Vismodegib A Promising Drug in BCC PDF

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Luc Dirix*1 & Annemie Rutten1

Sint-Augustinus Hospital, Oosterveldlaan 24, Antwerp, Belgium
*Author for correspondence: luc.dirix@gza.be
1
Hedgehog pathway signaling is important for embryonic development; however,

inappropriate reactivation of this pathway in adults has been linked to several
forms of cancer. Vismodegib (Erivedge), a first-in-class hedgehog pathway
inhibitor, blocks the pathway by inhibiting the activity of the signaling protein
SMO. Preclinical studies have provided promising indications of potential tumorreducing activity in several cancers. Thus far, clinical pharmacology and PhaseI
studies have demonstrated the unique pharmacokinetic profile of vismodegib,
its efficacy in certain types of tumors and a generally tolerable adverse-event
profile. A pivotal PhaseII clinical trial confirmed the favorable benefit:risk profile
of vismodegib in advanced basal cell carcinoma.
Normal cellular physiology involves several growth

signaling pathways, alteration of which through
dysregulation or genetic mutation can contribute
to the development of cancer in humans.
The Hedgehog (Hh) family of proteins are
secreted signaling proteins that were first discovered in Drosophila and have since been found in
mammals [1] . Three Hh ligand homologs Sonic,
Desert and Indian play a critical role in controlling epithelial and mesenchymal interactions
in many tissues during human embryogenesis
[1] . On target cells, Hh homologs bind to the
PTCH1 protein, preventing it from repressing
activation of the SMO protein (a 7-transmembrane receptor), thereby allowing downstream
activation of the Hh pathway (Figure 1) . This
Hh-mediated signaling is critical for cell growth
and differentiation during embryogenesis and
early development, controlling cell fate, patterning, proliferation, survival and differentiation in
several regions [2,3] . Hh signaling is also crucial
in ensuring that embryonic tissue develops to its
correct size with adequate vascularization and
innervation [4] .
Relevance of the Hh pathway in cancer
The Hh pathway is generally quiescent in adults,

but inappropriate reactivation of the pathway has
been shown to be involved in the development of
cancer. This was first recognized when it was discovered that a mutation in the PTCH1 gene was
the cause of basal cell nevus syndrome (BCNS),
also known as Gorlin syndrome, a rare condition associated with skeletal, skin and neural
abnormalities, as well as with the development
of multiple skin basal cell carcinomas (BCCs)
10.2217/FON.12.82 2012 Future Medicine Ltd
and an increased risk for medulloblastoma and

rhabdomyosarcoma [5] .
Two different mechanisms drive Hh pathway activation in cancer: ligand-dependent or
paracrine activation; and ligand-independent or
mutation-driven activation. Ligand-dependent
signaling involves overexpression of the Hh
ligand, which activates the pathway in a paracrine manner from the tumor to the surrounding
stroma. This activation feeds other signals back
to the tumor, thereby promoting tumorigenesis.
This mechanism can also regulate proliferation
of cancer stem cells and increases invasiveness
[3,4,6] . The ligand-dependent process is implicated
in the development of some types of solid tumors
including pancreatic cancer, ovarian cancer and
colorectal cancer [2] . Paracrine signaling has also
been implicated in hematologic malignancies,
such as chronic lymphocytic leukemia [7] .
Mutation-driven (ligand-independent) signaling involves inappropriate activation of the Hh
pathway due to the presence of loss-of-function
PTCH1 mutations or activating SMO mutations
in the genes that code for these key regulatory
proteins in the pathway [2] . In patients with
medulloblastoma, mutations in the tumor-suppressor gene, SUFU, have been implicated in
ligand-independent activation of the Hh pathway
[8] . In addition to these findings in medulloblastoma, evidence of ligand-independent activation
of the Hh pathway has been best established in
other tumors including BCC and rare variants of
rhabdomyosarcoma [2] .
Recent studies also indicate that the Hh protein signaling system plays a key role in cancer
stem cell biology, including regulation of stem
Future Oncol. (2012) 8(8), 915928
Drug Evaluation
Future Oncology
Vismodegib: a promising drug in

the treatment of basal cell
carcinomas
Keywords
basal cell carcinoma
hedgehog
pathway inhibitor n targeted
therapy n vismodegib
n
nErivedge n
part of
ISSN 1479-6694
915
Drug Evaluation
Dirix & Rutten
Endogenous
SMO ligand,
SMO agonist
Synthetic
antagonist
Soluble receptor
Small molecule
Inhibitors of
Hh processing
Hh
Cilium
-Hh monoclonal
antibody
SMO
PKA
PTCH1
G protein?
PTCH1
CK1
GSH3
Internalized
Endogenous Hh?
P
GLI1
GLI2
GLI3
GLI1
SUFU
GLI2
Nucleus
GLI3
GLIA
Iguana
Cytoplasm
GLIA
TrCP
SMO
GLIR
Hh target
genes
(PTCH1, GLI1)
Hh target
genes
Future Oncol. Future Science Group (2012)
Figure1. Hedgehog signaling pathway in vertebrates. The above model illustrates our current understanding of the vertebrate Hh
signaling pathway. The Hh signaling cascade is initiated in the target cell by the Hh ligand binding to the PTCH1 protein, a 12-span
transmembrane protein located on the plasma membrane. SMO, a 7-span transmembrane protein receptor, is located on the membrane
of the intracellular endosome. In vertebrates, the Hh signaling pathway is coordinated in the nonmotile primary cilium to which the SMO
and other downstream pathway components transit in order to activate the GLI transcription factors [4,6163] . An endogenous small
molecule acting as a SMO agonist is transported outside the cell by PTCH1, preventing its binding to SMO. In the absence of an Hh
ligand, PTCH1 catalytically inhibits the activity of SMO by affecting its localization to the cell surface. Full-length GLI proteins are thus
proteolytically processed to generate the repressor GLIR, largely derived from GLI3, which represses Hh target genes. Although the exact
mechanism of activation has yet to be determined, some evidence suggests that binding of Hh to PTCH1 internalizes and destabilizes
PTCH1, so that it can no longer transport the endogenous SMO agonist molecules outwards. Intracellular accumulation of this agonist
molecule activates SMO, which translocates to the plasma membrane, apparently concentrating in the cilia [64] . Relief of SMO inhibition
promotes generation of the activator GLIA, largely contributed by GLI2 and the subsequent expression of the Hh target gene [64] .
Hh: Hedgehog.
Adapted by permission from Macmillan Publishers Ltd from [4] 2006. Based on modifications presented in [3] .
cell self-renewal, differentiation and tumorigenic

potential, suggesting that SHH signaling could
contribute to chemoresistance, although more
research is needed [9] .
The discovery of the involvement of aberrant
overactivation of signaling along the Hh pathway in certain cancer types provides potential
targets for innovative therapies that can block
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Future Oncol. (2012) 8(8)
the Hh pathway and thwart the progression of

malignancies. Both invitro and invivo studies have shown that the Hh ligand produced by
colorectal, ovarian, endometrial and pancreatic
tumors stimulates ligand-dependent Hh pathway signaling in the surrounding stroma [1013] .
In tumors such as medulloblastoma, it is mutations in PTCH1 or SMO that lead to abnormal
future science group
Vismodegib: a promising drug in the treatment of basal cell carcinomas
increased cell proliferation and tumor development independent of the Hh ligand. This
mutation-driven process also occurs in BCC [2] .
BCC is a common nonmelanoma skin tumor
that is locally invasive; in some cases progression occurs to locally advanced BCC (laBCC),
in which successful resection can be challenging
[1416] , or metastatic disease (mBCC). The true
incidences of laBCC and mBCC are difficult to
estimate owing to potential selection bias, poor
reporting and the fact that BCC is not included
in the conventional cancer registries [17] . In
BCC, the rate of progression to mBCC has been
estimated from data obtained from case studies
and small case series to be between 0.0028 and
0.55% [17,18] .
Current treatment options for laBCC and
mBCC include surgery, radiotherapy and chemotherapy, although few evidence-based data
exist to guide treatment selection [17,1921] .
However, until very recently there has been no
approved treatment for laBCC or mBCC leaving
an immediate need for consistently efficacious,
well-tolerated pharmacologic therapy that can
increase life expectancy and quality of life for
patients.
Inhibition of the Hh pathway
The feasibility of blocking Hh signaling invivo

was first suggested with the teratogenic phenomena occurring in lambs whose mothers had
ingested the forage plant Veratrum californicum
[22] . A steroidal alkaloid called cyclopamine
was isolated from this plant and was shown to
induce midline deformities, including cyclopia,
by blocking SMO signaling in the developing
lamb fetuses [23] . Inhibition of the Hh pathway
by cyclopamine has been shown to inhibit cell
proliferation and induce apoptosis in several cancer cell lines, including ovarian carcinoma, glioblastoma, colorectal cancer and prostate cancer
[11,2426] . However, cyclopamine has limitations
as a viable therapeutic agent due to its structural complexity, scarcity, poor aqueous solubility and poor chemical stability in acid. These
issues led to efforts to identify small-molecule
Hh antagonists from a different chemical class
[2729] .
IPI-926, is being studied in a PhaseII trial in

patients with metastatic or locally advanced
(unresectable) chondrosarcoma [103] . The SMO
inhibitor BMS-833923 is being studied in several PhaseI trials including one in BCC [104] ,
and in combination with dasatinib in a PhaseII
trial in leukemia [105] . PhaseI trials are ongoing
for the SMO inhibitors PF-04449913 [106] and
TAK-441 [107] in hematologic malignancies and
advanced nonhematologic malignancies, respectively. In addition, the antifungal agent itraconazole has been shown to inhibit the Hh pathway
in mice, and trials are ongoing in patients with
breast and prostate cancer [32,108,109] . Finally,
there is the SMO inhibitor vismodegib (formerly
known as GDC-0449), which will be reviewed
here.
Vismodegib
Description of the molecule
Vismodegib (2-chloro-N-[4-chloro-3-(pyridin2-yl)phenyl]-4-[methylsulfonyl]benzamide)
(Erivedge, Genentech, Inc., CA, USA) is a
low-molecular-weight systemic inhibitor of the
Hh pathway developed by Genentech/Curis
(Figure2) [27] .
Molecule identification
During the molecule identification stage of vismodegib development, high-throughput screening was performed on potential molecules using
a luciferase reporter gene to identify molecules
with inhibitory activity against agonist components of the Hh pathway [27] . Hit-to-lead
optimization of active compounds yielded a
benzimidazole series of molecules but several
physicochemical weaknesses in this series led
to heterocyclic replacements being sought by
manipulating and optimizing 2-pyridyl amides.
This process eventually yielded a potent Hh
Cl
O
N
H
Cl
Hh pathway inhibitors
A number of Hh pathway inhibitors (HPIs) are

in clinical development. The SMO inhibitor
LDE225 has been evaluated as a topical treatment for BCC in PhaseII clinical trials [30,101]
and as an oral agent in PhaseI and II clinical
trials [31,102] . Another selective inhibitor of SMO,
Drug Evaluation
O
S
O
Figure2. Vismodegib.
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Drug Evaluation
Dirix & Rutten
inhibitor with acceptable pharmacokinetic (PK)

properties [27] . Several iterations of the resultant
Hh inhibitor were tested leading to the selection
of GDC-0449. This molecule, now known as
vismodegib, was evaluated in preclinical studies and then progressed into human clinical trials, where it was initially evaluated in advanced
solid tumors, including BCC. Since then, vismodegib has been evaluated in a number of other
indications.
Vismodegib is the first orally bioavailable
small-molecule inhibitor of the Hh pathway and
introduces HPIs as a new anticancer drug class
[33] . Vismodegib targets SMO, a central mediator of Hh pathway signaling, and inhibits both
ligand-dependent and mutation-driven SMOmediated signaling (Figur e 3) [33] . Preclinical
studies demonstrated the antitumor activity of
vismodegib in mouse models of medulloblastoma and in xenograft models of colorectal and
pancreatic cancer [34] .
PK characteristics
Nonlinear PK profile
The PK profile of vismodegib is characterized by less than dose-proportional increases

in plasma concentration with increasing dose
and lower than expected accumulation after
continuous daily dosing; these observations are
suggestive of nonlinear PKs (Figure4) [35] . The
nonlinear PK profile of vismodegib results from
two separate, nonlinear processes: saturable
absorption; and high-affinity, saturable protein
binding. Nonlinear absorption is consistent
with the poor solubility of vismodegib at physiologic pH and is the likely reason for the lack
of a dose-proportional increase in vismodegib
exposure after singledoses of 270 and 540mg

(Table1) . After multiple doses, saturable binding to -1-acid glycoprotein (AAG) results in
concentration-dependent changes in the PKs of
vismodegib [35] .
Unique plasma protein-binding profile
Results from vismodegib PK studies indicate

that, relative to other small molecules, vismodegib interacts uniquely with AAG. Analysis
of plasma samples from 40patients dosed with
vismodegib to steady state revealed a strong correlation between the total plasma concentration
of drug and both human serum albumin and
AAG, with concentrations of AAG and total
drug fluctuating in parallel over time [36] . This
strong correlation suggests high-affinity binding of vismodegib to AAG, which determines
the plasma levels of vismodegib in patients [35] .
Invitro studies found that high concentrations
of AAG (0.5mg/ml) reduced vismodegib inhibition of Hh signaling by more than 100-fold,
indicating that only free vismodegib inhibits Hh
signaling invitro. However, these invitro assays
also confirmed that vismodegib inhibits Hh signaling within the entire physiological range of
AAG concentrations observed in patients in the
PhaseI studies [36,37] .
Drugdrug interactions
Based on a combination of results from invitro

and invivo studies, there appears to be a very
low potential for drugdrug interactions
when vismodegib is administered with other
medications[38,39] .
Results from a dedicated drugdrug interaction study conducted in patients with cancer
Vismodegib
Hh activation
SMO
SMO
SMO
PTCH1
Signal
Constitutive signal
GLI1
GLI1
PTCH1, GLI1
Tumor growth
PTCH1, GLI1
Tumor growth
No signal
GLI1
Inhibition of tumor growth
Future Oncol. Future Science Group (2012)
Figure3. Hedgehog pathway: activation and inhibition. (A) The Hh signal transduction
pathway, (B) loss-of-PTCH1 mutations and (C)inhibition of SMO signaling by vismodegib. Hh
binding to PTCH1 (A) relieves inhibition of SMO activation by PTCH1. In the absence of PTCH1,
because of loss-of-PTCH1 mutations, SMO signaling occurs constitutively (B). Vismodegib inhibits
SMO signaling through direct interaction with SMO (C).
Hh: Hedgehog.
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0.06
150 mg (n = 7)
270 mg (n = 9)
540 mg (n = 4)
Unbound vismodegib plasma

concentration (mol/l)
Total vismodegib plasma

15
10
0
0
150 mg (n = 7)
270 mg (n = 9)
540 mg (n = 4)
0.04
0.02
0.00
0
Time (days)
150 mg (n = 40)
270 mg (n = 23)
540 mg (n = 4)
30
20
10
0
0
14
21
28
35
Time (days)
42
49
56
0.3
Unbound vismodegib plasma
Total vismodegib plasma

40
Drug Evaluation
150 mg (n = 40)
270 mg (n = 23)
540 mg (n = 4)
0.2
0.1
0.0
63
Time (days)
14
21
28
35
42
49
56
63
Time (days)
Figure4. Pharmacokinetics of vismodegib after single- and multiple-dose administration. Plasma concentrations of (A) total
and (B) unbound vismodegib over time are shown after a single dose and after multiple daily doses ((C) total and (D) unbound). For (C)
and(D), pharmacokinetic samples from a patient who discontinued from the study early were not collected after the initiation of
multiple dosing.
demonstrated that vismodegib did not alter the

PKs of rosiglitazone (a cytochrome P2C8 substrate) or of oral contraceptives (ethinyl estradiol
and norethindrone) [40] .
Despite the low potential for drugdrug interactions, caution is advised when dosing vismodegib concurrently with drugs that inhibit the
P-glycoprotein transport protein and drugs
that affect gastric pH, because formal clinical
studies have not been conducted with these
combinations [110] .
Dosing
Based on the PK properties characterized in the

PhaseI study, as well as the observed efficacy,
the 150mg oral daily (QD) continuous dosing
schedule of vismodegib was chosen for PhaseII
trials [35,41,42] . Overall, this dosing regimen is
appropriate for vismodegib based on its clinical activity, tolerability and favorable unbound
concentrations. Importantly, three-times a week
or once-weekly dosing regimens for vismodegib

150mg failed to achieve unbound plasma concentrations previously associated with efficacy
in patients with advanced BCC and medulloblastoma, even after a QD loading-dose phase
[41] . In addition, unbound steady-state vismodegib concentrations were 60 and 85% lower
for the three-times per week and once-weekly
150mg dose regimens, respectively, relative to
the 150mg QD dose regimen. Therefore, it is
essential to consider the nonlinear PKs of vismodegib prior to making a change in the recommended dose. The Hh pathway has been shown
to act as an on/off switch for tumor growth in
xenograft studies, suggesting that small changes
in vismodegib exposure and therefore pathway
suppression could result in large changes in
antitumor activity [43] . Additionally, increasing
the daily dose from 150 to 270 or 540mg did
not result in higher steady-state plasma concentrations of vismodegib. These results and the
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Drug Evaluation
Dirix & Rutten
Table1. Single-dose unbound and total vismodegib pharmacokinetic parameters

from patients enrolled in stage 1.
Patients by dose
cohort
Mean standard deviation

Tmax (days)
Cmax (mol/l)
AUClast (mol/l/h)
150mg (n=7)
2.43 2.22
0.00093 0.0121
0.577 0.769
270mg (n=9)
1.61 1.16
0.0324 0.0247
2.41 1.37
540mg (n=4)
0.834 0.871
0.0292 0.0289
2.43 1.45
150mg (n=7)
2.43 2.22
3.48 1.34
322 185
270mg (n=9)
2.11 0.928
6.34 3.40
839 458
540mg (n=4)
2.04 1.34
6.81 2.69
1010 446
Unbound vismodegib
Total vismodegib
AUClast: Area under the plasma concentrationtime curve from time zero to the last measurable concentration;
Cmax:Maximum plasma concentration of the drug; Tmax: Time to maximum plasma concentration.
Adapted with permission from [35].
lack of an exposureresponse relationship for

clinical efficacy [Graham RA, Jin JY, Benet LZ, Joshi
A, Dresser MJ; Genentech, Inc. (CA, USA). Data on file]
indicate that additional benefit is not expected

with a higher dose of vismodegib and that the
150mg QD schedule should be maintained in
patients with advanced BCC [35,4042] . In clinical trials, the QD vismodegib 150mg schedule
has shown good tolerability and clinical activity
in patients with advanced BCC [42,44] .
Clinical efficacy
PhaseI study
The potential clinical utility of vismodegib has

been explored in a multicenter, open-label, doseescalation, two-stage, PhaseI study involving
68patients with locally advanced or metastatic
tumors refractory to standard therapies or for
which no standard therapy existed (Table2) [37,42] .
Thirty three of these patients had mBCC or
laBCC; the rest included nine pancreatic cancer patients, one medulloblastoma patient and
17patients with other cancer types. In the doseescalation cohort (stage 1 of the study), patients
were treated at increasing vismodegib dose levels
of 150mg (n=41), 270mg (n=23) and 540mg
(n=4) QD to establish the maximum tolerated
dose. In the expansion cohort (stage 2 of the
study), patients received 150 or 270mg of vismodegib QD. Tumor response was assessed by
Response Evaluation Criteria in Solid Tumors
(RECIST) for patients with radiologically measurable disease. A complete or partial response
was confirmed if it was reported on two consecutive occasions at least 4 weeks apart. For patients
with laBCC tumors (and no radiologically measurable disease), tumor response was assessed by
physical examination. A complete response was
920
defined as the disappearance of a palpable or visible tumor, and a partial response was defined as a
reduction of >50% in the diameter of a palpable
or visible tumor.
At data cutoff, the median time of participation in the study was 9.8 months. Of the
33patients with mBCC or laBCC, 18 achieved
an objective response to vismodegib. Of those,
two patients, both with locally advanced disease,
had a complete response and 16patients had a
partial response (nine patients with metastatic
disease and seven with locally advanced disease).
Of the remaining 15patients, 11had stable disease and four had progressive disease. The overall response rate was 50% (95%CI: 2971%)
for patients with mBCC and 60% (95% CI:
3383%) for those with laBCC (Table2) .
In the expansion cohort, tumor responses were
observed in 20patients with BCC and medulloblastoma; 14patients had stable disease as best
response and 28patients had progressive disease
[42] . Overall, vismodegib exhibited an acceptable
safety profile in the PhaseI study with no doselimiting toxicities observed and encouraging
antitumor activity in advanced BCC [37,42] .
PhaseII studies
To date, there are 18 PhaseII studies of vismodegib, 14 of which are still ongoing and four
of which have been reported after completing
primary or final analysis. Two of the PhaseII
studies that have been reported were in patients
with BCC (one with BCNS); the other two were
in patients with non-BCC solid tumors (Table2) .
Basal cell carcinoma
The ERIVANCE BCC study was a pivotal, multicenter, international, two-cohort,

PhaseI (dose escalation/

expansion, two stage)
Open label
Multicenter
PhaseI (dose escalation/ Stage 1 and Stage 2

expansion, two stage)
150mg/day, 270mg/day or
Open label
540mg/day
Multicenter
PhaseII
Multicenter
Nonrandomized
Investigator initiated
PhaseII
Double blind
Placebo controlled
Randomized
Von Hoff etal.

(2009)
(NCT00607724)
LoRusso etal.
(2011)
(NCT00607724)
Sekulic etal. (2012)

(ERIVANCE)
(NCT00833417)
Tang etal. (2012)

(NCT00957229)
Patients with BCNS: n=41

Vismodegib: n=26
Placebo: n=15
n = 104
mBCC: n=33
laBCC: n=71
n = 68
aBCC: n=33
Pancreatic cancer: n=8
Medulloblastoma: n=1
n=33
mBCC: n=18
laBCC: n=15
Stage 1
n=3
Stage 2
n=30
Patients
Reduction in the rate of new

SEBs (per patient per year)
appearing 3months after study
medication (primary end point)
Vismodegib: 2.3per patient per
year (p<0.0001vsplacebo)
Placebo: 29per patient per year
ORR (primary end point)

mBCC: 30.3% (95%CI:
15.648.2%; p = 0.0011)
laBCC: 42.9% (95%CI:
30.556.0%; p < 0.0001)
Duration of objective response
(median)
mBCC: 7.6months
laBCC: 7.6months
PFS (median) by IRF
mBCC: 9.5months
laBCC: 9.5months
ORR:20patients
aBCC: n=19
Medulloblastoma: n=1#
ORR
mBCC: 50% (95%CI: 2971%)
laBCC: 60% (95%CI: 3383%)
Duration of response (median):
8.8months and ongoing
Main efficacy data
Patients with AEs

Grade 3: n=1
Grade 4: n=1
Grade 5: n=0
Patients with AEs

Grade 3: 27.9%
Grade 4: 7.7%
Grade 5: 6.7%
DLT: n=0
Patients with AEs
Grade 3: 29%
Grade 4: 9%
Grade 5: 7%
DLT: n=0
Patients with AEs
Grade 3: n=23
Grade 4: n=1
Grade 5: n=0
Main safety data
[45]
[44]
[42]
[37]
Ref.
Two reports of the PhaseI study SHH3925g were published. Article by Von Hoff etal. reported the treatment effect of vismodegib in advanced BCC patients [37]. Article by LoRusso etal. reported the overall results of
the PhaseI study at the completion of SHH3925g [42].
Eight patients with laBCC were excluded from the efficacy-evaluable population because the independent pathologist could not confirm the diagnosis of BCC.
Assessed by IRF.
In addition to those listed, 17 other types of cancer were present among 68patients.
#
Response observed in medulloblastoma was unconfirmed in the PhaseI study SHH3925g.
Unrelated to vismodegib.
aBCC: Advanced basal cell carcinoma; AE: Adverse event; BCC: Basal cell carcinoma; BCNS: Basal cell nevus syndrome; Bev: Bevacizumab; DLT: Dose-limiting toxicity; FOLFIRI: 5-fluorouracil/folinic acid + irinotecan;
FOLFOX: 5-fluorouracil/folinic acid + oxaliplatin; HR: Hazard ratio; IRF: Independent review facility; laBCC: Locally advanced basal cell carcinoma; mBCC: Metastatic basal cell carcinoma; mCRC: Metastatic colorectal
cancer; ORR:Overall response rate; PFS: Progression-free survival; QD: Daily; SEB: Surgically eligible basal cell carcinoma; SOC: Standard of care.
150mg/day
for 18months (vs placebo)
150mg/day
Stage 1
Single dose day 1, then same
dose from day 8:
150mg/day
270mg/day
540mg/day
Stage 2
150mg/day or 270mg/day QD
Treatment until disease
progression
Study design
Study (year)
(identifier)
Vismodegib dosing
schedule
Table2. Summary of vismodegib clinical studies.
Drug Evaluation
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Two reports of the PhaseI study SHH3925g were published. Article by Von Hoff etal. reported the treatment effect of vismodegib in advanced BCC patients [37]. Article by LoRusso etal. reported the overall results of
the PhaseI study at the completion of SHH3925g [42].
Eight patients with laBCC were excluded from the efficacy-evaluable population because the independent pathologist could not confirm the diagnosis of BCC.
Assessed by IRF.
In addition to those listed, 17 other types of cancer were present among 68patients.
#
Response observed in medulloblastoma was unconfirmed in the PhaseI study SHH3925g.
Unrelated to vismodegib.
aBCC: Advanced basal cell carcinoma; AE: Adverse event; BCC: Basal cell carcinoma; BCNS: Basal cell nevus syndrome; Bev: Bevacizumab; DLT: Dose-limiting toxicity; FOLFIRI: 5-fluorouracil/folinic acid + irinotecan;
FOLFOX: 5-fluorouracil/folinic acid + oxaliplatin; HR: Hazard ratio; IRF: Independent review facility; laBCC: Locally advanced basal cell carcinoma; mBCC: Metastatic basal cell carcinoma; mCRC: Metastatic colorectal
cancer; ORR:Overall response rate; PFS: Progression-free survival; QD: Daily; SEB: Surgically eligible basal cell carcinoma; SOC: Standard of care.
[51]
Safety profile was

reasonably consistent
with that of the
first-line mCRC
standard of care
treatment (Bev and
FOLFOX or FOLFIRI)
No clinical benefit was observed
from the addition of vismodegib
to standard first-line treatment
of mCRC
Patients with mCRC: n=199
Vismodegib: n=98
Placebo: n=101
FOLFIRI/Bev (SOC) +
placebo/vismodegib:
n=64/60
FOLFOX/Bev (SOC) +
placebo/vismodegib:
n=37/38
PhaseII
Randomized
Placebo controlled
Double blind
Berlin etal. (2010)
(NCT00636610)
150mg/day (or placebo)

All patients also received SOC
[50]
Patients with AEs

Grade 3/4
Vismodegib: n=12
(23.1%)
Placebo: n=6
(11.5%)
Grade 5: n=0
PFS (from randomization)
Vismodegib: 7.5months
Placebo: 5.8months
HR: 0.79 (95%CI: 0.461.35;
p=0.39)
Patients with ovarian cancer
in second or third complete
remission
Vismodegib: n=52
Placebo: n=52
PhaseII
Randomized
Placebo controlled
Kaye etal. (2010)
(NCT00739661)
Maintenance therapy
150mg/day (or placebo)
Study design
Vismodegib
Dirix & Rutten
Study (year)
(identifier)
Table2. Summary of vismodegib clinical studies (cont.).
Patients
Main efficacy data
Main safety data
Ref.
Drug Evaluation
nonrandomized study that enrolled patients with

mBCC and laBCC (Table2) [44] . The rationale
for conducting a study of vismodegib in these
patients was the established role of the Hh pathway in the pathogenesis of BCC, supported by
the preclinical data demonstrating specific inhibition of Hh signaling by vismodegib and the
objective responses (55%) observed in laBCC
or mBCC patients who were treated with vismodegib in the PhaseI trial. Due to the lack of
a standard therapy for these patients, and lack
of spontaneous responses expected in a placebo
arm, a randomized confirmatory trial was not
conducted. In the ERIVANCE trial, patients
with laBCC had histologically confirmed BCC
that was either inoperable or for which surgery
would be significantly deforming. Patients
with mBCC had histologically confirmed
RECIST-measurable disease.
Patients received vismodegib 150 mg/day
orally until disease progression or intolerable
toxicity. The primary end point of the study was
objective response rate (ORR), as assessed by an
independent review facility. Tumor response
was defined using RECIST for mBCC; however, because a standard end point for laBCC
did not exist, response was defined as a 30%
decrease in externally visible and/or radiologic
dimension (if applicable), and/or complete resolution of ulceration present at baseline (if applicable). Secondary end points included response
duration, response per investigator, and safety.
A total of 104 patients, 71 patients in the
laBCC cohort and 33 patients in the mBCC
cohort, were enrolled at 31 sites in the USA,
Europe and Australia. For laBCC, the independent review facility ORR was 43% (95%CI:
3156%; p<0.0001) and investigator ORR was
60% (95%CI: 4772%). For mBCC, the independent review facility ORR was 30% (95%CI:
1648%; p=0.0011) and investigator ORR was
46% (95%CI: 2862%). Responses were durable; median duration of response was 7.6months
by independent review facility for both laBCC
and mBCC cohorts. From this pivotal study, it
was concluded that vismodegib provides substantial clinical benefit for patients with advanced
BCC and that targeted inhibition of Hh with
vismodegib is a highly promising new therapy
for this patient population [44] .
Basal cell nevus syndrome
BCNS, also known as Gorlin syndrome, is a

condition in which patients may develop hundreds to thousands of BCCs. BCNS patients
inherit one defective copy of PTCH1, a primary
inhibitor of the Hh signaling pathway. PTCH1

gene mutations and loss of the remaining wildtype allele drive the overactivation of Hh signaling in BCNS as well as many sporadic BCCs
[45] . An investigator-initiated, randomized 2:1,
double-blind, placebo-controlled trial was conducted to evaluate the safety and antitumor
activity of vismodegib in the treatment of BCC
in BCNS. In this study, 41patients with BCNS,
and at least ten surgically eligible BCCs (SEBs)
present at study entry and/or removed during
the previous 2 years, received vismodegib for a
maximum of 18months until disease progression or intolerable toxicity. The primary end
point was reduction in the rate of new SEBs per
patient per year appearing 3months after receiving study medication. Vismodegib significantly
reduced the rate of new SEBs compared with
placebo (2.3vs29 new SEBs per patient per year;
p<0.0001). Furthermore, the size of existing
SEBs, as measured by change from baseline in
the sum of the longest diameters, reduced significantly more with vismodegib than with placebo
(65vs11%, respectively; p=0.003). Median
last study visit was 9months in the active treatment group (Table2) [45] . All tumors responded
to vismodegib treatment, with some patients
achieving near-complete clinical remission.
However, in four patients, once vismodegib was
discontinued, most of the SEBs regrew. Of note,
at interim analysis, the data and safety monitoring board recommended ending the placebo arm
due to statistically significant differences favoring the vismodegib arm. These results further
confirm the essential role of the Hh pathway in
BCCs, and indicate that vismodegib is highly
efficacious in preventing and treating BCCs in
patients with BCNS [45] .
Other tumors
Excessive or inappropriate expression of the Hh

ligand has also been implicated in the pathogenesis of several solid tumors [4649] , indicating that
disruption of Hh may be beneficial in a broad
array of tumor types. Two PhaseII studies have
been completed, one in patients with ovarian
cancer and the other in patients with untreated
metastatic colorectal cancer.
In a randomized, placebo-controlled study,
patients with ovarian cancer in second or third
complete remission received vismodegib 150mg
QD or placebo as maintenance therapy [50] .
Some clinical efficacy benefit was suggested as
being caused by treatment with vismodegib in
this patient population; however, while there
was a trend for improved progression-free
Drug Evaluation
survival compared with placebo, this did not

reach statistical significance (hazard ratio: 0.79;
95%CI: 0.461.35; p=0.39) (Table2) . In a subgroup analysis, greatest benefit was suggested in
patients in second complete remission, but this
was not significantly greater than in the placebo
arm (hazard ratio: 0.66; 95%CI: 0.361.20;
p=0.17). Based on the numerical improvement
in progression-free survival with maintenance
vismodegib, further assessment may be warranted in patients with ovarian cancer in second
complete remission.
Vismodegib was also investigated in combination with standard-of-care first-line therapy
for metastatic colorectal cancer [51,52] . However,
clinical efficacy in this setting was not enhanced
by the addition of vismodegib to either 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX)
plus bevacizumab or 5-fluorouracil/folinic acid
plus irinotecan (FOLFIRI) plus bevacizumab.
Compared with placebo-treated patients, treatment intensity (for all regimen components) was
lower in vismodegib-treated patients, which may
have contributed to the lack of efficacy. Safety
data are summarized in Table2 .
Overall, the results of PhaseII studies conducted to date demonstrate a significant and
substantial clinical benefit for patients with BCC
receiving vismodegib. More studies are needed
to determine the utility of vismodegib therapy
in other forms of cancer.
Drug resistance
It is important to note that drugs that inhibit

the Hh pathway may be susceptible to the familiar challenge of drug resistance. A case study
of a patient with medulloblastoma reported by
Rudin etal. provides an example. In this case,
the authors observed marked initial regression of
the tumor in response to vismodegib, followed
by rapidly acquired resistance [53] . Several mechanisms of acquired resistance to Hh signaling
blockade have been observed with vismodegib
and other SMO inhibitors in animal models,
including chromosomal amplification of Gli2
and SMO-independent activation of Hh by
parallel oncogenic signals, such as phosphatidylinositol 3-kinase [54] . Resistance to HPIs has
also been observed through acquired genetic
mutations leading to reactivated signaling and
restored tumor growth in mouse models [7] . Early
initiation of treatment with SMO inhibitors,
before treatment with DNA-damaging agents
or radiation, may mitigate this issue, as would
the identification of inhibitors of downstream
signaling molecules along the Hh pathway [7] .
923
Drug Evaluation
Dirix & Rutten
Safety & tolerability
Single-agent experience with vismodegib has

been reported for only four studies and is
summarized below [37,42,44,45,50] .
As mentioned previously, vismodegib was generally well tolerated, with no dose-limiting toxicities observed in the PhaseI study [37,42] . The
most frequently reported adverse events (AEs;
>30% of patients) were muscle spasms, dysgeusia, fatigue, alopecia and nausea. Grade5 (fatal)
events related to progression of cancer were
reported (per protocol as AEs) in five patients;
no other grade5 events were reported [42] .
In the ERIVANCE BCC study [44] , the
most common AEs (>30%) of any grade were
muscle spasms (68%), alopecia (64%), dysgeusia (51%), weight decrease (46%) and fatigue
(36%). A number of patients experienced grade
3/4 events, with the most common being weight
decrease (5% of patients), muscle spasm and
fatigue (both 4%). As of the data cutoff date
for primary analysis, approximately 50% of
the patients had discontinued participation in
the study and the median duration of exposure
was approximately 10months in both cohorts
(Table2) . The most common reasons for discontinuation were disease progression in the mBCC
cohort (18%) and patient decision in the laBCC
cohort (25%). Patients reasons for discontinuation due to patient decision were not collected.
In general, vismodegib was well tolerated in
patients with advanced tumors, with AEs mostly
mild-to-moderate in severity. In this study there
were seven grade 5 events: one patient each died
of hypovolemic shock, myocardial infarction,
meningeal disease and ischemic stroke; three
patients died of unknown causes. However, none
of the deaths were considered by the investigators
to be related to vismodegib treatment.
In patients with BCNS who received vismodegib, the majority experienced only grade 1/2
AEs (Table 2) [45] . Compared with those who
received placebo, a significantly greater proportion of patients receiving vismodegib (p<0.01
for all) had grade 1/2 alopecia (62vs7%), muscle cramps (81vs0%), dysgeusia (85vs7%) and
>5% weight decrease (42vs0%). In total, 27%
of patients (7 out of 26) discontinued medication because of AEs over a median period of
9months. Dysgeusia and muscle cramps resolved
within 1month of stopping medication and hair
regrowth started within 3months. There were
no grade 5 AEs reported, but two patients discontinued drug treatment because of grade 3/4
AEs (one grade 4 depression/suicidal ideation
and one grade 3 muscle cramps).
924
Vismodegib was also generally well tolerated

in a study in patients with ovarian cancer [50] .
The most common AEs among vismodegibtreated patients (vs placebo) were muscle spasms
(67.3vs1.9%), dysgeusia (67.3vs17.3%), alopecia (53.8vs7.7%), nausea (32.7vs17.3%),
fatigue (26.9 vs 28.8%) and constipation
(23.1vs9.6%). Most AEs were mild-to-moderate in severity. The number of grade 3/4 AEs
observed was higher in the vismodegib group
versus placebo (25vs11.5%); grade 3/4 events
reported in two or more patients in the vismodegib group were abdominal pain (n=2),
alanine aminotransferase increase (n=2) and
muscle spasms (n=3). No grade 5 AEs were
reported in this study. Six patients in the vismodegib group discontinued treatment due to AEs.
Three patients discontinued because of grade 3
AEs (mucosal inflammation, increased hepatic
enzymes and muscle spasms) and the other three
because of grade 1/2 AEs [50] .
Overall, the AEs experienced by patients in
PhaseI/II studies of vismodegib have been similar in type, severity and incidence [37,41,44,5052] .
Common AEs generally observed in studies of
vismodegib that are hypothesized to be related
to its mechanism of action include muscle
spasms, dysgeusia, alopecia, fatigue and weight
loss [5558] , although further study is needed.
Similar AE profiles have been observed in a
study of another HPI (LDE225) [31] . Decreasing
exposure to vismodegib through lower or less
frequent dose regimens in an effort to avoid these
AEs may have a negative impact on efficacy [41] .
Regulatory affairs
On 30 January 2012 the vismodegib capsule

was approved under the brand name Erivedge
by the US FDA for the treatment of adults with
BCC that has spread to other parts of the body
or that has returned after surgery or that their
healthcare provider decides cannot be resected
or irradiated. As of February 2012, submissions
have been made to several additional global
regulating bodies.
Conclusion
Inappropriate reactivation of the Hh signaling pathway has recently been linked to several human cancers. Therapeutic options that
block the aberrant Hh pathway signaling
involved in tumorigenesis have the potential
to dramatically improve outcomes in patients
with these malignancies. Vismodegib inhibits
the activity of the SMO signaling protein in
the Hh pathway and is the first Hh inhibitor
to gain regulatory approval. Preclinical studies

indicated potential antitumor activity in several cancers. Early clinical trials have revealed
a distinct PK profile for vismodegib and understanding the mechanism underlying these
unique PKs has led to a recommended dose
of 150mg QD. Vismodegib is generally well
tolerated, with some AEs that are class related.
Vismodegib has demonstrated efficacy in some
tumor types, particularly in ligand-independent
Hh signaling-driven tumors such as BCCs and
medulloblastomas. More research is needed to
determine which patients will most benefit from
vismodegib therapy.
Future perspective
While vismodegib has demonstrated safety and

efficacy in the treatment of mBCC and laBCC
it might also be a viable treatment option for
patients with multiple BCCs, even if operable.
Further study may determine the pathological
Drug Evaluation
clearance rate for vismodegib if used in early disease. In the early-disease setting, shorter drug
exposure or intermittent dosing (e.g., continuous
daily dosing for a period of time followed by a
drug holiday) may be an option for clinicians
to maximize outcomes for patients treated with
vismodegib.
The cancer stem cell hypothesis may explain
several phenomena such as drug resistance,
unchecked self-renewal and the development of
metastatic disease. The Hh signaling pathway
has been implicated in all of these processes.
Future studies may explore the potential of combination treatment of vismodegib with another
signal transduction inhibitor and/or cytotoxic
treatment as a means of targeting cancer stem
cells residual after cytotoxic treatment. However,
the diversity of Hh signaling across human cancers suggests that disease-specific factors must be
carefully considered to identify the optimal use
of HPIs such as vismodegib [59] .
Executive summary
Mechanisms of action
Vismodegib 150mg (Erivedge) is a first-in-class, oral medicine that selectively inhibits SMO, a central mediator of Hedgehog
signaling, a pathway implicated in a number of tumors including basal cell carcinoma (BCC).
Pharmacokinetic properties
Vismodegib binds to both -1-acid glycoprotein (AAG) and human serum albumin, with strong affinity for AAG.
Binding to AAG results in a strong correlation between concentrations of AAG and vismodegib in plasma.
Saturation of AAG with 150mg daily dosing is important to maximize unbound concentrations of vismodegib.
Clinical efficacy
Vismodegib has demonstrated substantial clinical benefit for patients with advanced BCC.
Overall response rates of 30% (95%CI: 1648%; p=0.0011) for patients with metastatic BCC and 45% (95%CI: 3156%;
p<0.0001) for those with locally advanced BCC were observed in a pivotal PhaseII study.
Overall response rates of 50% (95%CI: 2971%) for patients with metastatic BCC and 60% (95%CI: 3383%) for those with locally
advanced BCC were observed in a PhaseI study.
Vismodegib has demonstrated substantial clinical benefit for patients with basal cell nevus syndrome and multiple BCC.
Vismodegib was found to cause a significant reduction in the rate of new surgically eligible BCCs compared with placebo.
Vismodegib reduced the size of existing surgically eligible BCCs from baseline; the sum of the longest diameters reduced significantly
more with vismodegib than with placebo.
Safety & tolerability
In general, vismodegib was well tolerated in patients with advanced tumors, with adverse events mostly mild-to-moderate in severity.
Most frequently reported adverse events in clinical trials overall were muscle spasms, dysgeusia, fatigue, alopecia, weight decrease and
nausea.
These adverse events are hypothesized to be related to Hedgehog signaling inhibition.
Drug interactions
Based on a combination of results from invitro and invivo studies, there appears to be a very low potential for drugdrug interactions
when vismodegib is administered with other medications.
Dosage & administration
A 150mg daily regimen is appropriate for vismodegib, based on its clinical activity, tolerability and favorable unbound concentrations
at this dose level.
Regulatory affairs
Vismodegib was approved by the USFDA on 30 January 2012 for the treatment of adults with BCC that has spread to other parts of
the body or has returned after surgery, or that their healthcare provider decides cannot be resected or irradiated.
925
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Dirix & Rutten
The potential of targeting cancer stem cells

with Hh signaling inhibitors in combination
with a cytotoxic agent has been investigated
in mouse models by Olive etal. By targeting
the Hh signaling pathway in tumor-associated
stroma, and with their higher therapeutic index
and longer half-life relative to cytotoxic agents,
HPIs may improve the delivery and efficacy of
therapeutics in patients with difficult-to-treat
malignancies such as pancreatic carcinoma [60] .
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Luc Dirix*1 & Annemie Rutten1

Hedgehog pathway signaling is important for embryonic development; however,

Normal cellular physiology involves several growth

The Hh pathway is generally quiescent in adults,

and an increased risk for medulloblastoma and

Vismodegib: a promising drug in

Dirix & Rutten

Future Oncol. Future Science Group (2012)

cell self-renewal, differentiation and tumorigenic

Future Oncol. (2012) 8(8)

the Hh pathway and thwart the progression of

Vismodegib: a promising drug in the treatment of basal cell carcinomas

The feasibility of blocking Hh signaling invivo

IPI-926, is being studied in a PhaseII trial in

A number of Hh pathway inhibitors (HPIs) are

Dirix & Rutten

inhibitor with acceptable pharmacokinetic (PK)

The PK profile of vismodegib is characterized by less than dose-proportional increases

exposure after singledoses of 270 and 540mg

Results from vismodegib PK studies indicate

Based on a combination of results from invitro

Inhibition of tumor growth

Future Oncol. Future Science Group (2012)

Future Oncol. (2012) 8(8)

future science group

Vismodegib: a promising drug in the treatment of basal cell carcinomas

Unbound vismodegib plasma

Total vismodegib plasma

Total vismodegib plasma

demonstrated that vismodegib did not alter the

Based on the PK properties characterized in the

or once-weekly dosing regimens for vismodegib

Dirix & Rutten

Table1. Single-dose unbound and total vismodegib pharmacokinetic parameters

Mean standard deviation

lack of an exposureresponse relationship for

indicate that additional benefit is not expected

The potential clinical utility of vismodegib has

Future Oncol. (2012) 8(8)

The ERIVANCE BCC study was a pivotal, multicenter, international, two-cohort,

PhaseI (dose escalation/

PhaseI (dose escalation/ Stage 1 and Stage 2

Von Hoff etal.

Sekulic etal. (2012)

future science group

Tang etal. (2012)

Patients with BCNS: n=41

Reduction in the rate of new

ORR (primary end point)

Main efficacy data

Patients with AEs

Patients with AEs

Main safety data

Table2. Summary of vismodegib clinical studies.

Vismodegib: a promising drug in the treatment of basal cell carcinomas

Safety profile was

150mg/day (or placebo)

Patients with AEs

Dirix & Rutten

Table2. Summary of vismodegib clinical studies (cont.).

Main efficacy data

Main safety data