Randomized, Double-Blind Study of Sonidegib (Lde225) in Patients (Pts) with Advanced Basal Cell Carcinoma (Bcc)

Abstract

ABSTRACT Aim: The BOLT phase 2 study, comparing 2 doses of sonidegib, a hedgehog pathway inhibitor (HhPI), in pts with advanced BCC (aBCC; NCT01327053), met its primary endpoint of objective response rate ≥30% in both arms in analyses of data collected up to 6 mo after randomization of the last pt (June 28, 2013, cutoff; median follow-up [f/u], 13.9 mo; Migden, ASCO 2014). Associations of GLI1 (marker of Hh pathway activation) with clinical outcome (as of June 28, 2013) and updated 12-mo efficacy and safety data (Dec 31, 2013, cutoff; median f/u, 20.0 mo) are presented. Methods: Pts with locally advanced BCC (LaBCC; n = 194) not amenable to curative surgery or radiation or metastatic BCC (mBCC; n = 36) were randomized 1:2 to receive sonidegib 200 or 800 mg daily. Clinical response was assessed by central review using modified RECIST (LaBCC) or RECIST 1.1 (mBCC). Exploratory analyses in a subset of pts (LaBCC, n = 137; mBCC, n = 13) assessed GLI1 levels by qRT-PCR in tumor tissue collected at baseline (BL), wk 9, and wk 17. Results: GLI1 levels decreased from BL with both doses at wk 9 and 17 (median % changes [200 mg], -91.07 and -93.75; P Conclusions: Reduced GLI1 levels vs BL were seen in pts with disease control. With longer f/u, sonidegib continued to demonstrate clinically meaningful tumor shrinkage, sustained responses, and prolonged progression-free survival in pts with aBCC. The 200-mg dose had a better benefit-risk profile. Clinical Responsea with Sonidegib in Pts with Advanced BCC in the Full Analysis Setb by Central Review Parameter LaBCC mBCC Sonidegib 200 mg n = 66 Sonidegib 800 mg n = 128 Sonidegib 200 mg n = 13 Sonidegib 800 mg n = 23 ORR (CR + PR; 95% CI), % CR, % PR, % Disease control (CR + PR + SD), % 57.6 (44.8-69.7) 4.5 53.0 90.9 43.8 (35.0-52.8) 1.6 42.2 81.3 7.7 (0.2-36.0) 0 7.7 92.3 17.4 (5.0-38.8) 0 17.4 91.3 TTR, median (95% CI), mo 4.0 (3.8-5.6) 3.8 (3.7-5.5) 1.8 (NE) 1.0 (1.0-2.1) DOR Events (PD or death)/responders, n Median (95% CI), mo 12-mo event-free probability (95% CI), % 7/38 NE 62.3 (33.0 -81.7 ) 11/56 15.7 (NE) 71.5 (49.7-85.1) 0/1 NE 100 (NE) 1/4 NE NE PFS PFS events, n Median (95% CI), mo 12-mo event-free probability (95% CI), % 11 22.1 (NE) 82.1 (66.9-90.8) 22 21.5 (NE) 80.4 (67.4-88.6) 6 13.1 (5.6-16.9) 58.9 (23.4-82.5) 11 11.1 (NE) 42.0 (17.6-64.9) CR, complete response; DOR, duration of response, NE, not estimable; ORR, overall response rate; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; TTR, time to tumor response. a Data cutoff: December 31, 2013. b Intent-to-treat population. Disclosure: R. Dummer: has served an advisory role, received honoraria, and research funding from Astra Zeneca, Novartis, Cephalon, MSD, BMS, GSK, Roche, Amgen, and Bayer; A. Guminski: has served an advisory role for Novartis; R. Gutzmer: has served an advisory role for Roche, MSD, BMS, Novartis, GSK; received honoraria from Roche, BMS, MSD, Janssen, Amgen, GSK, Almirall, Novartis, MerckSerono, Pfizer; and has received research funding from Roche, Novartis, Pfizer; R. Herd: has received research funding from Novartis; M. Kaatz: declares research funding from:BMBF, Bristol-Myers-Squibb, Roche Pharma AG, GlaxoSmithKline GmbH, MSD SharpD A. Stratigos: discloses consultancy for Novartis and Roche Genentech; research funding from Pfizer; and honoraria from Leo Pharma and Bristol Myers Squib; R. Plummer: discloses research funding from Novartis; T. Yi: is employed by Novartis and owns stock; A.L.S. Chang: discloses research funding from Novartis, Genentech, and Lilly; R. Kudchadkar: has served an advisory role and received honoraria from Genentech and BMS; U. Trefzer: has served an advisory role and received honoraria from Roche; J. Lear: has received honoraria from Novartis; D. Sellami: is employed by Novartis and owns stock; M.R. Migden: has received honoraria from Genentech, Novartis, Lilly; has received institutional research funding from Genentech; and has provided expert testimony on behalf of Novartis. All other authors have declared no conflicts of interest.