The safety and efficacy of sonidegib for the treatment of locally advanced basal cell

carcinoma

Introduction:

Basal cell carcinomas (BCCs) are the commonest malignancy in the Western world.

Locally advanced BCCs (laBCCs) represent tumours that have developed in difficult-

to-treat facial sites, aggressively recurrent tumours, large neglected tumours and

those in which current treatment options are excluded by clinical or patient-driven

criteria. It is estimated laBCCs represent 1% of BCCs.

Areas covered:

Sonidegib is an oral hedgehog pathway inhibitor with a novel structure. It has

recently been licensed for the treatment of laBCC.

This article provides a comprehensive review of the literature regarding sonidegib,

detailing the pharmacology of the compound, clinical trial data, competitor

compounds and a future perspective.

Expert commentary:

Sonidegib is a novel smoothened (SMO) inhibitor with comparable efficacy to

vismodegib, with patient response rates of 44% (sonidegib) and 43% (vismodegib).

The adverse effect profile of these two treatments is similar with the main effects

being considered to be class effects of SMO inhibitors.

Keywords

Basal cell carcinoma; locally advanced basal cell carcinoma; sonidegib; hedgehog

pathway inhibitors; smoothened inhibitors; small-molecule inhibitors.

1. Introduction

Basal cell carcinoma (BCC) is the commonest malignancy in the Western world, with

an excellent prognosis in the majority of cases.1,2 Excisional surgery and in particular

Mohs micrographic surgery represent highly effective treatments, with 10 year follow-

up data for facial BCCs demonstrating cure rates of 88% and 96% respectively.3

Topical treatments have cosmetic advantages, but their cure rates are significantly

lower than those of surgical therapies. A study of nodular and superficial BCCs at

low-risk sites demonstrated cure rates at 3 years of 84% from imiquimod cream and

98% from surgical excision (p<0.0001).4 Rarely BCC can present in an advanced

manner which can produce severe disfigurement and even death.2 The proportion of

advanced BCC as a whole is small, but this small subset is responsible for significant

morbidity and mortality.5

Advanced BCCs (aBCCs) are defined as a subset of BCCs that are unable to be

effectively treated by conventional means, either due to the degree of local

invasiveness, the proximity of vital structures, or metastasis. This group includes

locally advanced BCC (laBCC) and metastatic BCC (mBCC). Metastatic BCC is

defined as primary cutaneous BCC which has spread to distant sites as histologically

similar metastatic deposits. A 2005 report shows that there were then fewer than 300

reported cases of mBCC.6,7 laBCCs are tumours that have developed in difficult-to-

treat facial sites, aggressively recurrent tumours, large neglected tumours and those

in which current treatment options are excluded by clinical or patient-driven criteria. 2

The pathogenesis of BCC is driven by inappropriate activation of the hedgehog

pathway, arising mainly through mutations in PTCH.8,9 The most important mutations

identified in BCCs result in the loss of function of PTCH1, which disables its tumour

suppressor role in the inactivation of the smoothened homologue SMO, resulting in

unregulated proliferation of basal cells.10 Our understanding of the role of hedgehog

signalling has been enhanced by progresses in basic developmental biology and

furthered through in vitro studies and mouse models. 11-14 A recent genomic analysis

of 293 BCCs showed that they had the highest mutation rate in all cancers (65

mutations/Mb) and furthermore, 85% of them showed mutations in hedgehog

pathway genes (PTCH1, 73%; SMO, 20%; SUFU, 8%) together with 61% which

show mutations in the TP53 gene.15

Recognition of the multiple roles of hedgehog signalling in cancer has prompted

intensive efforts to develop targeted pathway inhibitors.16,17 Inhibition of the

hedgehog pathway is central to BCC pathogenesis.18 Hedgehog inhibitor therapy

typically induces regression of BCCs.19 The original studies targeting the hedgehog

pathway were based on the natural product cyclopamine where topical application to

a small number of BCCs induced regression, attributed to apoptosis.19 The clinical

use of cyclopamine as a systemic treatment foundered due to its relatively poor oral

solubility, stability in acid, and specificity, with consequent off-target effects.9

Leading inhibitors now in clinical development act by binding to a common site within

SMO. This represents a promising treatment option, although long term data are

not yet available. There are already cases of acquired resistance documented and

the optimum duration of treatment remains undefined.19

Sonidegib, a small molecule potent inhibitor of SMO, is structurally distinct from

cyclopamine and pharmacokinetically distinct from the only other approved similar

drug, the first-in-class vismodegib.20 Many of the adverse effects are considered on-

target effects of SMO inhibitors, and, as vismodegib was approved three years

before sonidegib, reference to results with vismodegib will be incorporated in this

review as these are potentially relevant to sonidegib due to their similar role and

apparent sharing of on-target effects.

1. Body of Review

1.1 Overview of the market:

The incidence of BCC varies by geographical region, caused by underlying factors

including skin type, UV irradiation density and patient age. The incidence of BCC has

been estimated to be 76/100,000 in the UK.1 In the USA, incidence rates of

~170/100,000 were observed in two northern states (Minnesota and New England)

with higher rates of ~940/100,000 seen in Arizona and New Mexico.1 The highest

rates of >1000/100,000 were seen in Australia.1

The incidence of laBCC and hence the market potential of sonidegib are difficult to

estimate due to previous inconsistent definitions of laBCC and poor documentation

of BCCs in cancer registries.19 It has been estimated that laBCC accounts for about

1% of all BCC cases.19 This is based on a survey of local cancer centres in

Germany where the yearly laBCC incidence was 1511 and the yearly overall BCC

incidence was 114,944 in 2009.19

1.1.1 Unmet needs

There are currently few treatment options for patients with aBCCs.2 Until recently

such patients could only be offered palliative care.9 Vismodegib and sonidegib are

the currently approved hedgehog inhibitors for laBCC. Both of these treatments give

rise to adverse effects which can lead to discontinuation of treatment and also both

show examples of resistance. A significant risk of squamous cell carcinoma (SCC)

as a second malignancy had been shown to occur with vismodegib but this may well

occur with other hedgehog inhibitors such as sonidegib.21

There is the need to develop treatments which provide the ultimate goal of cure

rather than remission.9,22

1.1.2 Competitor compounds

Apart from sonidegib (Odomzo), the other currently available therapy for advanced

BCC is the first-in-class inhibitor, vismodegib (Erivedge), which has comparable

efficacy to sonidegib with response rates in clinical trials of 43% (vismodegib) and

44% (sonidegib).5 The adverse effect profile of these two treatments in patients is

similar, with the main effects being considered to be class effects of SMO

inhibitors.23

Interestingly, vismodegib was shown to possess unusual human non-linear

pharmacokinetics related to protein binding and slow elimination and furthermore its

plasma level did not correlate with the level of GLI downregulation.24,25 In contrast,

the pharmacokinetic profile of sonidegib is dose-proportional, allowing correlation of

dose with efficacy and determination of the dose-limiting toxicities of SMO

inhibitors.19,26

A range of other SMO inhibitors are in Phase I and II trials but have not yet been

approved. Furthermore, combination strategies to overcome resistance are in

development which include interrupting other pathways, such as the

phosphatidylinositol-3-kinase (PI3K)/Akt pathway.19

Itraconazole and arsenic trioxide were identified via screening of approved drugs

with potential inhibitory effects upon the hedgehog pathway. These have been found

in pre-clinical studies to only result in modest delay in tumour growth, consistent with

partial inhibition of the hedgehog pathway.9 The combination of itraconazole and

arsenic trioxide has been shown to be effective both against wild-type SMO and

resistance-associated mutated SMOs in murine models, leading to clinical trials of

this combination.27,28 The responses in patients in terms of tumour shrinkage have

been disappointing.28 This may be because of insufficient suppression of the

hedgehog pathway which needs to be near total in order to see tumour responses.9

An open-label exploratory Phase II trial of oral itraconazole for the treatment of BCC,

reduced cell proliferation by 45% , hedgehog pathway activity by 65%, and tumour

area by 24%, but those previously treated with vismodegib showed no significant

changes in proliferation or tumour size. This study shows that itraconazole has anti-

BCC activity in humans and absence of the on-target adverse effect of other SMO

antagonists.29,30 Higher doses of itraconazole (600mg per day) was shown to be

substantially more effective than lower doses in downregulating the hedgehog

pathway.30,31

Posaconazole, a second-generation triazole antifungal drug, has been shown, using

pre-clinical models, to inhibit the hedgehog pathway and progression of basal cell

carcinoma. No clinical studies are available relating to posaconazole and at present

it seems unlikely that sufficient control of the hedgehog pathway will be found to lead

to a clinical treatment.32

1.2 Introduction to the drug

The pathogenesis of BCC mainly depends on deregulation of the hedgehog

pathway. Smoothened inhibitors induce a clinical response which is time-limited.

Subsequent tumour regrowth and therapy failure are attributed to both activating

mutations and mutations in the binding sites of SMO antagonists.32

A search of the U.S. National Institutes of Health Clinical Trials website showed a

total of 36 clinical trials involving sonidegib which were at various stages from

recruiting to completed, of which eight involved BCC.

1.2.1 Chemistry

Sonidegib resulted from optimisation studies, of SMO antagonism, selectivity, safety

and PKs, of a series of biphenyl-3-carboxamides whose parent had been identified

via high-throughput screening.33

High-throughput screening identified a parent biphenyl-3-carboxamide as a potential

SMO antagonist and then molecular variants were optimised for antagonism,

selectivity, safety and PKs, resulting in sonidegib. 33 The structure of sonidegib is

shown in Figure 1.

The structure shows the free base which has poor aqueous solubility and acts as a

weak base (pKa 4.20).33 To increase the oral exposure a stable crystalline

diphosphate salt with an improved dissolution rate was developed.33 The orally

administered capsules contain sonidegib in this diphosphate form (although the

200mg relates only to the free base content), as this increases its bioavailability.33,34

1.2.2 Pharmacodynamics

Sonidegib is an orally available small molecular inhibitor of the hedgehog

pathway.26,33 It acts through binding to and inhibiting the activity of the SMO

transmembrane protein, which results in GLI transcription factor release and tumour

cell survival and growth.

Imaging of human BCCs showed reduction of features of BCC during sonidegib

treatment.35

Sonidegib, at 800mg once daily, does not prolong the QTc interval which indicates

no increase in proarrhythmic risk.34

Sonidegib has been shown to penetrate the blood-brain barrier in animal models.33

Sonidegib showed low absorption, extensive distribution and slow metabolisation in

14C labelled studies with healthy subjects.36

Hedgehog signalling controls cell differentiation and proliferation in many tissues. It

is active in taste papillae and taste buds.37,38 Dysgeusia is an adverse effect of

sonidegib shared with other hedgehog inhibitors. This is considered to be a class

effect due to disruption of the hedgehog signalling involved in taste.37 Similarly, mice

treated with vismodegib showed decreased growth rate of taste cells and reduced

response to sweet and bitter taste stimuli.39

The crucial role of the hedgehog pathway in embryogenesis makes hedgehog

inhibitors teratogenic and restricts their use in women and men of reproductive

potential.40 This is based on the mechanism of action of sonidegib and the results of

animal reproduction studies.34 Sonidegib can cause embryo-fetal death or severe

birth defects when administered to a pregnant woman. It is embryotoxic, fetotoxic,

and teratogenic in animals (at animal maternal exposures, during organogenesis,

below the recommended human dose of 200mg).34 It is necessary to verify the

pregnancy status of females of reproductive potential prior to initiating therapy.

Females of reproductive potential should be advised to use effective contraception

during treatment with sonidegib and for at least 20 months after the last dose. Males

should be advised of the potential risk of exposure through semen and to use

condoms (even after vasectomy) during treatment and for 8 months after the last

dose. This is a precaution in males as it is not known that sonidegib is present in

semen.34 Patients treated with sonidegib should be advised not to donate blood or

blood products during treatment and for at least 20 months after their last dose.34

1.2.3 Pharmacokinetics and metabolism

Early characterisation of the pharmokinetics of sonidegib was challenging, due to the

long terminal half-life of sonidegib (estimated to be 29.6 days in patients) and the

relatively short duration of pharmacokinetic data collection.41 Subsequently, a

population pharmacokinetic model has been developed which adequately describes

the pharmokinetics of sonidegib in healthy subjects and in patients with advanced

solid tumours.41 This model was based on data from five Phase I or II studies (n =

436) with doses ranging from 100 to 3000mg, and covariate analyses were

incorporated into the model.41 This model generated the following population-

predicted geometric means (inter-individual variability, coefficient of variation %) of

apparent oral clearance 9.5 L/h (71.4%), apparent volume of distribution at steady

state 9163 L (74.9%), accumulation ratio 21 (131%), and elimination half-life 29.6

days (109%).41

This model showed that the pharmacokinetics of sonidegib were not significantly

affected by gender, age, weight, total bilirubin, alanine aminotransferase, albumin,

creatinine clearance, or ethnicity (Western or Japanese). Thus, no dose adjustment

is needed for mild and moderate renal impairment, mild hepatic impairment, gender,

age, weight or ethnicity.41

Four clinically relevant covariate effects were noted which need to be taken into

account clinically. Firstly, a high-fat meal led to a fivefold increase in sonidegib

bioavailability, hence the dosage recommendation, “take on an empty stomach, at

least 1 hour before or 2 hours after a meal”.34,41 Secondly, healthy volunteers had a

threefold higher rate of clearance.41 Thirdly, sonidegib bioavailability decreased with

increasing dose levels, hence the 200mg daily dose recommendation.34,41 Fourthly,

co-administration of proton-pump inhibitors was estimated to reduce the

bioavailability of sonidegib by approximately 30% whereas co-administration of H2

receptor antagonists was found to not affect sonidegib bioavailability.41 This study

estimates that the inter-individual variability of steady-state area under the

concentration-time curve (AUC(0-24)) for the 200mg dose was 76%.41

1.3 Clinical efficacy:

Sonidegib was trialled in 9 advanced BCC patients who were resistant to vismodegib

but their BCCs also appeared refractory to treatment with sonidegib. All these

resistant patients demonstrated either progressive or stable disease with sonidegib,

suggesting that chemoresistance can occur between different SMO inhibitors.42

In a genomic analysis of SMO inhibitor resistance in BCC, two lines of evidence led

to the suggestion that chemically distinct SMO inhibitors may interact with

overlapping SMO residues and that cross-resistance between inhibitors might

occur.43 Thus use of sonidegib for patients showing resistance to vismodegib would

appear to be not indicated.

Although resistance to SMO inhibitors does occur it should be borne in mind that

laBCC is often at a late stage compared with the usual sporadic BCCs and the

tumour cells are therefore much more differentiated and heterogeneous and hence

predisposed to show resistance. By contrast early BCCs, for example those arising

in Gorlin Syndrome patients, are much less prone to resistance and Epstein notes

the absence of resistance in non-advanced BCCs during nearly six years of study.22

There have been indications that upregulation of the PI3K pathway (which can be

involved in crosstalk with hedgehog signalling and can induce GLI) is a potential

mechanism of resistance to sonidegib, albeit seen in medulloblastoma rather than

BCC.44 Certainly there is continuing interest in PI3K inhibitors, which have for

example recently been found to preferentially target the CD15+ cancer stem cell

(CSC) population in sonic hedgehog driven medulloblastoma.43 The combination of

a PI3K/Akt/mTOR inhibitor with sonidegib inhibited the self-renewal capacity of

pancreatic CSCs and suggested that this combination may offer promise for the

treatment of pancreatic cancer.45,46

1.3.1 (Phase I studies)

Sonidegib demonstrated anti-tumour activity in patients with advanced BCC in a

phase I study.26

A Phase I, open label, multi-center, single dose study has been completed to

evaluate the pharmacokinetics of sonidegib (LDE225) in healthy subjects with

normal hepatic function and in subjects with impaired hepatic function. This study

(clinicaltrials.gov; NCT01764776) evaluating the pharmacokinetics and safety of

800mg administration daily over 8 weeks, was completed in March 2015 and its

report is awaited.

An open-label pilot study of oral sonidegib in combination with the PI3K inhibitor

buparlisib (BKM120) in patients with advanced or metastatic BCC is currently

recruiting (NCT02303041) at the time of writing.

1.3.2 Phase II studies

The use of sonidegib formulated as a cream for topical application to BCC was

trialled (clinicaltrials.gov; NCT00961896; primary completion 2010) on 27 BCCs in

Gorlin Syndrome patients, as a proof of concept study. Regression was induced in

all but one of these BCCs and this topical route was well tolerated and showed no

skin irritation over the four week period. Complete histological clearance of BCC

was not achieved, immunohistochemistry showing remaining tumour nests.47 In the

13 BCCs treated with topical sonidegib, three complete responses and nine partial

responses resulted, whereas in the 14 BCCs treated with vehicle only one partial

response was observed.9

BOLT, a multicentre, randomised, double-blind, phase II trial, studied patients who

had locally advanced BCC not amenable to curative surgery or radiation or who had

metastatic BCC (mBCC).23 A summary of BOLT Phase II trial results is shown in

table 1.

1.4 Safety and tolerability.

Information regarding the safety and tolerability of sonidegib comes both from trials

in BCC and in a variety of other cancers. The pivotal BOLT trial showed that

sonidegib is associated with a manageable safety profile.23 Furthermore the 200mg

dose showed a more favourable profile than the 800mg dose.23

The BOLT study involved a majority of patients with laBCC together with a minority

of patients with (mBCC). Members of each of these two groups were exposed to

either 200mg or 800mg sonidegib as follows:( 200mg), laBCC (n=42) mBCC (n=13);

(800mg) laBCC (n=93) mBCC (n=23).23 The BOLT study showed that adverse

events most frequently reported were typically grades 1 and 2. Adverse events

included muscle spasms, alopecia, dysgeusia, nausea, fatigue, weight loss,

diarrhoea and decreased appetite.23 These effects were typical of hedgehog

pathway inhibitors consistent with a class effect. Most of these, including muscle

toxicity, dysgeusia and alopecia are considered to be on-target adverse reactions.19

Of the 71 patients who discontinued sonidegib because of adverse events 45 (63%)

of these experienced the lower grade 1 and 2 events.23

Risk of increase in creatine kinase concentration at grade 2 or greater was higher in

those receiving the 800mg dose than in those at the 200mg dose, but was

manageable by dose interruption or adjustment.23 With respect to rhabdomyolysis,

investigator-reported cases were not confirmed by the independent safety review

and adjudication committee on muscle toxicity.23 Most patients in the BOLT study

showed improved or stable quality of life.23 Amlodipine has been reported to

reduced the frequency of vismodegib-induced muscle cramps.48

The long term adverse effects of hedgehog pathway inhibitors, including the potential

for second malignancy, are not yet well known.21 Of the secondary malignancies

noted in the BOLT trial, the most frequently occurring was SCC. SCC was noted in

seven patients in all, comprising three of the 79 patients in the 200mg dose group

together with four patients of the 150 patients in the 800mg dose group.23 It is

noteworthy, in a study of extensive BCC records at a tertiary centre, that a

significantly greater frequency of basosquamous carcinoma was noted in patients

with moderate or severe BCCs (odds ratio 3.6; p< 0.0001).49 In BCC patients treated

with SMO inhibitors, SCCs with RAS/MAPK activation arose from the preceding

BCCs (91% of 1248 genetic variations shared between the pre-treatment BCC and

the post-treatment SCC). This suggests that the hedgehog-dependent BCC was

converted to a RAS/MAPK-dependent SCC, thereby developing resistance to SMO

inhibitors.50 It is possible that a tumour that is predominantly SCC could arise from a

BCC which had some basosquamous characteristics and the hedgehog inhibitor

would preferentially reduce the basocellular component while leaving the squamous

component unaffected. The hypothesis that BCC tumours, under selection pressure

from hedgehog inhibitors, activate RTK/RAS/MAPK signalling and thereby generate

SCCs is supported by sequencing of pre- and post-treatment tumour sampling.

Certainly there are reports of this BCC transformation to SCC leading to the clinically

relevant recommendation to re-biopsy remaining tumour following hedgehog inhibitor

treatment in order to exclude SCC.50,51

A recent case report documented the eruption of 3 cutaneous SCCs following a

patient with 2 BCCs being treated with vismodegib. Whilst this was highly successful

from the point of view of BCC remission, dermatologists and oncologists should be

alert to the potential of SCC occurrence following vismodegib treatment, and, by

extension, sonidegib treatment.52 A recent case-control study (180 participants)

evaluated the risk of developing a non-BCC malignancy following vismodegib

treatment of BCCs. The study demonstrated that most malignancies were SCCs,

with a hazard ratio of 8.12 (95% CI, 3.89-16.97; p<0.001). There was no significant

increase in other cancers.21

In a case-control study, patients receiving hedgehog inhibitor therapy (vismodegib)

were less likely to have in-situ SCC than the controls, suggesting that the SCCs

arising from this treatment may be more aggressive.21 Because of the risk of second

SCCs arising within one year of hedgehog inhibitor treatment it has been proposed

that surveillance over the course of one year may be required.21

In sonidegib the dose-limiting toxicity is muscle toxicity and unlike vismodegib this

shows a clear dose-toxicity relationship. This allows investigation of the dose

dependency of cure and regression rates and progression-free survival.19 A

summary of the characteristics of sonidegib (Odomzo) and vismodegib (Erivedge) is

shown in table 2.

1.5 Regulatory affairs:

1.5.1

Oral sonidegib is currently approved in the USA, EU, Australia and Switzerland for

the treatment of locally advanced BCC which has recurred following surgery or

radiation therapy or which is not otherwise amenable to curative surgery or

radiotherapy. In some jurisdictions it is additionally licensed for metastatic BCC as

shown in Table 3.

1.6 Conclusion

In July 2015, sonidegib was approved by the FDA to treat adult patients with laBCC,

thereby becoming the second approved hedgehog pathway inhibitor. Limited

treatments are available for laBCC which poses great morbidity and potential

mortality. Sonidegib can improve quality of life in patients with laBCC with large

symptomatic lesions and this is of considerable benefit to these patients.The BOLT

trial showed sonidegib to be a useful treatment in laBCC with 38% of patients

achieving a partial response (at least a 30% decrease in the sum of diameters of

target lesions) and 5% achieving a complete response. The study demonstrated

adverse events typical of hedgehog inhibitors; these were found overall in 95% of

patients (grade 1: 18%, grade 2: 47%, grade 3: 27% and grade 4: 4%).

There is evidence that sonidegib treatment of vismodegib-resistant BCCs is not

indicated with these two molecules appearing to compete for the same binding

pocket.

The pharmacokinetic profile of sonidegib is dose-proportional, unlike that of

vismodegib. This allows correlation of dose with efficacy and dose dependent side

effects.

There is evidence of BCC, particularly aggressive BCC types, transforming to SCC

following hedgehog pathway inhibition leading to the clinically relevant

recommendation to re-biopsy remaining tumour following treatment to exclude SCC.

It is regrettable that sonidegib has not yet been able to be developed into an

effective topical or locally injectable formulation so it could be offered to a wider

range of BCC patients.

2 Expert commentary

The use of hedgehog inhibitor therapy as a neoadjuvant prior to surgical resection

has been shown to decrease morbidity and increase the probability of a curative

resection.57 For patients with extensive BCC a combined neoadjuvant use of

sonidegib and surgical treatment could be considered.

Several SMO mutations have been found to drive most drug resistance in BCC via

two distinct mechanisms, disruption of ligand binding and induction of constitutive

activity. These two mechanisms have distinct mutation profiles.58,59 As the

emergence of drug-resistant SMO mutations is a key factor in limiting the efficacy of

SMO inhibitors as monotherapy, re-evaluation is taking place which includes the use

of strategic combinations of SMO inhibitors with other therapeutic modalities.60-62

It has been suggested that combination therapy with agents such as radiation, other

pathway inhibitors, or immunotherapy may be needed to control advanced BCC .42,63

Combination with other drugs, for example MEK inhibitors, EGFR inhibitors or

immunotherapeutic agents, shows potential to enhance efficacy compared with

sonidegib monotherapy.19 One would therefore expect vismodegib treatment of

sonidegib-resistant BCCs to be similarly not efficacious. In combination therapies,

vismodegib and sonidegib would be alternatives rather than each having a separate

independent role. This restriction may not apply to other SMO inhibitors which bind

differently, such as itraconazole.27,28 Recent work has led to the conclusion that

BCC, unlike other human cancers, is highly dependent on the hedgehog pathway

and may not as readily circumvent inhibitor therapy by using other pathways; this

increases the likelihood of future success with combination therapies either by using

SMO inhibitors which operate by different mechanisms or by targeting the hedgehog

pathway downstream of SMO.43,58,64,65 A possible example of this may be the use of

an atypical protein kinase Cι/λ or GLI2 inhibitors in combination with SMO inhibitors,

as recently outlined.58,64

The epigenetic targeting of hedgehog pathway transcriptional output, through

bromodomain and extra-terminal domain family (BET) inhibition, showed that BRD4

regulates GLI transcription downstream of SMO and SUFU directly occupies GLI1

and GLI2 promoters.66,67 Also, there was a clear BCC cell response to the small

molecule JQ1, an inhibitor targeting BRD4, even when the tumour shows resistance

to SMO inhibitors.66 This shows the potential of the BET inhibitor therapies which

are now entering clinical trials, an approach which circumvents the known SMO

inhibitor resistance mechanisms.66

3 Five-year view

Sonidegib is a recently licensed drug and has only been used in a relatively small

number of patients with limited follow-up to date. Over the coming years, additional

data through post-marketing surveillance and further clinical trials will inform, refine,

and clarify the understanding of this medication. With time, further reports will

improve the understanding of side effects, which may be rare or clustered in

particular populations, or currently unknown. Genomic analysis of tumour type and

specific mutations may allow a personalised approach to the choice of treatments.

The opinion of what constitutes a locally advanced BCC is somewhat fluid and varies

between different clinicians and patients. Five years hence there will be a clearer

understanding of the relative merits and drawbacks of hedgehog inhibitors, including

both the frequency and nature of recurrences, and the extent to which hedgehog

inhibitors cause tumours to undergo squamous transformation.

The two FDA-approved SMO antagonists for clinical use, vismodegib and sonidegib

have been shown to be highly effective in the otherwise unmet need for laBCC

treatment. Challenges remain due to chemoresistance which occurs with a

frequency which correlates with tumour grade.43,58,68

For advanced BCC, strategic combinations of treatments will be developed and the

efficacy of sonidegib is likely to be thereby enhanced.

The findings involving miRNA203 could potentially lead to development of additional

therapeutic targets for BCC resulting in either monotherapies or combinations with

hedgehog inhibitors such as sonidegib.69

Sonidegib in combination with PKCι inhibitor therapy offers the potential of improved

treatment in the large target patient population whose tumours harbor chromosome

3q26 copy number gains and a cancer stem cell (CSC) phenotype driven by PKCXι-

SOX2-Hedgehog pathway activation, not restricted to BCC.60 GLI antagonists, which

operate downstream of SMO, have been shown to be effective in suppressing

hedgehog pathway activation in the presence of any SMO variant. GLI antagonists

may be useful against SMO inhibitor-resistant tumours or in combination with SMO

inhibitors such as sonidegib.27,58,70

Repurposing of itraconazole or similar compounds with or without arsenic trioxide,

could possibly produce more promising results as a potential laBCC treatment. This

would allow exploitation of the lack of on-target SMO inhibitor adverse effects and

the pre-existing approved drug status. Itraconazole has been found to strongly

synergise in SMO inhibition with calcitriol, the latter having been suggested as the

elusive endogenous transmitter of the PTCH to SMO interaction. 71 Interestingly,

related vitamin D-based secosteroids are being investigated as potent inhibitors of

hedgehog signalling with chemotherapeutic potential.72

Hedgehog pathway inhibitors not only inhibit proliferation in BCC but induce

recruitment of cytotoxic T cells into the BCC and upregulate MHC class 1 in BCC

cells. These findings led to the suggestion of trialling combinations of hedgehog

inhibitors with immune modifiers to enhance long-term BCC control.73,74

The development of future treatments must take into account the following two

distinct mechanisms of resistance and tumour evolution. Firstly, that involving loss

of the repressor SUFU, which reactivates the pathway downstream of SMO, thereby

causing resistance. Secondly, that activating the RAS/MAPK pathway overriding

oncogenic addiction to hedgehog signalling, allowing BCCs to transition to SCCs.50

Financial & competing interests disclosure

Conflicts of interest: J.T.L. has accepted honoraria for speaking at meetings by LEO

Pharma, Galderma, Almirall, Astellas and GSK. The authors have no other relevant

affiliations or financial involvement with any organization or entity with a financial

interest in or financial conflict with the subject matter or materials discussed in the

manuscript apart from those disclosed.

Key issues

Sonidegib parallels vismodegib, broadly sharing efficacy and limitations.

Sonidegib is an approved treatment for locally advanced BCC.

The pharmacokinetic profile of sonidegib is dose-proportional, unlike that of

vismodegib.

Adverse effects limit use outside locally advanced BCCs.

Acquired SMO resistance can limit its therapeutic response.

Monitor remaining tumour following hedgehog inhibitor treatment for

squamous differentiation.

Combination therapies offer future promise.

Information resources

Sekulic and Von Hoff presents a one page summary of the essentials of hedgehog

pathway inhibition featuring both sonidegib and vismodegib.5

Rimkus and co-workers have provided a recent review of smoothened and GLI

inhibitors, which also covers the wide variety of, as yet not approved, hedgehog

inhibitors.75 Other reviews of sonidegib have been published.76,77

Annotated bibliography

1 Lomas A, Leonardi-Bee J, Bath-Hextall F. A systematic review of worldwide incidence of nonmelanoma skin cancer. Br J Dermatol 2012; 166: 1069-80.

2 Lear JT, Corner C, Dziewulski P et al. Challenges and new horizons in the management of advanced basal cell carcinoma: a UK perspective. British journal of cancer 2014; 111: 1476-81.

3 van Loo E, Mosterd K, Krekels GA et al. Surgical excision versus Mohs' micrographic surgery for basal cell carcinoma of the face: A randomised clinical trial with 10 year follow-up. Eur J Cancer 2014; 50: 3011-20.

4 Bath-Hextall F, Ozolins M, Armstrong SJ et al. Surgical excision versus imiquimod 5% cream for nodular and superficial basal-cell carcinoma (SINS): a multicentre, non-inferiority, randomised controlled trial. Lancet Oncol 2014; 15: 96-105.

5 Sekulic A, Von Hoff D. Hedgehog Pathway Inhibition. Cell 2016; 164: 831.6 von Domarus H, Stevens PJ. Metastatic basal cell carcinoma. Report of five cases and review

of 170 cases in the literature. Journal of the American Academy of Dermatology 1984; 10: 1043-60.

7 Ting PT, Kasper R, Arlette JP. Metastatic basal cell carcinoma: report of two cases and literature review. Journal of cutaneous medicine and surgery 2005; 9: 10-5.

8 Briscoe J, Therond PP. The mechanisms of Hedgehog signalling and its roles in development and disease. Nature reviews. Molecular cell biology 2013; 14: 416-29.

9 Basset-Seguin N, Sharpe HJ, de Sauvage FJ. Efficacy of Hedgehog pathway inhibitors in Basal cell carcinoma. Molecular cancer therapeutics 2015; 14: 633-41.

10 Aszterbaum M, Rothman A, Johnson RL et al. Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome. The Journal of investigative dermatology 1998; 110: 885-8.

11 Nusslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature 1980; 287: 795-801.

12 Romer JT, Kimura H, Magdaleno S et al. Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+/-)p53(-/-) mice. Cancer Cell 2004; 6: 229-40.

13 Sasai K, Romer JT, Lee Y et al. Shh pathway activity is down-regulated in cultured medulloblastoma cells: implications for preclinical studies. Cancer Res 2006; 66: 4215-22.

14 Wong H, Alicke B, West KA et al. Pharmacokinetic-pharmacodynamic analysis of vismodegib in preclinical models of mutational and ligand-dependent Hedgehog pathway activation. Clin Cancer Res 2011; 17: 4682-92.

15 Bonilla X, Parmentier L, King B et al. Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma. Nat Genet 2016.

16 Amakye D, Jagani Z, Dorsch M. Unraveling the therapeutic potential of the Hedgehog pathway in cancer. Nature medicine 2013; 19: 1410-22.

17 Arnhold V, Boos J, Lanvers-Kaminsky C. Targeting hedgehog signaling pathway in pediatric tumors: in vitro evaluation of SMO and GLI inhibitors. Cancer Chemother Pharmacol 2016; 77: 495-505.

18 Lear JT. Oral hedgehog-pathway inhibitors for basal-cell carcinoma. The New England journal of medicine 2012; 366: 2225-6.

19 Dreier J, Dummer R, Felderer L et al. Emerging drugs and combination strategies for basal cell carcinoma. Expert Opin Emerg Drugs 2014; 19: 353-65.

20 Gould SE, Low JA, Marsters JC, Jr. et al. Discovery and preclinical development of vismodegib. Expert Opin Drug Discov 2014; 9: 969-84.

21 Mohan SV, Chang J, Li S et al. Increased Risk of Cutaneous Squamous Cell Carcinoma After Vismodegib Therapy for Basal Cell Carcinoma. JAMA dermatology 2016.

22 Epstein EH. Everything Is Connected. The Journal of investigative dermatology 2015; 135: 2341-4.

23 Migden MR, Guminski A, Gutzmer R et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. The lancet oncology 2015; 16: 716-28.

24 Graham RA, Lum BL, Cheeti S et al. Pharmacokinetics of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors: the role of alpha-1-acid glycoprotein binding. Clinical cancer research : an official journal of the American Association for Cancer Research 2011; 17: 2512-20.

25 Von Hoff DD, LoRusso PM, Rudin CM et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. The New England journal of medicine 2009; 361: 1164-72.

26 Rodon J, Tawbi HA, Thomas AL et al. A phase I, multicenter, open-label, first-in-human, dose-escalation study of the oral smoothened inhibitor Sonidegib (LDE225) in patients with advanced solid tumors. Clinical cancer research : an official journal of the American Association for Cancer Research 2014; 20: 1900-9.

27 Kim J, Aftab BT, Tang JY et al. Itraconazole and arsenic trioxide inhibit Hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists. Cancer cell 2013; 23: 23-34.

28 Ally MS, Ransohoff K, Sarin K et al. Effects of Combined Treatment With Arsenic Trioxide and Itraconazole in Patients With Refractory Metastatic Basal Cell Carcinoma. JAMA dermatology 2016: 1-5.

29 Kim DJ, Kim J, Spaunhurst K et al. Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2014; 32: 745-51.

30 Dirix L. Discovery and exploitation of novel targets by approved drugs. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2014; 32: 720-1.

31 Antonarakis ES, Heath EI, Smith DC et al. Repurposing itraconazole as a treatment for advanced prostate cancer: a noncomparative randomized phase II trial in men with metastatic castration-resistant prostate cancer. Oncologist 2013; 18: 163-73.

32 Chen B, Trang V, Lee A et al. Posaconazole, a second-generation triazole antifungal drug, inhibits the Hedgehog signaling pathway and progression of basal cell carcinoma. Molecular cancer therapeutics 2016.

33 Pan S, Wu X, Jiang J et al. Discovery of NVP-LDE225, a Potent and Selective Smoothened Antagonist. ACS medicinal chemistry letters 2010; 1: 130-4.

34 Young AM, Hobson EA, Lackey LB et al. Survival on the ark: life history trends in captive parrots. 2012; 15: 28-53.

35 Maier T, Kulichova D, Ruzicka T et al. Noninvasive monitoring of basal cell carcinomas treated with systemic hedgehog inhibitors: pseudocysts as a sign of tumor regression. Journal of the American Academy of Dermatology 2014; 71: 725-30.

36 Zollinger M, Lozac'h F, Hurh E et al. Absorption, distribution, metabolism, and excretion (ADME) of (1)(4)C-sonidegib (LDE225) in healthy volunteers. Cancer Chemother Pharmacol 2014; 74: 63-75.

37 Kumari A, Ermilov AN, Allen BL et al. Hedgehog pathway blockade with the cancer drug LDE225 disrupts taste organs and taste sensation. J Neurophysiol 2015; 113: 1034-40.

38 Castillo D, Seidel K, Salcedo E et al. Induction of ectopic taste buds by SHH reveals the competency and plasticity of adult lingual epithelium. Development 2014; 141: 2993-3002.

39 Yang H, Cong WN, Yoon JS et al. Vismodegib, an antagonist of hedgehog signaling, directly alters taste molecular signaling in taste buds. Cancer Med 2015; 4: 245-52.

40 Teglund S, Toftgard R. Hedgehog beyond medulloblastoma and basal cell carcinoma. Biochim Biophys Acta 2010; 1805: 181-208.

41 Goel V, Hurh E, Stein A et al. Population pharmacokinetics of sonidegib (LDE225), an oral inhibitor of hedgehog pathway signaling, in healthy subjects and in patients with advanced solid tumors. Cancer Chemother Pharmacol 2016.

42 Danial C, Sarin KY, Oro AE et al. An Investigator-Initiated Open-Label Trial of Sonidegib in Advanced Basal Cell Carcinoma Patients Resistant to Vismodegib. Clinical cancer research : an official journal of the American Association for Cancer Research 2015.

43 Sharpe HJ, Pau G, Dijkgraaf GJ et al. Genomic analysis of smoothened inhibitor resistance in basal cell carcinoma. Cancer cell 2015; 27: 327-41.

44 Buonamici S, Williams J, Morrissey M et al. Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Science translational medicine 2010; 2: 51ra70.

45 Singh AR, Joshi S, Zulcic M et al. PI-3K Inhibitors Preferentially Target CD15+ Cancer Stem Cell Population in SHH Driven Medulloblastoma. PloS one 2016; 11: e0150836.

46 Sharma N, Nanta R, Sharma J et al. PI3K/AKT/mTOR and sonic hedgehog pathways cooperate together to inhibit human pancreatic cancer stem cell characteristics and tumor growth. Oncotarget 2015; 6: 32039-60.

47 Skvara H, Kalthoff F, Meingassner JG et al. Topical treatment of Basal cell carcinomas in nevoid Basal cell carcinoma syndrome with a smoothened inhibitor. The Journal of investigative dermatology 2011; 131: 1735-44.

48 Ally MS, Tang JY, Lindgren J et al. Effect of Calcium Channel Blockade on Vismodegib-Induced Muscle Cramps. JAMA dermatology 2015; 151: 1132-4.

49 Dreier J, Cheng PF, Bogdan Alleman I et al. Basal cell carcinomas in a tertiary referral centre: a systematic analysis. The British journal of dermatology 2014; 171: 1066-72.

50 Zhao X, Ponomaryov T, Ornell KJ et al. RAS/MAPK Activation Drives Resistance to Smo Inhibition, Metastasis, and Tumor Evolution in Shh Pathway-Dependent Tumors. Cancer research 2015; 75: 3623-35.

51 Saintes C, Saint-Jean M, Brocard A et al. Development of squamous cell carcinoma into basal cell carcinoma under treatment with Vismodegib. Journal of the European Academy of Dermatology and Venereology : JEADV 2015; 29: 1006-9.

52 Orouji A, Goerdt S, Utikal J et al. Multiple highly and moderately differentiated squamous cell carcinomas of the skin during vismodegib treatment of inoperable basal cell carcinoma. The British journal of dermatology 2014; 171: 431-3.

53 Young AM, Stoker TB. Audio-induced psychogenic non-epileptic seizures. Scott Med J 2012; 57: 60.

54 Young RD, Lawes DJ, Hill AF et al. Observation of a tungsten alkane sigma-complex showing selective binding of methyl groups using FTIR and NMR spectroscopies. J Am Chem Soc 2012; 134: 8294-7.

55 Young E, Smith RM, Sharp BL et al. Liquid chromatography-flame ionisation detection using a nebuliser/spray chamber interface. Part 1. Design and testing. J Chromatogr A 2012; 1236: 16-20.

56 Young JM, Choy JS, Kassab GS et al. Slackness between vessel and myocardium is necessary for coronary flow reserve. Am J Physiol Heart Circ Physiol 2012; 302: H2230-42.

57 Ching JA, Curtis HL, Braue JA et al. The impact of neoadjuvant hedgehog inhibitor therapy on the surgical treatment of extensive basal cell carcinoma. Ann Plast Surg 2015; 74 Suppl 4: S193-7.

58 Atwood SX, Sarin KY, Whitson RJ et al. Smoothened variants explain the majority of drug resistance in basal cell carcinoma. Cancer cell 2015; 27: 342-53.

59 Atwood SX, Sarin KY, Li JR et al. Rolling the Genetic Dice: Neutral and Deleterious Smoothened Mutations in Drug-Resistant Basal Cell Carcinoma. The Journal of investigative dermatology 2015; 135: 2138-41.

60 Justilien V, Fields AP. Molecular pathways: novel approaches for improved therapeutic targeting of Hedgehog signaling in cancer stem cells. Clinical cancer research : an official journal of the American Association for Cancer Research 2015; 21: 505-13.

61 Atwood SX, Whitson RJ, Oro AE. Advanced treatment for basal cell carcinomas. Cold Spring Harb Perspect Med 2014; 4: a013581.

62 Kieran MW. Targeted treatment for sonic hedgehog-dependent medulloblastoma. Neuro-oncology 2014; 16: 1037-47.

63 Brechbiel J, Miller-Moslin K, Adjei AA. Crosstalk between hedgehog and other signaling pathways as a basis for combination therapies in cancer. Cancer treatment reviews 2014; 40: 750-9.

64 Ridky TW, Cotsarelis G. Vismodegib resistance in basal cell carcinoma: not a smooth fit. Cancer cell 2015; 27: 315-6.

65 Gonnissen A, Isebaert S, Haustermans K. Targeting the Hedgehog signaling pathway in cancer: beyond Smoothened. Oncotarget 2015; 6: 13899-913.

66 Tang Y, Gholamin S, Schubert S et al. Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition. Nature medicine 2014; 20: 732-40.

67 Long J, Li B, Rodriguez-Blanco J et al. The BET bromodomain inhibitor I-BET151 acts downstream of smoothened protein to abrogate the growth of hedgehog protein-driven cancers. J Biol Chem 2014; 289: 35494-502.

68 Chen JK. I only have eye for ewe: the discovery of cyclopamine and development of Hedgehog pathway-targeting drugs. Nat Prod Rep 2016.

69 Sonkoly E, Loven J, Xu N et al. MicroRNA-203 functions as a tumor suppressor in basal cell carcinoma. Oncogenesis 2012; 1: e3.

70 Atwood SX, Li M, Lee A et al. GLI activation by atypical protein kinase C iota/lambda regulates the growth of basal cell carcinomas. Nature 2013; 494: 484-8.

71 Linder B, Weber S, Dittmann K et al. A Functional and Putative Physiological Role of Calcitriol in Patched1/Smoothened Interaction. J Biol Chem 2015; 290: 19614-28.

72 DeBerardinis AM, Raccuia DS, Thompson EN et al. Vitamin D3 analogues that contain modified A- and seco-B-rings as hedgehog pathway inhibitors. Eur J Med Chem 2015; 93: 156-71.

73 Otsuka A, Levesque MP, Dummer R et al. Hedgehog signaling in basal cell carcinoma. J Dermatol Sci 2015; 78: 95-100.

74 Otsuka A, Dreier J, Cheng PF et al. Hedgehog pathway inhibitors promote adaptive immune responses in basal cell carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 2015; 21: 1289-97.

75 Rimkus TK, Carpenter RL, Qasem S et al. Targeting the Sonic Hedgehog Signaling Pathway: Review of Smoothened and GLI Inhibitors. Cancers (Basel) 2016; 8.

76 Burness CB. Sonidegib: First Global Approval. Drugs 2015; 75: 1559-66.77 Burness CB, Scott LJ. Sonidegib: A Review in Locally Advanced Basal Cell Carcinoma. Target

Oncol 2016.