sites are needed to evaluate whether combination therapy at lower doses of buparlisib may optimize clinical benefit while minimizing AEs.