LBA33 - Randomized, double-blind study of sonidegib (LDE225) in patients (pts) with advanced basal cell carcinoma (BCC)

Date 27 September 2014
Event ESMO 2014
Session Melanoma and other skin tumours
Topics Anticancer Agents
Skin Cancers
Biological Therapy
Presenter Reinhard Dummer
Citation Annals of Oncology (2014) 25 (5): 1-41. 10.1093/annonc/mdu438
Authors R. Dummer1, A. Guminski2, R. Gutzmer3, L. Dirix4, K. Lewis5, P. Combemale6, R. Herd7, M. Kaatz8, C. Loquai9, A. Stratigos10, H. Schulze11, R. Plummer12, T. Yi13, A.L.S. Chang14, F. Cornelis15, R. Kudchadkar16, U. Trefzer17, J. Lear18, D. Sellami19, M.R. Migden20
  • 1Department Of Dermatology, UniversitätsSpital Zürich, Skin Cancer Center University Hospital, 8091 - Zürich/CH
  • 2Department Of Medical Oncology, Royal North Shore Hospital, St Leonards/AU
  • 3Department Of Dermatology And Allergy, Skin Cancer Center, Medizinische Hochschule Hannover, Hannover/DE
  • 4Clinical Trials Oncology, Oncologisch Centrum Sint-Augustinus, Antwerp/BE
  • 5Division Of Medical Oncology, University of Colorado Cancer Center, Aurora/US
  • 6Oncodermatology Unit, Centre Leon Bérard, Lyon/FR
  • 7Department Of Dermatology, Glasgow Royal Infirmary, Glasgow/GB
  • 8Department Of Dermatology And Allergology, University Hospital Jena, Freiburg/DE
  • 9Skin Cancer Center, Johannes Gutenberg-Universität Mainz, Mainz/DE
  • 10Department Of Dermatology, Andreas Sygros Hospital, University of Athens, Athens/GR
  • 11Department Of Dermatology, Fachklinik Hornheide, Münster/DE
  • 12Northern Centre For Cancer Care, Freeman Hospital, Newcastle Upon Tyne/GB
  • 13Biometrics & Data Management, Novartis Pharmaceuticals Corporation, East Hanover/US
  • 14Department Of Dermatology, Stanford University School of Medicine, 94063 - Redwood City/US
  • 15Cancer Center, Department Of Medical Oncology, Cliniques Universitaires Saint-Luc, Bruxelles/BE
  • 16Department Of Cutaneous Oncology, Moffitt Cancer Center, Tampa/US
  • 17Department Of Dermatology, Allergology, And Tumor Therapy, Dermatologikum Berlin, Berlin/DE
  • 18Department Of Dermatology, Manchester Royal Infirmary, Manchester/GB
  • 19Oncology Global Development, Novartis Pharmaceuticals Corporation, East Hanover/US
  • 20Departments Of Dermatology And Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston/US



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.


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.


GLI1 levels decreased from BL with both doses at wk 9 and 17 (median % changes [200 mg], −91.07 and −93.75; P < .0001 vs BL) and in pts with disease control (CR, PR, SD). Median % changes (200 mg) at wk 17 by response were CR, −99.47; PR, −90.79; SD, −96.58; PD, +10.19; unknown, −94.24. With an additional 6-mo f/u, median exposure duration was 11.0 (200 mg) and 6.6 mo (800 mg). More than half of pts with LaBCC in the 200-mg arm responded, and tumor responses in both arms were durable (Table). The safety profile of sonidegib was typical of HhPIs; the most common adverse events (200/800 mg) were muscle spasms (52%/69%), alopecia (49%/57%), and dysgeusia (41%/60%).


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
Sonidegib200 mgn = 66 Sonidegib800 mgn = 128 Sonidegib200 mgn = 13 Sonidegib800 mgn = 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.


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 Sharp&Dohme GmbH, and Janssen Cilag GmbH; 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.