Original Article

DOI: 10.1111/jdv.14542 JEADV

ORIGINAL ARTICLE

Long-term efﬁcacy and safety of sonidegib in patients with

locally advanced and metastatic basal cell carcinoma:

30-month analysis of the randomized phase 2 BOLT study

J.T. Lear,

* M.R. Migden,

K.D. Lewis,

A.L.S. Chang,

A. Guminski,

R. Gutzmer,

L. Dirix,

P. Combemale,

A. Stratigos,

R. Plummer,

H. Castro,

11,†

T. Yi,

12,†

M. Mone,

J. Zhou,

U. Trefzer,

M. Kaatz,

C. Loquai,

R. Kudchadkar,

D. Sellami,

R. Dummer

Manchester Academic Health Science Centre, University of Manchester, Manchester, UK

Departments of Dermatology and Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO, USA

Stanford University School of Medicine, Redwood City, CA, USA

Royal North Shore Hospital, St Leonards, NSW, Australia

Medizinische Hochschule Hannover, Hannover, Germany

Sint-Augustinus Ziekenhuis, Antwerp, Belgium

Anti Cancer Institute, , Lyon, France

Andreas Syggros Hospital, University of Athens, Athens, Greece

Northern Centre for Cancer Care, Freeman Hospital, Newcastle upon Tyne, UK

Novartis Pharma AG, Basel, Switzerland

Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

Dermatologikum Berlin, Berlin, Germany

University Hospital Jena, Jena, Germany

University Medical Center Mainz, Mainz, Germany

Winship Cancer Institute of Emory University, Atlanta, GA, USA

Universit

€

urich-Skin Cancer Center, University Hospital, Z

€

atsSpital Z

€

urich, Switzerland

*Correspondence: J.T. Lear. E-mail: john.lear@cmft.nhs.uk

Abstract

Background Patients with locally advanced basal cell carcinoma (laBCC) or metastatic BCC (mBCC), two difﬁcult-to-

treat populations, have had limited treatment options. Sonidegib, a hedgehog pathway inhibitor (HPI), was approved in

laBCC based on results from the BOLT trial.

Objective To evaluate long-term efﬁcacy and safety of sonidegib in laBCC and mBCC in the BOLT 18- and 30-month

analyses.

Methods BOLT (NCT01327053, ClinicalTrials.gov), a double-blind phase 2 study, enrolled patients from July 2011 until

January 2013. Eligible HPI-treatment–na

€

ıve patients with laBCC not amenable to curative surgery/radiotherapy or mBCC

were randomized 1 : 2 to sonidegib 200 mg (laBCC, n = 66; mBCC, n = 13) or 800 mg (laBCC, n = 128; mBCC,

n = 23). Tumour response was assessed per central and investigator review.

Results With 30 months of follow-up, among patients treated with sonidegib 200 mg (approved dose), objective

response rates were 56.1% (central) and 71.2% (investigator) in laBCC and 7.7% (central) and 23.1% (investigator) in

mBCC. Tumour responses were durable as follows: median duration of response was 26.1 months (central) and

15.7 months (investigator) in laBCC and 24.0 months (central) and 18.1 months (investigator) in mBCC. Five patients

with laBCC and three with mBCC in the 200-mg arm died. Median overall survival was not reached in either population;

2-year overall survival rates were 93.2% (laBCC) and 69.3% (mBCC). In laBCC, efﬁcacy was similar regardless of

aggressive or non-aggressive histology. Sonidegib 200 mg continued to have a better safety proﬁle than 800 mg, with

lower rates of grade 3/4 adverse events (43.0% vs. 64.0%) and adverse events leading to discontinuation (30.4% vs.

40.0%).

†Afﬁliation at the time the study was conducted. HC and TY are no longer

afﬁliated with Novartis Pharmaceuticals.

on behalf of European Academy of Dermatology and Venereology.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use,

distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Leon



Berar



373 Sonidegib for advanced BCC

Conclusion Sonidegib continued to demonstrate long-term efﬁcacy and safety in these populations. These data sup-

port the use of sonidegib 200 mg per local treatment guidelines.

Received: 14 March 2017; Accepted: 7 August 2017

Conﬂicts of interest

Dr Lear has served as a consultant or speaker for and received honoraria from Novartis Pharmaceuticals

Corporation. Dr Migden has participated on advisory boards and received honoraria from Genentech, Inc.;

Novartis Pharmaceuticals Corporation; and Eli Lilly and Company. Dr Lewis has received research funding paid

to the institution from Novartis Pharmaceuticals Corporation. Dr Chang is a primary investigator for and has

served as a consultant for and received research grant/funding paid to the institution from Novartis

Pharmaceuticals Corporation. Dr Guminski has participated on advisory boards for Bristol-Myers Squibb, Pﬁzer

Inc. and Sanoﬁ; received honoraria from Novartis Pharmaceuticals Corporation; and received travel support from

Astellas and Bristol-Myers Squibb. Dr Gutzmer has received research grants paid to the institution from Roche,

Novartis Pharmaceuticals Corporation, Johnson & Johnson and Pﬁzer Inc.; received honoraria from Roche,

Bristol-Myers Squibb, MSD, GlaxoSmithKline, Novartis Pharmaceuticals Corporation, Merck Serono, Almirall,

Janssen, Amgen Inc., Galderma and Boehringer Ingelheim; and served as a consultant for Roche, Bristol-Myers

Squibb, MSD, GlaxoSmithKline, Novartis Pharmaceuticals Corporation, Almirall, LEO Pharma Inc., Amgen Inc.

and Pﬁzer Inc. Dr Dirix has no conﬂict of interest to declare. Dr Combemale has no conﬂict of interest to declare.

Dr Stratigos has received a research grant from Roche and Novartis Pharmaceuticals Corporation and received

honoraria from LEO Pharma Inc., Meda Pharmaceuticals Inc. and Janssen-Cilag. Dr. Plummer has participated

on an advisory board and received honoraria from Astex, Roche, Bristol-Myers Squibb, Vertex, Bayer, Pierre

Faber, Novartis Pharmaceuticals Corporation and Clovis Oncology. Dr Castro was an employee of Novartis

during the development of this manuscript and is currently an employee of Bristol-Myers Squibb. Dr Yi was an

employee of Novartis during the development of this manuscript. Dr Mone is an employee and stockholder of

Novartis Pharmaceuticals Corporation. Dr Zhou is an employee of Novartis Pharmaceuticals Corporation. Dr

Trefzer has been an advisor for and received honoraria from F. Hoffmann-La Roche Ltd, participated on an

advisory board and received honoraria from MSD, and has been a speaker and received honoraria from Novartis

Pharmaceuticals Corporation. Dr Kaatz has participated on advisory boards and received honoraria from Roche,

MSD, Novartis Pharmaceuticals Corporation, Bristol-Myers Squibb and Janssen. Dr Loquai has served as a

consultant for Bristol-Myers Squibb, Roche, Novartis Pharmaceuticals Corporation, Amgen, BioNTech and MSD.

Dr Kudchadkar has participated on an advisory board and received honoraria from Bristol-Myers Squibb and

Genentech, Inc. Dr Sellami is an employee and stockholder of Novartis Pharmaceuticals Corporation. Dr Dummer

has received research funding from Novartis Pharmaceuticals Corporation, MSD, Bristol-Myers Squibb, Roche

and GlaxoSmithKline and has served as a consultant or participated on an advisory board for Novartis

Pharmaceuticals Corporation, MSD, Bristol-Myers Squibb, Roche, GlaxoSmithKline, Amgen and Takeda.

Funding sources

This study was funded by Novartis Pharmaceuticals Corporation. Novartis Pharmaceuticals Corporation was

involved in design and conduct of the study; collection, management, analysis and interpretation of data;

preparation, review and approval of the manuscript; and decision to submit the manuscript for publication.

Introduction

Patients with locally advanced basal cell carcinoma (laBCC) or

metastatic BCC (mBCC) have historically had limited treatment

options.

Surgery, the primary course of treatment for most

BCCs, and radiotherapy are often not viable options in advanced

BCC.

1–3

In recent years, hedgehog (Hh) pathway inhibitors

(HPIs) were developed to block aberrant Hh signalling that is

found in most sporadic BCCs; HPIs have demonstrated efﬁcacy

in patients with laBCC and those with mBCC.

4–13

Sonidegib (LDE225), which inhibits Hh signalling by target-

ing the Hh pathway component smoothened,

was approved

(200 mg once daily) in the United States and Europe for the

treatment of laBCC, in Australia for the treatment of laBCC and

mBCC and in Switzerland for the treatment of advanced BCC

that cannot be treated with curative surgery or radiotherapy.

14–17

These approvals were based on results from the pivotal phase 2

Basal Cell Carcinoma Outcomes With LDE225 Treatment

(BOLT) study (NCT01327053), in which the primary analysis

on behalf of European Academy of Dermatology and Venereology.

374 Lear et al.

was performed using data based on 6 months of follow-up.

8,9

Here, we report long-term efﬁcacy and safety results from BOLT,

with up to 30 months of follow-up after the last patient was ran-

domized.

Materials and methods

BOLT study design and patients

BOLT is a randomized, double-blind, phase 2 study conducted

in 58 centres across 12 countries that assessed the efﬁcacy and

safety of sonidegib 200 and 800 mg once daily, as described pre-

viously.

Patients ≥18 years of age with histologically conﬁrmed

disease, either laBCC not amenable to curative surgery or radio-

therapy or mBCC, were eligible. Patients were required to have

adequate organ function and a World Health Organization

(WHO)

performance status ≤2. Patients with previous HPI

treatment were not eligible. Full inclusion and exclusion criteria

were reported previously.

Patients were randomized 1 : 2 to 200 or 800 mg based on

previous data suggesting that 800 mg would show better efﬁ-

cacy.

Randomization was performed using the central Interac-

tive Response Technology system (Cenduit, Allentown, PA).

Stratiﬁcation of patients was based on disease type (laBCC vs.

mBCC), histological subtype (aggressive vs. non-aggressive) and

geographic region. All patients and study personnel were blinded

until the time of the primary analysis.

The study protocol was approved at each centre by indepen-

dent ethics committee or institutional review board, and all

patients provided written informed consent prior to enrolment.

Sonidegib treatment and assessments

Sonidegib capsules were taken orally on a once-daily continuous

schedule until disease progression, intolerable toxicity, with-

drawal of patient consent, discontinuation at the discretion of

the investigator, death or study termination. Tumour evalua-

tions were conducted at baseline, during treatment and post-

treatment follow-up (weeks 5 and 9, then every 8 weeks during

year 1 and every 12 weeks thereafter), and at discontinuation

using BCC-modiﬁed Response Evaluation Criteria In Solid

Tumors (mRECIST)

8,9

for laBCC and RECIST v1.1

for mBCC.

mRECIST

8,9

is a stringent multimodal assessment tool that

incorporates magnetic resonance imaging (MRI) per RECIST

v1.1

[≥30% reduction in the sum of the longest diameters of

target lesions required for a partial response (PR)], standard and

annotated color photography per bidimensional WHO guideli-

nes

(≥50% reduction in the sum of the products of perpendic-

ular diameters of target lesions required for a PR), and histology

in multiple biopsies surveying the lesion area to determine a

composite overall response. Complete responses (CRs) and PRs

had to be conﬁrmed on repeat assessments separated by

≥4 weeks. Fresh tumour biopsies were used to conﬁrm CRs in

the presence of confounding ulceration, cyst formation and/or

scarring/ﬁbrosis. An independent review committee re-evaluated

all central assessments for patients with laBCC.

In a prespeciﬁed analysis, responses were re-evaluated in

patients with laBCC using BCC-RECIST-like, less-stringent cri-

teria similar to those used in ERIVANCE, a phase 2 study of vis-

modegib.

Both mRECIST and BCC-RECIST-like integrate

MRI per RECIST v1.1, standard and annotated color photogra-

phy per WHO guidelines, and histology; however, the algorithm

used to determine overall response for each is different: multiple

scenarios exist for which the response is lower with mRECIST

vs. BCC-RECIST-like (Table S1, Supporting Information).

Blood samples for pharmacokinetic (PK) assessments were

collected from all patients through week 69; trough plasma con-

centrations were analysed at predose on weeks 1, 3, 5 and 9, then

every 4 weeks through week 21 and every 12 weeks thereafter.

Adverse events (AEs) were monitored throughout the treat-

ment period until 30 days following the last sonidegib dose

according to Common Terminology Criteria for Adverse Events

v4.03.

BOLT study outcomes

The primary study endpoint was objective response rate (ORR;

proportion of patients with a best overall response of CR or PR)

per central review. Secondary endpoints included ORR per

investigator review; CR rate, duration of response (DOR) and

progression-free survival (PFS) per central and investigator

review; overall survival (OS); and safety.

Statistical methods

Results were analysed based on two database cut-offs: 11 July

2014 and 10 July 2015 (18 and 30 months after the last patient

was randomized, respectively). ORR and CR rates were esti-

mated with 95% CIs. Kaplan–Meier nonparametric maximum

likelihood estimates of median time and 95% CIs were estimated

for DOR and PFS for each arm and by disease. Statistical com-

parisons of the 200- and 800-mg arms were not planned. Addi-

tional details on the statistical methods used in the study were

published previously.

8,9

Results

Patient demographics and disposition

Two-hundred and thirty patients with laBCC (n = 194) or mBCC

(n = 36) were enrolled between 20 July 2011 and 10 January

2013. Patients were randomized to sonidegib 200 mg (laBCC,

n = 66; mBCC, n = 13) or 800 mg (laBCC, n = 128; mBCC,

n = 23; Fig. S1, Supporting Information). Baseline demographics

were well balanced between arms.

8,9

Most patients with laBCC

(200 mg, 56.1%; 800 mg, 58.6%) had aggressive tumour histol-

ogy. By the data cut-off for the 18-month analysis (median fol-

low-up, 26.3 months), 87.0% of patients (200 mg, 86.1%;

800 mg, 87.4%) had discontinued treatment; by the data cut-off

on behalf of European Academy of Dermatology and Venereology.

375 Sonidegib for advanced BCC

for the 30-month analysis (median follow-up, 38.2 months),

93.0% (200 mg, 92.4%; 800 mg, 93.4%) had discontinued treat-

ment (Fig. S1, Supporting Information). The most common

reasons for treatment discontinuation were AEs [30-month anal-

ysis (200 vs. 800 mg), 29.1% vs. 37.7%], progressive disease

(36.7% vs. 14.6%) and patient decision (10.1% vs. 21.9%).

Efﬁcacy in patients with laBCC

ORRs in patients with laBCC increased compared with the pri-

mary analysis (Table 1; Table S2, Supporting Information).

Tumour shrinkage was observed in most patients (Fig. S2, Sup-

porting Information). In the 30-month analysis, ORRs in the

200-mg arm were 56.1% (central review) and 71.2% (investiga-

tor review); in the 800-mg arm, ORRs were 45.3% and 58.6%,

respectively. Per central review, 26 of 37 patients with laBCC in

the 200-mg arm who achieved an objective response by the 30-

month data cut-off maintained the response (Fig. 1a; Fig. S3a,

Supporting Information), and the estimated median DOR in the

200-mg arm was 26.1 months (15.7 months per investigator

review). Among patients with laBCC who responded to treat-

ment in the 800-mg arm, 38 of 58 maintained an objective

response per central review (Fig. S3b, Fig. S4a, Supporting Infor-

mation), and the estimated median DOR was 23.7 months

(26.0 months per investigator review). At the 30-month data

cut-off, the median durations of PFS among patients with laBCC

were 22.1 months (central review) and 19.4 months (investiga-

tor review) in the 200-mg arm (Fig. 1b) and 22.0 and

28.0 months, respectively, in the 800-mg arm (Fig. S4b, Sup-

porting Information).

Response in patients with laBCC was also assessed using

BCC-RECIST–like criteria. Although ORRs and DORs were sim-

ilar with both sets of criteria, CR rates were higher with BCC-

RECIST-like criteria (Table S3, Supporting Information). In the

200-mg arm, CR rates in the 30-month analysis per central

review were 21.2% (BCC-RECIST-like) vs. 4.5% (mRECIST).

Efﬁcacy was similar among patients with laBCC with aggres-

sive or non-aggressive histological subtypes. In the 30-month

analysis, ORRs in patients with aggressive vs. non-aggressive his-

tology in the 200-mg arm were 59.5% vs. 51.7% per central

review and 70.3% vs. 72.4% per investigator review (Table 1);

respective ORRs in the 800-mg arm were 44.0% vs. 47.2% per

central review and 54.7% vs. 64.2% per investigator review

(Table S2, Supporting Information). Tumour responses were

durable regardless of tumour aggressiveness.

At the time of the 18-month analysis, efﬁcacy in patients with

laBCC was also assessed based on tumour burden at baseline.

Responses were found to be durable regardless of tumour bur-

den with both doses, with >58% of patients in each group hav-

ing responses lasting >6 months (Table S4, Supporting

Information).

Five patients with laBCC in the 200-mg arm died by the 30-

month analysis; median OS was not yet reached and the

estimated 2-year OS was 93.2% (Table 1; Fig. 2). In the 800-mg

arm, 11 patients with laBCC died; median OS was not reached

and the estimated 2-year OS was 90.7% (Table S2, Fig. S5, Sup-

porting Information). Numerically more deaths were reported

in patients with aggressive (200 mg, 4; 800 mg, 8) vs. non-

aggressive (200 mg, 1; 800 mg, 3) histology; median OS was not

reached in either population with either dose, and 2-year OS

rates were 91.8% vs. 94.7% (200 mg) and 86.6% vs. 95.8%

(800 mg).

Efﬁcacy in patients with mBCC

Tumour shrinkage was reported in most patients with mBCC

(Fig. S6, Supporting Information). ORRs in the 200-mg arm

were 7.7% (central review) and 23.1% (investigator review) in

the 30-month analysis, and estimated median DOR was

24.0 months (central review) and 18.1 months (investigator

review; Table 2). ORRs in the 800-mg arm were 17.4% (central

review) and 34.8% (investigator review); estimated median DOR

was not reached per central review and was 10.2 months per

investigator review (Table S5, Supporting Information). The dis-

ease control rate (CR + PR + stable disease) was high with soni-

degib 200 mg (central, 92.3%; investigator, 84.6%) and 800 mg

(central, 91.3%; investigator, 82.6%). The median PFS with

sonidegib 200 mg was 13.1 months per central and investigator

review (Fig. 1b) and with sonidegib 800 mg was 11.1 months

per central review and 14.3 months per investigator review

(Fig. S4b, Supporting Information).

In the 30-month analysis, 11 patients (200 mg, 3; 800 mg, 8)

with mBCC had died. With sonidegib 200 mg, the estimated

median OS was not reached, and the estimated 2-year OS was

69.3% (Fig. 2). With sonidegib 800 mg, the estimated median

OS was 36.7 months, and the estimated 2-year OS was 69.1%

(Fig. S5, Supporting Information).

Sonidegib PK

Sonidegib PK was evaluated based on the 18-month data cut-off

(by which time all patients had completed the scheduled PK

assessments). Mean sonidegib plasma concentrations rose until

week 13–17 with daily 200 and 800 mg dosing (Fig. S7, Sup-

porting Information). By week 17, an approximate steady state

was reached for both doses. Sonidegib demonstrated under

dose-proportional increases in plasma exposure between the two

doses tested: at week 17, the geometric mean trough concentra-

tion was 689 ng/mL with 200 mg and 1574 ng/mL with 800 mg,

corresponding to a 2.3-fold increase in trough concentration

over a fourfold dose increase.

Safety

No new safety concerns emerged with an additional 24 months

of follow-up since the primary analysis. At the 30-month data

cut-off, the median duration of exposure was 11.0 months

(range, 1.3–41.3 months) in the 200-mg arm and 6.6 months

on behalf of European Academy of Dermatology and Venereology.

376 Lear et al.

Table 1 Efﬁcacy in patients with laBCC treated with sonidegib 200 mg by central and investigator review

Patients with laBCC Sonidegib 200 mg QD

Primary analysis* 18-month analysis† 30-month analysis‡

All patients All patients All patients Patients with Patients with

n = 66 n = 66 n = 66 aggressive non-aggressive

histology§ histology¶

n = 37 n = 29

ORR, n (%); 95% CI**

Central review 31 (47.0); 34.6–59.7 37 (56.1); 43.3–68.3 37 (56.1); 43.3–68.3 22 (59.5); 42.1–75.2 15 (51.7); 32.5–70.6

Investigator review 43 (65.2); 52.4–76.5 47 (71.2); 58.7–81.7 47 (71.2); 58.7–81.7 26 (70.3); 53.0–84.1 21 (72.4); 52.8–87.3

BOR, n (%)††

Central review 2 (3.0) 3 (4.5) 3 (4.5) 2 (5.4) 1 (3.4)

Investigator review 5 (7.6) 6 (9.1) 6 (9.1) 3 (8.1) 3 (10.3)

Central review 29 (43.9) 34 (51.5) 34 (51.5) 20 (54.1) 14 (48.3)

Investigator review 38 (57.6) 41 (62.1) 41 (62.1) 23 (62.2) 18 (62.1)

Central review 29 (43.9) 23 (34.8) 23 (34.8) 12 (32.4) 11 (37.9)

Investigator review 16 (24.2) 14 (21.2) 13 (19.7) 8 (21.6) 5 (17.2)

Central review 1 (1.5) 1 (1.5) 1 (1.5) 1 (2.7) 0

Investigator review 1 (1.5) 1 (1.5) 1 (1.5) 0 1 (3.4)

Unknown

Central review 5 (7.6) 5 (7.6) 5 (7.6) 2 (5.4) 3 (10.3)

Investigator review 6 (9.1) 4 (6.1) 5 (7.6) 3 (8.1) 2 (6.9)

DOR‡‡

Events§§/responders, n/n;

KM median (95% CI), months

Central review 4/31; NR 10/37; NR 11/37; 26.1 (NE) 7/22; 26.1 (NE) 4/15; NR

Investigator review 10/43; 20.2 (10.1–20.2) 21/47; 14.3 (12.0–20.2) 22/47; 15.7 (12.0–20.2) 9/26; 20.2 (NE) 13/21; 15.7 (11.0–20.2)

PFS¶¶

Events§§, n; KM median

(95% CI), months

Central review 7; NR 15; 22.1 (NE) 16; 22.1 (NE) 11; 22.1 (NE) 5; NR

Investigator review 15; 16.6 (13.7–22.0) 26; 19.4 (16.6–22.6) 28; 19.4 (16.6–

23.6) 12; 19.0 (NE) 16; 19.4 (9.2–22.6)

OS***

Deaths, n; KM median 1; NR 3; NR

5; NR 4; NR 1; NR

(95% CI), months

2-year OS (95% CI), % – – 93.2 (80.2–97.8) 91.8 (70.9–97.9) 94.7 (68.1–99.2)

BOR, best overall response; CR, complete response; DOR, duration of response; KM, Kaplan–Meier; laBCC, locally advanc ed basal cell carcinoma; NE, not

estimable; NR, not reached; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progressio n-free survival; PR, partial

response; QD, once daily; SD, stable disease; –, indicates not reported.

*Data cut-off, 28 June 2013; median follow-up (200- and 800-mg arms), 13.9 months.

†Data cut-off, 11 July 2014; median follow-up (200- and 800-mg arms), 26.3 months.

‡Data cut-off, 10 July 2015; median follow-up (200- and 800-mg arms), 38.2 months.

§Aggressive histological subtypes of BCC include micronodular, inﬁltrative, multifocal, basosquamous and sclerosing.

¶Non-aggressive histological subtype s of BCC include nodular and superﬁcial.

**Proportion of patients with a BOR of CR or PR on repeat assessments ≥4 weeks apart.

††Best response recorded from the time of randomization until the earliest occurrence of disease progression, start of other antineoplastic therapy or data

cut-off date.

‡‡Time from ﬁrst observed objective response (CR or PR) until disease progression or death due to any cause (responder data only).

§§Progressive disease or death due to any cause.

¶¶Time from randomization to ﬁrst documented disease progression or death due to any cause.

***Time from randomization to the date of death due to any cause or the last date the patient was known to be alive.

(range, 0.3–43.5 months) in the 800-mg arm. The incidence of fatigue, appetite decreased, myalgia and vomiting (Fig. 3). The

many of the most common AEs was lower with sonidegib most common AEs reported in patients with laBCC (Fig. S8,

200 mg than 800 mg, including muscle spasms, alopecia, dys- Supporting Information) and mBCC (Fig. S9, Supporting Infor-

geusia, nausea, weight decreased, creatine kinase (CK) increased, mation) were similar. Among all patients, grade 3/4 AEs

on behalf of European Academy of Dermatology and Venereology.

377 Sonidegib for advanced BCC

(a)

0 2 4 6 8 10 12 14 16 18

Time since response (months)

Probability of remaining in

response (%)

Central review

20 22 24 26 28 30 32 34 36

100

0 2 4 6 8 10 12 14 16 18

Time since response (months)

Investigator review

20 22 24 26 28 30 32 34 36 38 40

100

(b)

Kaplan–Meier median: 15.67 months

Censoring times

laBCC (n/N = 22/47)

Kaplan–Meier median: 26.09 months

Censoring times

laBCC (n/N = 11/37)

Number of patients still at risk

laBCC 35 31 23 21 18 11 9 7 7 7 7 6 5 1 1 1 1 0 47

Number of patients still at risk

laBCC 45 42 30 26 26 23 15 12 12 79 6 5 4 3 2 2 1 1 0

Probability of remaining in

response (%)

Central review

Kaplan–Meier medians:

mBCC: 13.11 months

laBCC: 22.11 months

Censoring times

mBCC (

n/N = 8/13)

laBCC (n/N = 16/66)

Probability of event-free

0 2 4 6 8 10 12 14 16 18

Time since randomization (months)

Investigator review

20 22 24 26 28 30 32 34 36 38 40

Kaplan–Meier medians:

mBCC: 13.11 months

laBCC: 19.35 months

Censoring times

mBCC (

n/N= 9/13)

laBCC (n/N = 28/66)

100 100

Probability of event-free

survival (%)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38

Time since randomization (months)

Number of patients still at risk Number of patients still at risk

mBCC 13 12 10 8 8 5 5 4 4 3 2 2 2 1 1 1 1 0 0 0 mBCC 13 11 11 10 10 6 6 5 5 4 2 1 1 1 1 1 1 1 0 0 0

laBCC 66 60 54 47 39 32 24 17 14 12 10 10 7 6 6 5 3 3 3 0 laBCC 66 60 56 50 39 33 28 26 23 18 14 13 8 7 7 5 3 3 3 1 0

Figure 1 Duration of response (DOR) in patients with locally advanced basal cell carcinoma (laBCC) and progression-free survival (PFS)

by central and investigator review in patients with laBCC or metastatic BCC (mBCC) treated with sonidegib 200 mg. (a) Kaplan–Meier

plots of DOR in patients with laBCC who responded to treatment with sonidegib 200 mg per central (n = 37) and investigator (n = 47)

review. (b) Kaplan–Meier plots of PFS in patients with laBCC (n = 66) and mBCC (n = 13) treated with sonidegib 200 mg per central and

investigator review.

occurred less frequently with sonidegib 200 mg (43.0%) than

with 800 mg (64.0%); similar results were reported for grade 3/4

AEs suspected to be related to treatment, with a lower incidence

in the 200-mg arm (30.4%) than the 800-mg arm (43.3%).

Increased CK was the most common grade 3/4 AE (10.9%;

200 mg, 6.3%; 800 mg, 13.3%); only one additional patient

(800 mg) had a grade 3/4 increase in CK after the primary analy-

sis cut-off. The median time to onset (range) of grade 2/3/4 CK

elevation was 12.9 (2–39) and 6.7 (2–40) weeks in the 200- and

800-mg arms, respectively; the median time to resolution (95%

CI) to grade ≤1 was 12.0 (8.0–14.0) and 15.0 (9.0–15.0) days,

respectively.

AEs requiring dose interruption and/or reduction were

reported in 43.0% and 66.7% of patients in the 200- and 800-mg

arms, respectively; the most common AEs leading to dose inter-

ruption/reduction (200 mg vs. 800 mg) were muscle spasms

(1.3% vs. 16.7%), CK increased (6.3% vs. 12.0%), and nausea

(6.3% vs. 12.0%). AEs leading to treatment discontinuation also

occurred less frequently with the 200-mg dose (30.4%) than the

800-mg dose (40.0%), with most (60.7%; 200 mg, 54.2%;

800 mg, 63.3%) being grade 1/2. The most common AEs leading

to discontinuation (200 mg vs. 800 mg) were muscle spasms

(5.1% vs. 8.0%), weight decreased (2.5% vs. 6.0%), dysgeusia

(3.8% vs. 4.7%) and alopecia (1.3% vs. 6.0%).

Serious AEs (SAEs) irrespective of cause were reported in

20.3% and 38.7% of patients treated with sonidegib 200 mg and

800 mg, respectively (Table S6, Supporting Information); SAEs

related to sonidegib treatment occurred in 3.8% and 16.0%,

respectively. Increased CK and rhabdomyolysis were the most

commonly reported SAEs among all patients (2.6% each;

200 mg, 1.3% each; 800 mg, 3.3% each); due to a lack of renal

impairment, none of the cases of rhabdomyolysis were con-

ﬁrmed by an independent review and adjudication committee of

experts on muscle toxicity.

On-treatment deaths were reported in eight patients

(200 mg, 1; 800 mg, 7), four of whom had laBCC (200 mg, 1;

800 mg, 3) and four had mBCC (800 mg, 4); none of these

deaths were considered treatment related. Four on-treatment

deaths [two due to progressive disease (both with mBCC) and

one each due to congestive cardiac failure (laBCC) and cardiac

death (laBCC)] were reported in the primary analysis,

and

four occurred following the primary analysis, including one

on behalf of European Academy of Dermatology and Venereology.

378 Lear et al.

Probability of survival (%)

100

Time since randomization (months)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46

Kaplan–Meier medians:

mBCC: NE

laBCC: NE

Censoring times

mBCC (n/N = 3/13)

laBCC (n/N = 5/66)

Number of patients still at risk

13mBCC 13 12 12 12 10 10 10 10 10 9 6 6 6 6 5 4 3 2 2 1 1 1 0

laBCC 66 66 65 63 58 55 53 49 48 45 41 39 38 37 35 32 21 18 13 6 3 1 1 0

Figure 2 Overall survival (OS) in patients with locally advanced basal cell carcinoma (laBCC) or metastatic BCC (mBCC) treated with

sonidegib 200 mg. Kaplan–Meier plot of OS in patients with laBCC (n = 66) or mBCC (n = 13) treated with sonidegib 200 mg. NE, not

estimable.

patient treated with sonidegib 200 mg (laBCC) who died of

acute respiratory distress on study day 612, and three patients

treated with 800 mg who died of cardiac arrest (laBCC), sepsis

(mBCC) and respiratory arrest (mBCC) on study days 349,

391 and 433, respectively.

Discussion

With long-term follow-up in BOLT, sonidegib 200 and 800 mg

continued to demonstrate sustained efﬁcacy in patients with

laBCC (regardless of histology) and mBCC. Since the time of the

primary analysis, ORRs in the 200-mg arm improved in patients

with laBCC and remained similar in patients with mBCC. Higher

rates of response were observed by investigator vs. central review,

which could be due to investigators having the opportunity to

physically examine lesions that are often complicated by post-

treatment ulceration, cyst formation, scarring/ﬁbrosis and ill-

deﬁned borders.

Responses in patients with laBCC were durable

regardless of tumour burden at baseline, with most patients (cen-

tral, 70.3%; investigator, 53.2%) who responded to treatment

with sonidegib 200 mg maintaining an objective response at the

30-month data cut-off. Moreover, when responses in patients

with laBCC were scored using less-stringent response criteria

(BCC-RECIST-like criteria, similar to criteria used in ERI-

VANCE

), CR rates were similar to those reported with vismod-

egib in ERIVANCE.

This analysis underscores the efﬁcacy of

sonidegib in patients with laBCC. However, efﬁcacy in patients

with disease that recurred following prior HPI therapy is

unknown because these patients were excluded from BOLT.

The rate of survival in patients with BCC is extremely

high

21,22

; however, the prognosis for patients with advanced

BCC is less clear.

In patients with laBCC, the survival rate is

unknown due in part to a lack of reporting of these data in

patient registries. In patients with mBCC, the median survival

prior to 1990 was estimated to be  8 months and recently has

been estimated to be as high as  7 years due to improved thera-

pies, including HPIs.

23–25

In BOLT, the median OS in patients

with laBCC was not reached with either dose by the 30-month

analysis, and the estimated 2-year OS was >90% in both arms; in

patients with mBCC, the median OS was not yet reached with

sonidegib 200 mg and was 36.7 months with 800 mg, and the

estimated 2-year OS was  69% in both arms. These survival

rates are similar to those reported with vismodegib [85.5%

(laBCC) and 62.3% (mBCC) at 2 years in ERIVANCE], the only

other approved HPI.

The PK of sonidegib is different from that of vismodegib. Vis-

modegib exposure did not increase above the 150-mg daily

dosage due to saturated protein binding, and the half-life was

4 days after repeated dosing.

26,27

In contrast, sonidegib exposure

increased 2.3-fold between 200 and 800 mg and reached an

approximate steady state at 17 weeks. Previously, PK expo-

sure–response and exposure–safety analyses including the 200-

and 800-mg doses (based on the 18-month data cut-off) showed

no exposure–efﬁcacy relationship but a reduced risk of grade 3/4

800 mg. Additionally, in population PK model, sonidegib

CK elevation with lower exposure, further supporting the

favourable beneﬁt–risk proﬁle of sonidegib 200 mg vs.

had a predicted elimination half-life of 29.6 days and an accu-

mulation ratio of 21.

Sonidegib 200 mg continued to be better tolerated than soni-

degib 800 mg, and no additional safety concerns were reported

on behalf of European Academy of Dermatology and Venereology.

379 Sonidegib for advanced BCC

Table 2 Efﬁcacy in patients with mBCC treated with sonidegib 200 mg by central and investigator review

Patients with mBCC Sonidegib 200 mg QD

n = 13

Primary analysis* 18-month analysis† 30-month analysis‡

ORR, n (%); 95% CI§

Central review 2 (15.4); 1.9–45.4 1 (7.7)¶; 0.2–36.0 1 (7.7); 0.2–36.0

Investigator review 3 (23.1); 5.0–53.8 3 (23.1); 5.0–53.8 3 (23.1); 5.0–53.8

BOR, n (%)**

Central review 0 0 0

Investigator review 0 0 0

Central review 2 (15.4) 1 (7.7)¶ 1 (7.7)

Investigator review 3 (23.1) 3 (23.1) 3 (23.1)

Central review 10 (76.9) 11 (84.6) 11 (84.6)

Investigator review 8 (61.5) 8 (61.5) 8 (61.5)

Central review 0 0 0

Investigator review 2 (15.4) 2 (15.4) 2 (15.4)

Unknown

Central review 1 (7.7) 1 (7.7) 1 (7.7)

Investigator review 0 0 0

DOR††

Events/responders, n/n‡‡;

KM median (95% CI), months

Central review 0/2; NR 0/1; NR 1/1; 24.0 (NE)

Investigator review 0/3; NR 1/3; 17.7 (NE) 2/3; 18.1 (17.7–18.4)

PFS§§

Events, n; KM median (95% CI), months‡‡

Central review 4; 13.1 (5.6–13.1) 6; 13.1 (NE) 8; 13.1 (5.6–33.1)

Investigator review 7; 13.1 (9.2–16.6) 8; 13.1 (NE) 9; 13.1 (9.2–19.4)

OS¶¶

Deaths, n; KM median (95% CI), months 1; NR 3; NR 3; NR

2-year OS (95% CI), % – – 69.3 (31.2–89.1)

BOR, best overall response; CR, complete response; DOR, duration of response; KM, Kaplan–Meier; mBCC, metastatic basal cell carcinoma; NE, not estim-

able; NR, not reached; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response;

QD, once daily; SD, stable disease; –, indicates not reported.

*Data cut-off, 28 June 2013; median follow-up (200- and 800-mg arms), 13.9 months.

†Data cut-off, 11 July 2014; median follow-up (200- and 800-mg arms), 26.3 months.

‡Data cut-off, 10 July 2015; median follow-up (200- and 800-mg arms), 38.2 months.

§Proportion of patients with a BOR of CR or PR on repeat assessments ≥4 weeks apart.

¶BOR of one patient changed from a PR to SD due to identiﬁcation of a new lesion by central rereview in a photograph received after the cut-off for the primary

analysis (28 June 2013).

**Best response recorded from the time of randomization until the earliest occurrence of disease progression, start of other antineoplastic therapy or data cut-

off date.

††Time from ﬁrst observed objective response (CR or PR) until disease progression or death due to any cause (responder data only).

‡‡Progressive disease or death due to any cause.

§§Time from randomization to ﬁrst documented disease progression or death due to any cause.

¶¶Time from randomization to the date of death due to any cause or the last date the patient was known to be alive.

with either dose. Lower incidences of grade 3/4 AEs, SAEs and

AEs leading to discontinuation were observed with 200 mg vs.

800 mg. The majority of the most common AEs were generally

grade 1 or 2 and were similar to those reported with other

HPIs

10–12,30–39

; muscle-related AEs and the increase in CK that

can accompany these AEs are thought to be a class effect of

HPIs.

11,12,30,31,35,39

Muscle-related AEs were effectively managed

with dose adjustments or interruptions. In the future, patients

who experience sonidegib-related AEs will be managed using this

approach in an attempt to prolong exposure and enhance

on behalf of European Academy of Dermatology and Venereology.

380 Lear et al.

All grades (%)

0 102030405060708090 100

800

200

800

200

800

200

800

200

800

200

800

200

800

200

800

200

800

200

800

200

800

200

Grade 1

Grade 2

Grade 3

Grade 4

Muscle

spasms

Alopecia

Dysgeusia

Nausea

Diarrhoea

Weight

decreased

increased

Fatigue

Appetite

decreased

Myalgia

Vomiting

AEs in ≥20% of all patients (laBCC + mBCC)

treatment beneﬁt. In addition, future clinical trials designed to

optimize the treatment regimen of HPIs may further improve

outcomes.

Overall, these results support the use of sonidegib 200 mg as a

treatment option for patients with advanced BCC according to

local guidelines.

14–17

Acknowledgements

We thank the patients and their families, the study investigators,

their clinical teams and the study site staff, and the members of

the study committees. We also thank the Novartis BOLT clinical

study team, Yi Wu of Novartis for statistical support, the inde-

pendent data monitoring committee (Mark R. Pittelkow, J

€

urgen

C. Becker and Stephen L. George), the efﬁcacy independent

review (Vernon K. Sondak, James Grichnik and Lawrence

Schwartz), and the muscle safety review and adjudication com-

mittee (Robert S. Rosenson, Vinay Chaudhry and Paul D.

Thompson). Medical editorial assistance was provided by Karen

Kaluza, PhD (ArticulateScience LLC) and funded by Novartis

Pharmaceuticals Corporation.

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Supporting information

Additional Supporting Information may be found in the online

version of this article:

Table S1. Composite overall response in locally advanced basal

cell carcinoma (laBCC) determined by mRECIST and BCC-

RECIST-like criteria

Table S2. Efﬁcacy in patients with locally advanced basal cell

carcinoma (laBCC) treated with sonidegib 800 mg by central

and investigator review

Table S3. Efﬁcacy in patients with locally advanced basal cell

carcinoma (laBCC) by central and investigator review per BCC-

recist-like criteria (30-month analysis)

Table S4. Efﬁcacy in patients with locally advanced basal cell

carcinoma (laBCC) by baseline tumor burden by treatment arm

(18-month analysis)

Table S5. Efﬁcacy in patients with metastatic basal cell carci-

noma (mBCC) treated With Sonidegib 800 mg by central and

investigator review

Table S6. Serious adverse events reported in ≥1% of patients in

either arm, regardless of causality (30-month analysis)

Figure S1. BOLT trial proﬁle.

Figure S2. Waterfall plots of best change from baseline in the

size of target lesions in patients with locally advanced basal cell

carcinoma (laBCC).

Figure S3. Duration of response (DOR) in patients with locally

advanced basal cell carcinoma (laBCC).

Figure S4. Kaplan–Meier plots of duration of response (DOR)

in patients with locally advanced basal cell carcinoma (laBCC)

and of progression-free survival (PFS) in patients with laBCC

and metastatic BCC (mBCC) treated with sonidegib 800 mg by

central and investigator review.

Figure S5. Kaplan–Meier plot of overall survival (OS) in patients

with locally advanced basal cell carcinoma (laBCC) and meta-

static BCC (mBCC) treated with sonidegib 800 mg.

Figure S6. Waterfall plots of best change from baseline in the

size of target lesions in patients with metastatic basal cell carci-

noma (mBCC).

Figure S7. Mean trough-concentration time proﬁles for sonide-

gib 200 or 800 mg.

Figure S8. Adverse events (AEs), regardless of causality, reported

in ≥20% of patients with locally advanced basal cell carcinoma

(laBCC) treated with sonidegib, by treatment arm.

Figure S9. Adverse events (AEs), regardless of causality, reported

in ≥20% of patients with metastatic basal cell carcinoma

(mBCC) treated with sonidegib, by treatment arm.

on behalf of European Academy of Dermatology and Venereology.