Expert Opinion on Drug Safety

ISSN: 1474-0338 (Print) 1744-764X (Online) Journal homepage: http://www.tandfonline.com/loi/ieds20

Efficacy and safety of vismodegib: a new

therapeutic agent in the treatment of basal cell
carcinoma
Tomas G Lyons, Grainne M OKane & Catherine M Kelly
To cite this article: Tomas G Lyons, Grainne M OKane & Catherine M Kelly (2014) Efficacy and
safety of vismodegib: a new therapeutic agent in the treatment of basal cell carcinoma, Expert
Opinion on Drug Safety, 13:8, 1125-1132, DOI: 10.1517/14740338.2014.939952
To link to this article: http://dx.doi.org/10.1517/14740338.2014.939952

Published online: 17 Jul 2014.

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Date: 05 April 2016, At: 18:55

Drug Safety Evaluation

Efficacy and safety of vismodegib:

a new therapeutic agent in the
treatment of basal cell carcinoma
1.

Introduction

2.

The Hh pathway

3.

Pharmacology of vismodegib

4.

Drug--drug interactions

5.

Clinical effectiveness of

Tomas G Lyons, Grainne M OKane & Catherine M Kelly

vismodegib
6.

Safety and tolerability of

Downloaded by [University of Ottawa] at 18:55 05 April 2016

vismodegib
7.

Resistance to vismodegib

8.

Conclusion

9.

Expert opinion

Mater Misericordiae University Hospital, University College Dublin,

Department of Medical Oncology, Dublin, Ireland

Introduction: Basal cell carcinoma (BCC) is the most common human malignancy. Treatment options for the minority of patients presenting with locally
advanced inoperable or metastatic BCC are very limited. The hedgehog (Hh)
pathway plays a crucial role in the pathogenesis of BCC. Recent advances
in targeting this pathway have led to the development of a first-in-class,
small-molecule oral Hh inhibitor, vismodegib (Erivedge
, Genentech).
Areas covered: In this article, we review vismodegib with regard to its mechanism of action, clinical efficacy, safety and tolerability, and we consider the
causes of emerging resistance to the drug.
Expert opinion: Vismodegib is a welcome addition to the treatment paradigm
for BCC. Approval was based on Phase II evidence, the patient number was
relatively small, there was no control group or a comparator group and
survival data have not been presented so longer term follow-up and larger
exposure to the drug is required to fully appreciate its clinical utility into
the future. With ongoing use of the drug in the nontrial population and
further studies investigating its use in both early- and later-stage disease,
we will get a better understanding of the drug and determine its place in
the armamentarium against BCC.
Keywords: basal cell carcinoma, hedgehog pathway, vismodegib
Expert Opin. Drug Saf. (2014) 13(8):1125-1132

1.

Introduction

Basal cell carcinoma (BCC) is a slow-growing neoplasm with its cell of origin not
yet defined. It is believed that the tumor arises from progenitor cells in the interfollicular epidermis or hair follicle stem cells [1,2]. BCC is the most common human
malignancy, accounting for 25% of all human cancers and 80% of non-melanoma
skin cancers. It is estimated that over 2 million cases of BCC are treated annually in
the United States each year [3,4]. This locally invasive tumor can result in extensive
morbidity through local recurrence and tissue destruction. Surgical excision is adequate treatment for the majority of BCC cases. Radiation therapy may be preferred
in certain cases after consideration of resectability, function, cosmesis and patient
preference [5]. Although early reports suggested a poor outcome with radiation
therapy alone for larger or more deeply invasive tumors, series using modern radiation techniques suggest adequate control rates with good cosmesis and functional
outcomes. In one report 4-year locoregional control rates were 86% for large and/
or locally advanced BCCs (laBCCs) with radiation [6]. Treatment options for the
minority of patients who do present with extensive locally advanced inoperable or
metastatic BCC (mBCC) are very limited. In laBCC, the BCC has progressed
locally and has invaded into underlying tissues, such that resection is not technically
possible or cannot yield an acceptable functional and cosmetic outcome. Most cases
of laBCC arise due to recurrence after previous local treatment(s). Occasionally,
10.1517/14740338.2014.939952 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X
All rights reserved: reproduction in whole or in part not permitted

1125

T. G. Lyons et al.

Box 1. Drug summary.

Drug name
Phase
Indication
Pharmacology
description

Route of
administration
Chemical
structure

Vismodegib
Phase II
Locally advanced, inoperable or
metastatic basal cell carcinoma (BCC)
It exerts its mode of action by potently
inhibiting smoothened on the target
cell, thereby inhibiting the Hedgehog
pathway. This pathway plays a key role
in BCC development.
Oral
2-chloro-N-(4-chloro-3-(pyridin-2-yl)
phenyl)-4-(methanesulfonyl)benzamide
CH3

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analysis of patients with NBCCS has revealed the molecular

pathogenesis of BCC associated with this syndrome but also
furthered our understanding of sporadic BCC development.
The essential pathway involved in BCC tumorogenesis is the
Hedgehog (Hh) pathway [8]. This pathway is mutated in virtually all patients with BCC. Recent advances in targeting this
pathway have led to the development of a first-in-class,
small-molecule oral Hh inhibitor. On the 30 January 2012,
based on a Phase II clinical trial the US FDA approved vismodegib (Box 1) (Erivedge
, Genentech) for the treatment of
locally advanced inoperable and mBCC. And since then, vismodegib has also received marketing authorization in the
EU, Switzerland, Canada, Australia and many other countries
around the world. In this article, we review vismodegib with
regard to its clinical efficacy, safety and tolerability and the
emergence of resistance in patients with BCC.
2.

CI

HN

CI

Pivotal trial(s)

A Phase II, multicenter, international,

nonrandomized study (ERIVANCE BCC)
study [21].

Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa

business). Readers are referred to Pipeline (http://informa-pipeline.
citeline.com) and Citeline (http://informa.citeline.com).

patients present with laBCC because they did not seek medical attention at an earlier disease stage. Although extremely
rare, BCC can metastasize, estimates in the literature are in
the range of < 0.5% [7].
Environmental and genetic factors contribute to the development of BCC. Exposure to ultraviolet radiation in sunlight
is the most important. Sun overexposure during childhood
and adolescence presents the highest relative risk. Other risk
factors include chronic arsenic exposure, radiation therapy,
immunosuppression (organ transplant, immunosuppressive
medications and HIV) and the nevoid BCC syndrome
(NBCCS; Gorlin syndrome).
NBCCS is a rare autosomal-dominant genetic disorder
characterized by a mutation in the human patched (PTCH)
gene and predisposition to multiple BCC and other tumors [8].
PTCH gene acts as a tumor suppressor gene. BCC development in patients with NBCCS is related to sun exposure, as
BCCs develop most frequently in sun-exposed areas. Genomic
1126

The Hh pathway

The Hh pathway is a signaling cascade that was originally

discovered in Drosophila (fruit fly) [9]. This pathway is fundamental in the development of embryonic cells and is important in stem cell proliferation and tissue regeneration in
adults [10]. The PTCH protein I is a membrane receptor on
the surface of target cells. In its normal function, it inhibits
smoothened (SMO), another membrane protein. The Hh
ligand binds to the PTCH1 protein. This binding removes
the PTCH1-dependent inhibition of SMO and SMO
becomes activated (Figure 1) [11]. The details of the pathway
downstream from SMO are not fully understood, but the
most accepted theory is that, SMO enters the primary cilium
and promotes release and activation of the glioma-associated
oncogene (GLi) family from the cytoplasmic complex,
suppressor of fused. Release of GLi transcription factors
(GLi 1 -- 3) then results in their nuclear translocation and
upregulation of associated target genes within the cell [11].
Upregulation of the Hh pathway leads to increased cell proliferation and cell survival [12]. It has also been shown to regulate
the epithelial--mesenchymal transition and dissemination of
cancer stem cells in solid tumors and enhance metastatic
disease progression [13]. NBCCS is an autosomal-dominant
inherited disease, which is caused by a germline mutation in
PTCH1 gene. These patients only need one somatic hit to
their functional PTCH gene. The mutation in PTCH1
relieves the inhibition of SMO and therefore the downstream
signaling cascade is activated and the Hh pathway is upregulated leading to BCC development along with other tumors [8].
In sporadic BCC, two hits to the PTCH1 gene are required.
These somatic mutations (loss of function) in PTCH1
account for approximately 90% of cases with the remainder
being made up of mutations (gain of function) in SMO [14].
Vismodegib is a first-in-class, small-molecule oral Hhinhibitor. It binds to the extracellular domain of SMO and
potently suppresses the downstream signaling cascade of the
Hh pathway.

Expert Opin. Drug Saf. (2014) 13(8)

Vismodegib

Hedgehog ligand
Vismodegib

PTCH1

SMO

PTCH1

Mutation in
PTCH1

SMO
Mutation in
PTCH1

SUFU

SUFU

GLi

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GLi

No nuclear
translocation
GLi
No tumour
growth

Tumour growth
Tumour survival
Metastasis and invasion

Figure 1. The Hedgehog pathway and mechanism of action of vismodegib. In the absence of Hh ligand, PCTH1 inhibits SMO.
When Hh ligand is present, PTCH1 inhibition of SMO is released and SMO goes on to activate GLi, which undergo nuclear
translocation, serve as transcription factors that upregulate genes involved in cell growth and survival. This is the process
involved in normal Hedgehog pathway signaling. In the presence of a mutation in PTCH1, SMO signaling occurs constitutively.
Vismodegib inhibits SMO signaling through direct interaction with SMO.
GLi: Glioma-associated oncogenes; Hh: Hedgehog; PCTH: Patched; SMO: Smoothened; SUFU: Suppressor of fused.

CI

O
N
H

O
CI

Figure 2. Vismodegib chemical structure.

3.

Pharmacology of vismodegib

The chemical name of vismodegib is 2-chloro-N-(4chloro-3-(pyridin-2-yl)phenyl)-4-(methanesulfonyl)benzamide (Figure 2). It is an oral agent with an approved dose
of 150 mg once daily. It exerts its mode of action by
potently inhibiting SMO on the target cell (Figure 1).
Pharmacokinetic analysis of vismodegib has revealed a
number of unusual properties. Vismodegib is avidly protein
bound and strongly correlated with a-1-acid glycoprotein
(AAG) levels. Parallel fluctuations of AAG and total drug exist

over time and consistently low, unbound drug levels are also
evident [15]. The Phase I study of vismodegib explored three
dose levels: 150, 270 and 540 mg orally once daily [16].
Patients given a single dose followed by a 7-day washout
period revealed very little decline in plasma concentrations
between days 2 and 8, which would indicate a very long
half-life. Continuous daily dosing, irrespective of dose level
used, revealed steady-state plasma concentrations were
reached within 7 -- 14 days. Based on these observations and
given that clinical efficacy was seen at the 150 mg dose, this
became the dose level to move forward in to Phase II trials.
A subsequent pharmacokinetic study reaffirmed this to be
the most appropriate dose level [17]. In this study, a daily
dosing at 150mg was compared to a 3-times-weekly and
once-weekly schedule. Plasma levels of vismodegib were
found to be 50% lower in the 3-times-weekly and 80% lower
in the once-weekly schedule compared with continuous daily
dosing. As the adverse events and efficacy associated with vismodegib are probably a result of interaction with the same
pathway, decreasing vismodegib exposure to avoid adverse

Expert Opin. Drug Saf. (2014) 13(8)

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T. G. Lyons et al.

Table 1. Clinical studies of vismodegib in basal cell carcinoma.

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Ref.

Phase

Patients

Von Hoff et al. (2009) [19]

LoRusso et al. (2011) [16]

n = 18 mBCC
n = 15 laBCC

Sekulic et al. (2012) [20]

II

n = 33 mBCC
n = 63 laBCC

Tang et al. (2012) [23]

II

Chang et al. (2014) [22]

Expanded access

n
n
n
n

Sekulic et al. (2014) [21]

II (24 mts follow-up data)

=
=
=
=

41
26 vismodegib
15 placebo
119

n = 33 mBCC
n = 63 laBCC

Response
mBCC = OR 50%
laBCC = OR 60%
MDR 12.8 mts
mBCC = OR 30%, PFS 9.5 mts, MDR 7.6 mts*
laBCC = OR 43%, CR 21%, PFS 9.5 mts,
MDR 7.6 mts*
Rate of new BCC
2 (vismodegib) versus 29 (placebo) p < 0.001
mBCC = OR 30.8%
laBCC = OR 46.4%
mBCC = OR 48.5% MDR 14.8 mtsz
laBCC = OR 60.3% MDR 26.2 mtsz

*Independently assessed objective response rate.

z
Investigator assessed objective response rate.
BCC: Basal cell carcinoma; CR: Complete response; laBCC: Locally advanced BCC; mBCC: Metastatic BCC; MDR: Median duration of response; mts: Months;
OR: Objective response; PFS: Progression-free survival.

events by lower or less frequent dose regimens may have a

negative impact on efficacy and should be avoided [17].
A study that evaluated the food effect on the pharmacokinetics of vismodegib showed there are no pharmacokinetic
or safety differences between fasting and fed groups at steady
state. Vismodegib may be taken with or without food for daily
dosing [18]. Vismodegib is metabolized by oxidation, glucuronidation and pyridine ring cleavage. Excretion is via feces
(82%) and urine (4%). There are currently no published studies investigating if a dose modification is required in either
renal or hepatic impairment.
4.

Drug--drug interactions

Concomitant treatment with strong CYP inducers (e.g.,

rifampin, carbamazepine or phenytoin) should be avoided,
as a risk for decreased plasma concentrations and decreased
efficacy of vismodegib cannot be excluded.
Vismodegib is a substrate of P-glycoprotein (P-gp). When
vismodegib is co-administered with drugs that inhibit P-gp
(e.g., clarithromycin, erythromycin, azithromycin), systemic
exposure of vismodegib and incidence of adverse events of
vismodegib may be increased.
Vismodegib is highly protein bound. When co-administered with drugs that are also protein bound, there is potential
for displacement. Monitor closely for agents with a narrow
therapeutic index that are highly protein bound such as warfarin, which may result is warfarin displacement and elevations
in international normalised ratio.
5.

Clinical effectiveness of vismodegib

The efficacy of vismodegib in BCC has been demonstrated in

both Phase I and II clinical trials (Table 1). A Phase I study
enrolled 68 patients with refractory, locally advanced or
1128

metastatic solid tumors, of which 33 patients had advanced

BCC. The initial results of the BCC cohort were published
in 2009 with longer follow-up data reported in 2011 [16,19].
The overall response rate (complete and partial) in advanced
BCC was 19 of 33 (58%). The median duration of response
was 12.8 months (range 3.7 -- 26.4 and ongoing).
A Phase II, multicenter, international, nonrandomized
study (ERIVANCE BCC) enrolled 33 patients with mBCC
and 63 patients with locally advanced disease [20]. The study
met its primary end point of independently assessed objective
response rate (ORR) in both cohorts. For mBCC they used
Response Evaluation Criteria in Solid Tumors, version 1.0.
Because a standard end point for laBCC did not exist when
this study was designed, response was defined as a decrease
in 30% or more in externally visible or radiographic dimension or complete resolution of ulceration. The primary
objective was to test whether the response rate was > 10% in
mBCC patients and > 20% among patients with laBCC.
The ORR in the metastatic group was 30%, median duration
of response 7.6 months (range 2.1 -- 11.1) and progressionfree survival (PFS) was 9.5 months. In the locally advanced
group, the ORR was 43%, with 13(21%) achieving a
complete response. The median duration of response was
7.6 months (range 1.0 -- 12.9) and PFS was 9.5 months.
Overall survival data for both cohorts were not mature at
the time of publication [20]. A recently updated analysis of
the ERIVANCE study with a further 24 months of followup has been reported [21]. The results are based on investigator
assessment not independent assessment as reported in the
original paper. The ORR was 60.3% among patients with
laBCC and 48.5% among patients (10/33) with mBCC [21].
These results are similar to the investigator assessment in the
original publication (ORR in laBCC 60% and mBCC
45%) [20]. The median duration of response was 26.2 months
for patients with laBCC and 14.8 months for patients with

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Vismodegib

mBCC compared with 7.6 months (laBCC) and 12.9 months

(mBCC) from the prior report as by investigator review [21].
An expanded access study of patients with advanced BCC
treated with vismodegib involved 119 patients who received
the drug for a median of 5.5 months. The ORR was 46.4%
in those with locally advanced disease and 30.8% in those
with metastatic disease [22].
Tang et al. in 2012 conducted a Phase II, randomized,
double-blind, placebo-controlled trial in patients with basal
cell nevus syndrome. Forty-one patients at three clinical centers were enrolled. These patients were followed for a mean
of 8 months (range 1 -- 15) after enrolment. The rate of
new surgically eligible BCCs was lower with vismodegib
than placebo (2 vs 29 cases; p < 0.001), as was the size of existing clinically significant BCCs (p = 0.003). In some patients,
all BCCs clinically regressed. No tumors progressed during
treatment with vismodegib [23].
Based on the results of the above-mentioned trials, specifically the pivotal Phase II ERIVANCE BCC study [20], on the
30 January 2012 vismodegib (Erivedge, Genentech) was
approved in a priority review program by the FDA, for the
treatment of metastatic or laBCC [24].
6.

Safety and tolerability of vismodegib

The adverse effect profile of vismodegib has been consistent

throughout Phase I and II studies. The drug is generally
well tolerated with the majority of adverse events being of
grade 1 or 2 severities. The most commonly reported adverse
events include, muscle spasms (68%), alopecia (63%), dysgeusia (51%), decrease in weight (46%) and fatigue (36%)
[20]. Amenorrhea was experienced in 50% of premenopausal
women (four of eight patients) [22]. The Hh pathway is crucial
to embryogenesis and therefore the potential for teratogenesis
is high. This risk was demonstrated in rat studies [25]. The
FDA has issued a black box warning regarding the potential
for embryo--fetal death. Pregnancy status must be verified
prior to the initiation of vismodegib and during treatment.
Advise male and female patients of the risks of embryo--fetal
death and severe birth defects. If vismodegib is used during
pregnancy or if the patient becomes pregnant while taking
(or for a male patient, if his female partner is exposed to)
vismodegib, the patient should be appraised of the potential
hazard to the fetus. All female patients must be counseled
regarding these risks and use effective contraception and
men are advised to use barrier contraception to avoid female
exposure to vismodegib through semen.
One significant observation noted from the clinical trials
with the use of vismodegib was the high rate of drug discontinuation for reasons other than disease progression. In the
Phase II study, over 25% of patients in the locally advanced
group discontinued vismodegib for personal reasons [20], the
reasons for this decision were not documented. In the basal
cell nevus syndrome trial by Tang et al., 54% of patients
had discontinued vismodegib due to side effects [23]. Although

the adverse effect profile is generally mild-to-moderate in

most cases, the persistence and chronicity of these side effects
do limit the duration in which patients are willing to continue
taking this drug.
7.

Resistance to vismodegib

Despite impressive objective responses, including complete

responses, in both metastatic and in laBCC treated with vismodegib, the median duration of response was 7.6 months
in Phase II studies [20]. The development of drug resistance
is an issue with this agent and other targeted agents (Figure 3).
Several mechanisms of resistance to vismodegib have been
identified.
Yauch et al. showed how a male patient treated with vismodegib in the Phase I setting for metastatic medulloblastoma,
initially had a dramatic response in all sites of disease but
progressed after 3 months of treatment [26]. In the pretreatment samples taken from this patient, a somatic mutation in
PTCH1 (PTCH1-W844C) was identified. Further biopsies
taken on progression, revealed the presence of the same mutation in PTCH1 in addition to a second new mutation in
SMO. This was a heterozygous G-to-C missense mutation,
which changed a single amino acid, Asp to His at codon
473 [26]. SMO-D473H mutation was not identified in the
pretreatment biopsies. The single amino acid substitution
caused by SMO-D473H mutation results in loss of physical
interaction between vismodegib and SMO and thereby prevents drug binding to its target and confers resistance [26].
A secondary mutation in SMO has also been identified in a
patient with BCC who progressed on vismodegib, suggesting
that similar methods of acquired resistance may apply [27].
In vitro studies carried out by Dijkgraaf et al. revealed resistance mechanisms that included mutations at SMO-E518K,
which conferred complete resistance to vismodegib [28].
Amplifications of the transcription factor GLI 2 and the target
gene Ccnd1, which act downstream of SMO may also
contribute to resistance [28]. The PI3K pathway has been
implicated in the pathogenesis and resistance of Hh-driven
medulloblastoma in mouse models [29].
Approaches to overcome resistance are being studied.
One such approach is to develop second-generation SMO
inhibitors that will still be active in the presence of resistant
mutations [28]. Itraconazole, an approved antifungal drug,
inhibits the Hh pathway, and has a different mechanism of
action compared to vismodegib, and is less potent [30]. An
open-label exploratory Phase II trial of this agent was carried
out [31]. The primary goals were to evaluate whether
itraconazole-induced inhibition of the Hh pathway activity
(GLI1) could reduce tumor proliferation (Ki67) and tumor
size in human BCC. Twenty-nine patients were enrolled
over two sites, 19 of whom received itraconazole and 10
patients in the control group. Of the 19 patients, cohort A
(n = 15) received itraconazole 200 mg twice daily and cohort
B (n = 4) received itraconazole 100 mg twice daily. Initial

Expert Opin. Drug Saf. (2014) 13(8)

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T. G. Lyons et al.

A.

Before treatment

B.

After treatment

and in the neoadjuvant setting may expand the clinical role

for this drug.

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9.

Figure 3. Vismodegib activity and development of resistance

in a patient with locally advanced basal cell carcinoma
(BCC). A. Shows a picture of a 52-year-old male patient
treated at our facility. He presented with a locally advanced
BCC on his posterior neck and back and was treated with
vismodegib. B. Shows a picture of the same patient after
26 weeks of treatment with vismodegib, showing the
excellent response to therapy but also the development of
two new biopsy-proven BCC nodules (arrows).

biopsy and post-treatment excision were available for analysis.

Results for the 19 patients, showed reduced cell proliferation
by 45%, Hh pathway activity by 65% and reduced tumor
area by 24% [31]. Tumors from the untreated control group
showed no significant changes in proliferation or tumor size.
This trial shows activity of the drug in BCC and larger trials
of longer duration directly comparing or in combination
with other Hh pathway inhibitors may provide additional
treatment options. Finally, using antagonists of targets downstream of SMO such as Gant61 that blocks GLI function may
overcome resistance of SMO inhibition [32].

8.

Conclusion

The Hh pathway plays a crucial role in the pathogenesis of

BCC. The identification of a drugable target with the subsequent development of vismodegib, a first-in-class SMO inhibitor marks a great advance in the management of patients with
metastatic or laBCC. This drug provides an important therapeutic option that until recently was lacking for this stage of
disease. Although generally well tolerated, cumulative toxicity
can be an issue. An understanding of the long-term impact of
use of this drug and its effect on patient quality of life and
compliance is critical. The high rate of drug discontinuation
may limit its role in the treatment of BCC. Mechanisms of
resistance and strategies to overcome it are under investigation
and promising approaches include second-generation SMO
inhibitors that are active despite presence of resistant mutations and use of antagonists to block targets downstream of
SMO. Vismodegib is approved only for metastatic or laBCC
but ongoing studies examining its role in earlier stage disease
1130

Expert opinion

Vismodegib is a new therapeutic option for individuals

presenting with metastatic or locally advanced stage BCC.
Current systemic treatment options for these patients are limited. Response to platinum-based chemotherapy has been
reported in a small number of limited case series. There are
no randomized trial data available to guide best practice.
However, based on impressive response rates in a Phase II
study, vismodegib received approval as a first-in-class, smallmolecule oral Hh inhibitor, for patients with laBCC or
mBCC. Vismodegib should not be offered as an alternative
to surgery or radiotherapy in earlier stage disease outside
of well-designed clinical trials. A number of such trials are
underway, investigating its use in the neoadjuvant setting
(Clinicaltrials.gov NCT01898598 and NCT01201915) and
in combination with radiation therapy (Clinicaltrials.gov
NCT01835626). FDA approval was based on Phase II evidence, the patient number was relatively small, there was no
control group or a comparator group and survival data have
not been presented so longer term follow-up and larger exposure to the drug is required to fully appreciate its clinical
utility into the future. The STEVIE study (A Study of Vismodegib in patients with locally advanced or metastatic BCC,
Clinicaltrials.gov NCT01367665) aims to provide more efficacy and safety information with the use of this drug. It plans
to enroll 1200 patients and estimated date of completion
is 2016.
The clinical effectiveness of the drug is offset by a toxicity
profile that is generally regarded as mild-to-moderate, but a
proportion of patients discontinued the drug due to intolerability, most commonly muscle cramps and taste disturbance.
Methods to improve tolerance are needed for this drug and
other Hh inhibitors under development.
As with most targeted agents, drug resistance is a challenge
and understanding mechanisms of resistance is an active
area of research. With regard to vismodegib, acquisition of a
secondary mutation in SMO has been shown to confer resistance. The development of second-generation SMO inhibitors,
which are active despite this additional mutation, may
overcome this resistant pathway. Another approach that could
be very interesting is the development of drugs whose targets
are downstream of SMO. This approach has been used in other
cancer types, for example, BRAF mutant melanoma and use of
MEK inhibitors. The targeting of GLI with Gant61 may overcome resistance to vismodegib. If these drugs are shown to be
effective then the question of combination therapies versus
sequencing will arise. Further studies will then be required to
provide answers to these clinical questions. Although BCC is
the most common human cancer, advanced stage disease is relatively rare. Therefore, international collaboration is essential
in further clinical trials to accrue patient numbers that will

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Vismodegib

provide statistically robust data to guide clinical practice in this

disease in to the future.
Vismodegib has received approval for patients with
advanced stage disease but its potential in earlier stage disease
is not to be overlooked. The use of the drug in the neoadjuvant setting is promising. Patients who before the availability
of this drug would have been deemed inoperable may now
become operable with the potential for cure a real possibility.
But given the high chance of resistance one must be vigilant to
perform any surgery at the most appropriate time interval in
order to achieve the best outcome for the patient. In patients
with metastatic disease, vismodegib should be used only in
those who are symptomatic. BCC is a slow-growing tumor
and unnecessary exposure to the drug will result in toxicity,
risk in development of resistance, with no supportive
published survival benefit to date. Finally, vismodegib has
the potential to be used at a much earlier stage of disease if
a topical or intralesional formulation is developed. This agent
could prove superior to other topical therapies, which are
being used at present and would carry less systemic toxicity.
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Declaration of interest
The author has no 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. This includes employment,
consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.

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Affiliation
Tomas G Lyons1, Grainne M OKane1 &
Catherine M Kelly2

Author for correspondence

1
Specialist Registrar in Medical Oncology,
Mater Misericordiae University Hospital,
University College Dublin,
Department of Medical Oncology,
Eccles Street, Dublin 7, Ireland
2
Consultant Medical Oncologist,
Mater Misericordiae University Hospital,
University College Dublin,
Department of Medical Oncology,
Eccles Street, Dublin 7, Ireland
Tel: +353 1 8032990;
Fax: +353 1 8056284;
E-mail: ckelly@mater.ie