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EADV: Vismodegib treatment breaks don’t hurt efficacy
BY BRUCE JANCIN
Frontline Medical News
At the EADV congress 2015, Copenhagen
T
reatment breaks due to adverse
events in patients taking vismo-
degib for advanced basal cell
carcinoma do not appear to com-
promise the oral hedgehog pathway
inhibitor’s efficacy; in fact, they
might even enhance it, according
to a prespecified interim analysis of
the STEVIE trial.
STEVIE is an ongoing phase II,
long-term, open-label international
study designed primarily to assess
the safety of vismodegib in a situa-
tion similar to routine clinical prac-
tice. Efficacy and impact on quality
of life are secondary endpoints. Al-
though STEVIE has enrolled 1227
patients, a prespecified interim
analysis was conducted in the first
499 followed for at least 12 months,
of whom 468 had locally advanced
basal cell carcinoma (BCC) and
31 had metastatic BCC, explained
Dr Johan Hansson, an oncolo-
gist at the Karolinska Institute in
Stockholm.
The drug was dosed at 150 mg
once daily continuously in 28-day
cycles until disease progression,
intolerable toxicity, or study with-
drawal. Safety follow-up was con-
ducted at 1, 3, 5, 9, and 12 months.
In an earlier report, the complete
and partial response rates were 34%
and 33%, respectively, in patients
with locally advanced BCC, and
7% and 31% in those with meta-
static disease
(Lancet Oncol
2015
Jun;16[6]:729–36).
Dr Hansson presented new data on
efficacy outcomes broken down ac-
cording to treatment breaks, as well
as quality of life results, at the annual
congress of the European Academy
of Dermatology and Venereology.
Twenty-six percent of patients
had one or more treatment breaks.
Seventy-six patients had one, 41 had
two, and 14 had three or more. The
median duration of the breaks was 22
days. The two most frequent reasons
for treatment breaks were intolerable
adverse events in 53% of cases, and
lesser adverse events in 23%.
Close to 100% of STEVIE par-
ticipants had treatment-emergent
adverse events. The most common
were muscle spasms, alopecia, al-
tered sense of smell, and weight loss.
Although the number of pa-
tients with treatment breaks was
relatively small, the response rates
were higher in patients with more
treatment breaks. So was median
treatment duration as well as the
median number of capsules taken.
Median progression-free survival
was 19.8 months in patients with no
treatment breaks, was 19.0 months
in those with one, and hasn’t yet
been reached in patients with two
or more breaks.
In interpreting these findings,
Dr Hansson said, “We have to re-
member that although intriguing,
these are tentative results from an
exploratory analysis of subgroups
in an ongoing study and should be
interpreted with caution.”
The oncologist added, however,
based upon these promising results
he and his coinvestigators plan to
look further into the concept of
deliberate intermittent dosing of
vismodegib.
Quality of life was assessed using
the Skindex-16 questionnaire at
baseline, again after two and seven
28-day cycles of vismodegib, and
at 12 months. Three domains were
examined: emotion, function, and
symptoms.
A clinically meaningful improve-
ment – defined as a 10-point or greater
reduction from baseline – was seen in
the emotion domain at all time points
in patients with locally advanced
BCC, with median improvements of
14.3 points after two cycles and 23.8
points after seven cycles and at the
12-month mark. Clinically meaning-
ful improvement in symptom scores
on the Skindex-16 were noted in pa-
tients aged 65 and older, in women,
and in those with BCCs in locations
other than the head or neck. However,
no clinically meaningful improvement
in the domain of function was seen
at any time in patients with locally
advanced BCC.
Patients with metastatic BCC
didn’t show significant improvement
in any of the three quality of life
domains at any time point, added
Dr Hansson.
The STEVIE trial is sponsored by
F. Hoffmann–La Roche/Genentech.
Dr Hansson reported receiving re-
search grants from and serving as a
consultant to Bristol-Myers Squibb,
GlaxoSmithKline, Merck, Novartis,
and Roche.
We have to remember that
although intriguing, these
are tentative results from
an exploratory analysis of
subgroups in an ongoing study
and should be interpreted
with caution.
Impact of vismodegib treatment breaks
Number of treatment breaks
None
One
Two
Three or
more
Median treatment duration, days
223.5
289
399
454
Median dose intensity
97% 89% 86% 81%
Median number of capsules taken
215
256
354
380
Occurrence of grade 3 or higher
TEAEs*
39% 45% 66% 79%
Grade 5 events
5% 4%
0
7%
Complete response
30% 33% 51% 39%
Partial response
31% 32% 44% 46%
Stable disease
28% 32% 5% 15%
*treatment-emergent adverse event
Note: The interim analysis included the first 499 patients followed for at least 12 months.
Source: Dr Hansson
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SEE APPROVED PRODUCT INFORMATION BEFORE PRESCRIBING. APPROVED PRODUCT INFORMATION AVAILABLE FROM
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Minimum Product Information ZYDELIG
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(idelalisib) 100 mg and 150 mg Tablets. INDICATIONS:
with rituximab for CLL/SLL where chemo-immunotherapy is unsuitable, either: upon relapse after at least one
prior
therapy, or first-line with 17p deletion or
TP53
mutation. Monotherapy of refractory follicular lymphoma after at least two prior systemic therapies.
DOSAGE AND ADMINISTRATION:
150 mg twice daily. Dose modification may be required.
CONTRAINDICATIONS:
hypersensitivity.
PRECAUTIONS: Hepatotoxicity:
monitoring required.
Hepatitis Infection and Reactivation:
prior screen for HBV and HCV.
Diarrhoea/Colitis:
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shouldbeconsidered inseverecases.
Pneumonitis:
Dose interruptionshouldbeconsideredwithanyseverityofsymptomaticpneumonitis.
Immunisation:
Vaccinationprior to treatmentofpatientsatsubstantialriskofan infection.
Neutropenia,
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life-threatening (Grade
≥
3) cutaneous reactions. Fatal cases of SJS-TEN have occurred when patients were treated with Zydelig when administered
concomitantly with other medications associated with SJS-TEN. Treatment should be interrupted immediately if SJS or TEN is suspected and permanently discontinued where there is a case of severe cutaneous reaction.
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discontinue permanently.
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Effects on Fertility:
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Pregnancy (Cat. D). Lactation. Children (<18 years). INTERACTIONS WITH OTHER MEDICINES:
Effects of other drugs on Zydelig:
CYP3A Inducers (rifampin, phenytoin, St. John’s Wort, or carbamazepine). CYP3A Inhibitors (ketoconazole).
Effects of Zydelig on other drugs:
CYP3A Substrates (alfentanil, cyclosporine, sirolimus,
tacrolimus, cisapride, pimozide, fentanyl, quinidine, ergotamine, dihydroergotamine, midazolam, certain antiarrhythmics, calcium channel blockers, benzodiazepines, HMG-CoA reductase inhibitors, phosphodiesterase-5 (PDE5) inhibitors,
and warfarin), refer to full PI.
ADVERSE EFFECTS:
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This is not the full Product Information. Please
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Date of preparation 16 December 2015.
References: 1.
Furman RR
et al. N Engl J Med
2014;370:997–1007.
2.
Sharman JP SE
et al.
Second Interim Analysis of a Phase 3 Study of Idelalisib (ZYDELIG ) Plus Rituximab (R) for Relapsed Chronic
Lymphocytic Leukemia (CLL): Efficacy Analysis in Patient Subpopulations with Del(17p) and Other Adverse Prognostic Factors. The American Society of Hematology (ASH) 56th Annual Meeting, 6–9
December 2014, San Francisco, CA, USA: Abstract 330.
3.
Coutre SE
et al.
Second interim analysis of a phase 3 study evaluating idelalisib and rituximab for relapsed CLL.
J Clin Oncol
2014;32(Suppl):
Abstract 7012.
4.
Gopal AK
et al. N Engl J Med
2014;370:1008–18
4.
Salles G
et al.
Idelalisib efficacy and safety in follicular lymphoma patients from a phase 2 study.
J Clin Oncol
2015;33(Suppl):
Abstract 8529.
6.
Zydelig Product Information, 16 December 2015.
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