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[Dermatology Reports 2011; 3:e55] [page 125]
Long-term safety, tolerability,
and efficacy of vismodegib in
two patients with metastatic
basal cell carcinoma and basal
cell nevus syndrome
Glen J. Weiss,1 Raoul Tibes,1
Lisa Blaydorn,1 Gayle Jameson,1
Molly Downhour,1 Erica White,1
Ivor Caro,2 Daniel D. Von Hoff1
1Virginia G. Piper Cancer Center at
Scottsdale Healthcare, Scottsdale, AZ,
2Genentech, South San Francisco, CA,
USA
Abstract
Tumor responses in advanced basal cell car-
cinoma (BCC) have been observed in clinical
trials with vismodegib, a SMO antagonist. The
result of SMO antagonism is inhibition
Hedgehog Signaling Pathway (HHSP) down-
stream target genes. HHSP inhibition has
been shown to affect stem cells responsible for
blood, mammary, and neural development. We
report on our experience of treating two
patients with advanced BCC participating.
These two patients have had no new BCCs
develop for at least 2.25 years. Both patients
have been receiving ongoing daily treatment
with vismodegib for greater than 2.75 years
without experiencing any significant side
effects. After prolonged continuous daily dos-
ing with a SMO antagonist, we have not
observed a significant alteration in hematolog-
ic parameters or physical abnormalities of the
pectoral regions of two patients with advanced
BCC.
Introduction
The hedgehog signaling pathway (HHSP)
is an important pathway for growth and devel-
opment, including promotion of primitive
hematopoietic,1 neural,2 and mammary3 stem
cells. It is also required to bring the hair folli-
cle from the resting to the growth phase.4
Loss of heterozygosity and inactivation muta-
tions in PTCH1 and SMO have been implicat-
ed in the development of the majority of basal
cell carcinomas (BCCs)5-7 and in patients
with basal cell nevus syndrome (BCNS).7,8
Vismodegib (GDC-0449) is a synthetic small
molecule inhibitor of SMO that blocks down-
stream HHSP target genes; it has favorable
pharmaceutical properties and greater poten-
cy than cyclopamine.9,10 A phase I dose-find-
ing, safety, and tolerability study of vismodeg-
ib in patients with advanced BCC and solid
tumors was conducted, demonstrating prima-
rily mild to moderate side effects.6,7 Here we
report on our experience of treating two
patients with advanced BCC participating in
the phase I study6,7 who have received ongo-
ing daily treatment for 2.75–>3 years without
experiencing any significant side effects that
might be anticipated with chronic HHSP inhi-
bition.
Case Report #1
A 49-year-old Caucasian man presented to
our clinic with BCC metastatic to the lung and
lymph nodes of the left neck. Eight years ear-
lier he had been treated with cryotherapy and
imiquimod cream for BCCs on the neck.
Approximately 6.5 years later, he underwent
his first surgical excision of cutaneous BCC
of the neck and margins were reportedly pos-
itive. Subsequently, he was found to have
multifocal metastatic BCC in the lungs, con-
firmed by video-assisted thoracic surgery
(VATS) removal of a 1.5 cm left lower lung
mass 1 month before evaluation at our clinic.
His medical history was otherwise unremark-
able except for approximately 2 years of heavy
drinking; he had since abstained for over 2
years.
Physical examination was significant for
healed left flank scar from VATS, several hard,
fixed palpable lymph nodes in the left posteri-
or cervical chain measuring 1-3 cm, and a 3.1
cm hard fixed left supraclavicular lymph node.
There were small cutaneous BCCs in the left
supraclavicular region, left neck (Figure 1A),
and left forearm (one each). Computed
tomography (CT) imaging revealed multiple
pulmonary nodules (~20, the largest was 1.4
cm) (Figure 1B) and multiple left neck
(Figure 1C) and supraclavicular lymph node
involvement (size ranging from 1.4 to 3.1
cm). Fluorine-18-2-fluoro-2-deoxy-D-glucose
positron-emission tomography (PET)/CT
imaging identified 3-5 hypermetabolic foci in
the right and left lung (peak standardized
uptake value [SUV] 12.3) and 10-15 hyperme-
tabolic foci in the left neck and supraclavicu-
lar fossa (peak SUV 14.8).
The patient started receiving oral vismod-
egib 270 mg daily in October 2008. By January
2009, the patient had a confirmed partial
response on CT by Response Evaluation
Criteria in Solid Tumors (RECIST11) and a
complete response on PET/CT (absence of
hypermetabolic foci). By April 2009, only a 0.8
cm pulmonary nodule could be measured on
CT scan. In December 2009, his vismodegib
dose was increased to 300 mg daily when he
transitioned from the phase I protocol to the
extension study; with the transition to the
extension study, the 270 mg dose was no
longer available. He maintained a continuing
partial response until January 2011 (Figures
2A and 2B), when a left axilla metastasis
(non-target progression by RECIST11) was
identified and excised. As of October 2011, he
continues on vismodegib 300 mg daily with-
out evidence of progression or disease recur-
rence elsewhere with continued resolution of
cutaneous BCC (Figure 2C). His only drug-
associated adverse events (AEs) according to
the National Cancer Institute Common
Toxicity Criteria (version 3.0) have been
grade 2 dysgeusia, intermittent grade 1 mus-
cle cramps and fatigue (diminished in fre-
quency by calcium and magnesium supple-
mentation), and grade 2 alopecia. During the
phase I study this patient also reported drug-
related grade 1 intermittent heartburn and
grade 1 weight loss.
Dermatology Reports 2011; volume 3:e55
Correspondence: Glen J. Weiss, Virginia G. Piper
Cancer Center at Scottsdale Healthcare 10510 N.
92nd St., Ste 200, Scottsdale, AZ 85238, USA.
Tel. +1 480 323-1350 - Fax: +1 480 323-1359.
E-mail: gweiss@tgen.org
Key words: basal cell carcinoma, vismodegib,
basal cell nevus syndrome, hedgehog signaling
pathway.
Funding: this study was supported in part by
Genentech.
Acknowledgments: we thank the patients and
their families, Jody Emery, Vickie Marsh, and
Lisa Rumble, and clinical staff for their assis-
tance. Support for third-party writing assistance
for this manuscript was provided by Genentech
Inc. Through the Genentech-Curis collaboration,
vismodegib was discovered by Genentech and
was jointly validated by the parties through a
series of preclinical studies. Genentech and
Roche collaborate on the clinical development
and commercialization of vismodegib.
Disclosures: Genentech provided funding for the
clinical trial involving vismodegib. GJW and
DDVH are investigators on trials involving hedge-
hog signaling pathway inhibitors. IC is an
employee of Genentech.
Received for publication: 11 October 2011.
Accepted for publication: 9 September 2011.
This work is licensed under a Creative Commons
Attribution NonCommercial 3.0 License (CC BY-
NC 3.0).
©Copyright G.J. Weiss et al., 2011
Licensee PAGEPress, Italy
Dermatology Reports 2011; 3:e55
doi:10.4081/dr.2011.e55
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Case Report #2
A 49-year-old Caucasian man with BCNS
and active multifocal cutaneous BCCs was
referred to our clinic. He underwent multiple
therapies for BCC beginning in his 30s includ-
ing Mohs surgeries, some requiring skin graft-
ing, and cryosurgeries. He had recently aver-
aged 5-10 surgeries for BCC annually.
Pertinent medical history included several
family members with BCNS.
Physical examination was significant for
healed surgical scars, and several BCCs of
approximately 0.5 cm on the left cheek and the
right and periorbital region. On high-resolu-
tion ultrasound (HRU), six sonographic abnor-
malities were identified, the largest measur-
ing 0.5 cm in the longest dimension.
The patient started receiving oral vismodeg-
ib 270 mg daily in March 2008. By December
2008, the patient had complete resolution of all
six skin lesions on his face. In November 2009,
his vismodegib dose was increased to 300 mg
daily when he transitioned from the phase I
protocol to the extension study. After more
than 3 years of continuous daily dosing with
vismodegib, his only drug-associated AEs are
grade 1 dysgeusia, intermittent grade 1 muscle
cramps (diminished with exercise), and grade
1 alopecia. Grade 1 fatigue was also reported
during the phase I study. The patient continues
to receive vismodegib 300 mg daily.
Discussion
Inhibition of the HHSP has been shown to
affect stem cells responsible for blood, mam-
mary, and neural development. After at least 3
years of continuous daily dosing, these two
patients have not experienced significant
alteration in hematologic parameters, nor
physical abnormalities of their pectoral
regions. The drug-related AEs observed in
these two patients are all grade 1 or 2, with
dysgeusia, possibly due to an effect on taste
bud papillae.12 Since our initial report on
results treating advanced BCC >18 months
ago,6 these two patients have had no new BCCs
develop for at least 2.25 and 3+ years, respec-
tively, and are tolerating therapy well. Based on
the pharmacokinetic and pharmacodynamic
profile of vismodegib, a dose of 150 mg daily is
under evaluation in further studies.7 Overall,
based on data from these two patients, it
appears that long-term vismodegib use in
adults with advanced BCC can be an effective
therapy with manageable AEs.
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Case Report
Figure 1. Baseline photograph and com-
puted tomography (CT) images of Patient
1: A) photograph of left neck area at base-
line; B) CT scan at baseline showing mul-
tifocal pulmonary nodules several of which
were >1 cm; C) CT scan at baseline show-
ing left neck adenopathy >1 cm.
Figure 2. Response photograph and com-
puted tomography (CT) images of Patient
1: A) CT scan after approximately 28
months of treatment with vismodegib
showing near complete resolution of all
pulmonary nodules; B) CT scan after
approximately 28 months of treatment
with vismodegib showing resolution of left
neck adenopathy.; C) recent photograph of
left neck area following 31 months of treat-
ment with vismodegib.
A
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Case Report
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