Vorinostat, capsule, 100 mg, Zolinza® - March 2011
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Public Summary Document
Product: Vorinostat, capsule, 100 mg,
Zolinza®
Sponsor: Merck Sharp & Dohme Australia Pty
Ltd
Date of PBAC Consideration: March 2011
1. Purpose of Application
The submission sought an Authority Required listing for the
treatment of advanced (stage IIB-IV) cutaneous T-cell lymphoma
(CTCL) where treatment has failed with four systemic
therapies.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Vorinostat was TGA registered on 15 December 2009 for the treatment
of cutaneous manifestations in patients with cutaneous T-cell
lymphoma (CTCL) who have progressive, persistent or recurrent
disease subsequent to prior systemic therapies.
4. Listing Requested and PBAC’s View
Authority Required
Initial PBS-subsidised treatment, as monotherapy, in advanced stage
(stage IIB - IV) Cutaneous T-cell Lymphoma, where treatment failure
has occurred with four systemic therapies, unless contraindicated.
At least one of these therapies should be a chemotherapy
regimen.
Treatment failure is defined as:
(a) disease progression following treatment, or
(b) intolerance or toxicity to a particular treatment.
Patients will be eligible for a maximum of 3 scripts as initial
therapy to enable their response to treatment to be assessed. If no
response is achieved after 3 months, the patient is no longer
eligible for PBS-subsidised treatment with vorinostat.
Authority Required
Continuing PBS-subsidised treatment, as monotherapy, in patients
with advanced stage (stage IIB - IV) Cutaneous T-cell Lymphoma who
have taken vorinostat for up to 3 months and whose disease has
improved. Improvement is defined as a 50% reduction in the mSWAT
score.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Cutaneous T-cell lymphoma (CTCL) is collective term for a group of
non-Hodgkin lymphomas (NHL) that initially present in the skin and
may ultimately involve lymph nodes, blood and internal organs. CTCL
is a rare disease and accounts for about 3.9% of all NHLs.
The disease initially presents as red or pink scaly patches, which
evolve into skin tumours as the disease progresses. The tumours may
ulcerate and result in secondary infection. The disease may also
present as erythroderma, a mass of red lesions covering greater
than 80% of the body area which may or may not include clinically
significant blood involvement. In addition to disfiguring, painful
skin lesions, CTCL patients are often troubled with intense
pruritus (itching).
Early stage disease is usually managed with topical steroids,
topical nitrogen mustard, topical retinoids, phototherapy,
localised radiotherapy or total skin electron beam (TSEB). Advanced
stage disease is usually managed with systemic treatments such as
interferon alfa (with or without phototherapy or acitretin),
extracorporeal photopheresis, and single agent or combination
chemotherapy.
The submission proposed that vorinostat would provide a further
treatment option for patients with advanced stage CTCL when other
alternative treatments have failed, prior to palliative care.
6. Comparator
The submission nominated palliative care, comprising of radiation;
topical steroids; occlusive dressings, wet wraps, wound dressings
and bandages; and related hospital admissions.
Although the submission presented multiple case series of various
chemotherapy treatments used to manage advanced stage cutaneous
T-cell lymphoma (CTCL), no formal comparison between vorinostat and
these chemotherapies was conducted.
For PBAC’s view, see Recommendation and
Reasons.
7. Clinical Trials
The submission presented one ‘key’ case series study
(P001) of vorinostat and 13 supplementary open-label studies (one
vorinostat dose finding study (P005), 8 case series chemotherapy
studies, three non-randomised studies comparing different
chemotherapies and one case series study of bortezomib (Zinzani
(2007). The patient populations, study treatments, endpoints and
follow-up varied considerably among these studies.
The trials and associated reports published at the time of the
submission are in the table below:
| Trial ID / First author | Protocol title / Publication title | Publication citation |
| Single arm studies or single arms of studies presented in the submission | ||
| “Key” Single arm study: Vorinostat | ||
| P001 Olsen et al. | Phase II multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. | J Clin. Oncology 2007; 25(21): 3109-15 |
| Duvic M et al | The systemic effects of vorinostat in patients with cutaneous T-cell lymphoma (CTCL): Post-hoc analyses in patients with high blood tumor burden. | Blood 2009; ASH Annual Meeting Abstracts(114):1709. |
| Duvic M et al | Evaluation of the long-term tolerability and clinical benefit of vorinostat in patients with advanced cutaneous T-cell lymphoma. | Clinical Lymphoma & Myeloma 2009; 9(6):412-416. |
| Supplementary single arm studies | ||
| Vorinostat | ||
| P005 Duvic et al | Phase II trial of oral vorinostat (suberoylanilide hydroxamic acid, (SAHA)) for refractory cutaneous T-cell lymphoma. | Blood 2007; 109: 31-39 |
| CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and it variations: COP/ CVP (cyclophosphamide, vincristine, prednisone) or HOP (doxorubicin, vincristine, prednisone) | ||
| Fierro et al | Systemic polychemotherapy in the treatment of primary cutaneous lymphomas: a clinical follow-up study of 81 patients treated with COP or CHOP. | Leukaemia and Lymphoma 1998;34:583-588 |
| Molin et al | Combination chemotherapy in tumour stage of mycosis fungoides with cyclophosphamide, vincristine, VP-16, Adriamycin and prednisolone (COP, CHOP, CAVOP) A report from the Scandinavian Mycosis Fungoides Group. | Acta Derm Verneol 1980;60:542-4 |
| Fludarabine + cyclophosphamide or cladribine | ||
| Mazur et al | Treatment of cutaneous T-cell lymphomas with purine analogues (fludarabine and 2-chlorodeoxyadenosine). | Journal of BUON 2003;8:247-251 |
| Scarrisbrick et al | A trial of fludarabine & cyclophosphamide combination chemotherapy in the treatment of advanced refractory primary cutaneous T-cell lymphoma. | British J Derm 2001;144:1010-1015 |
| Kong LR et al | 2-chlorodeoxyadenosine in cutaneous T-cell lymphoproliferative disorders. | Leukemia & Lymphoma 1997;26(1-2):89-97 |
| Gemicitabine | ||
| Duvic et al | Phase II evaluation of gemcitabine monotherapy for cutaneous T Cell lymphoma. | Clinical Lymphoma & Myeloma 2006;7(1):51-58 |
| Zinzani et al. | Gemcitabine treatment in pre-treated CTCL. Experience in 44 patients. | Clin Oncology 2000;18(13):2603-2606 |
| Zinzani PL et al | Therapy with gemcitabine in pre-treated peripheral T-cell lymphoma patients. | Annals of Oncology 1998;9(12):1351-1353. |
| Zinzani PL et al | Gemcitabine as single agent in pretreated T-cell lymphoma patients: evaluation of the long-term outcome. | Annals of Oncology 2010;21(4):860-863 |
| Bortezomib | ||
| Zinzani PL et al | Phase II trial of proteasome inhibitor bortezomib in patients with relapsed or refractory cutaneous T-cell lymphoma. | Journal of Clinical Oncology 2007;25(27):4293-4297. |
| Liposomal doxorubicin | ||
| Quereux G et al | Prospective multicenter study of pegylated liposomal doxorubicin treatment in patients with advanced or refractory mycosis fungoides or Sezary Syndrome. | Arch Dermatol 2008; 144(6): 727-733. |
| Pulini S et al | Pegylated liposomal doxorubicin in the treatment of primary cutaneous T-cell lymphomas. | Haematologica 2007; 92: 686-689. |
8. Results of Trials
Study P001:
The results for the primary outcome, objective response and time to progressive disease,
from the single vorinostat arm are summarised below:
Response rates:
The objective response rate (as measured by the modified Severity Weighted Assessment
Tool (mSWAT) (a ≥ 50% reduction in skin disease from baseline using mSWAT) in advanced
stage CTCL disease (Stage IIB or higher) was 29.5% (95% CI: 18.5, 42.6) and this exceeded
the pre-specified criteria for vorinostat to be considered as an “active drug” defined
as a response rate of at least 20% with the lower limit of the confidence interval higher than and excluding 5%. Only one
response (in patients with Stage IIB or higher) from the total number of objective
responses (1/18) was a complete response (the rest were partial responses).
The median time to objective response was around 2 months for patients with Stage
IIB disease or higher. The duration of objective response ranged from 34-322 days
in all patients treated with vorinostat and from 34-280 days for patients with Stage
IIB or greater disease.
Pruritus relief:
The PBAC noted of 59 patients, 18 (30.5%) with Stage IIB or higher disease had pruritus
relief and 8 (13.6%) had complete resolution of their pruritus symptoms. Relief in
pruritus was maintained for at least 4 weeks without any increase in pruritus medication.
Supplementary studies:
The PBAC noted there was substantial heterogeneity in the definitions of response
and numerical estimates of objective response, partial response and complete response
rates, among the supplementary studies included in the submission. The proportion
of patients experiencing 1) an overall response varied from 24% in Kong (1997) to
84% in Pulini (2007), 2) a partial response varied from 8% in Scarrisbrick to 60%
in Zinzanni (2000) and 3) a complete response varied from 0% (P005, Molin and Mazur)
to 42% in Pulini.
Comparison of vorinostat with chemotherapy:
The PBAC noted that the submission presented one comparison analysis conducted by
Prince et al (2010) to examine the effectiveness and safety of vorinostat compared
to different chemotherapy regimens using different sources of clinical data (Combined
Skin Lymphoma Clinic data).
For PBAC’s view, see Recommendation and Reasons.
Overall, about 27% of patients had a serious adverse event and approximately 16% of
patients discontinued vorinostat therapy due to an adverse event. Thrombocytopenia
and anaemia were the most common haematologic toxicities. Other laboratory abnormalities
reported included increased serum glucose in 69% of CTCL patients (59 of 86), transient
increases in serum creatinine in 46.5% of patients (40 of 86), and proteinuria in
51.4% of patients (38 of 74). Serious adverse events included pulmonary embolism (4.7%);
squamous cell carcinoma (3.5%); and anaemia (2.3%).
9. Clinical Claim
The submission described vorinostat as superior in terms of
comparative effectiveness and inferior in terms of comparative
safety over the main comparator of palliative care.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
The submission presented a partially modelled (primarily
trial-based) evaluation. This is a cost-effectiveness model where
in one arm (incremental) costs and effects are estimated from the
single arm study P001, and other arm is assumed to have zero
(incremental) costs/effects. The time horizon of the evaluation is
one year. The outcomes in the model are: the incremental
cost per additional patient with response (≥50% and ≥25%
decrease in mSWAT); and the incremental cost per additional year
with response (≥50% and ≥25% decrease in mSWAT).
For the surrogate outcome number of patients with response (≥25%
decrease in SWAT) in patients with stage IIB or greater disease,
the submission estimated the incremental cost/additional responder
to be in the range $75,000 to $105,000.
For the surrogate outcome years with response (≥50% decrease in
SWAT) in patients with stage IIB or greater disease, the submission
estimated the incremental cost/additional year of response to be
greater than $200,000.
For PBAC’s view, see Recommendation and Reasons.
11. Estimated PBS Usage and Financial Implications
The net financial cost per year to the PBS was estimated by the
submission to be less than $10 million in Year 5.
12. Recommendation and Reasons
The PBAC noted that the submission proposed palliative care as the
comparator. However, the PBAC considered that a comparison with
best available care, as represented by chemotherapy, is more
appropriate than end-of life palliative care as the drug may not be
used as last-line treatment. The PBAC noted that consumer comments
and expert comments indicated that vorinostat would be used earlier
in the treatment algorithm than proposed in the requested
restriction (after failure of at least four systemic therapies) and
that more toxic treatments would be reserved for patients with
refractory disease.
The submission presented one ‘key’ case series study
(P001) of vorinostat, several supplementary open-label and case
series chemotherapy studies, three non-randomised studies comparing
different chemotherapies and one case study of bortezomib. The
objective response rate (a ≥ 50% reduction in skin disease from
baseline using mSWAT) of Study P001 was 29.5%, (95% CI 18.5, 42.6)
and only one response (in patients with Stage IIB or higher) from
the total number of objective responses (1/18) was a complete
response (the rest were partial responses). Of 59 patients, 18
(30.5%) with Stage IIB or higher disease had pruritis relief and 8
(13.6%) had complete resolution of their symptoms. The median
duration of response was not reached but was estimated to be
greater than 4 months with a range of 1 month to 9 months or more.
The application would have been stronger if additional data about
durability of benefit was presented. The PBAC noted that no
survival data are available/presented from Study P001 or from the
non-comparative chemotherapy studies.
The PBAC noted that the quality of the data is extremely limited
and the studies presented in the submission are small, non
comparative and heterogeneous. The PBAC acknowledged that a
meaningful comparison of the effectiveness of vorinostat relative
to chemotherapy is difficult. A comparison analysis was conducted
by Prince et al (2010) to examine the effectiveness and safety of
vorinostat compared to different chemotherapy regimens using
different sources of clinical data (Combined Skin Lymphoma Clinic
data) but was methodologically flawed. The PBAC noted that better
evidence about therapeutic advances may be forthcoming as there are
numerous clinical trials being undertaken which are recruiting
patients with cutaneous T-cell lymphoma (Clinical
trials.gov).
The submission claimed that vorinostat is superior in terms of
comparative effectiveness and inferior in terms of comparative
safety over the main comparator of palliative care. The PBAC agreed
that vorinostat is an active drug that has superior efficacy to
palliative care. However, no conclusion can be reached with respect
to comparisons with other available therapies. The PBAC agreed that
vorinostat has significant toxicities, and is inferior in safety to
palliative care. However, expert testimony suggests it is less
toxic than cytotoxic chemotherapies.
A partially modelled (primarily trial-based) evaluation is
presented. This is a cost-effectiveness model where in one arm
(incremental) costs and effects are estimated from the single arm
study P001, and other arm is assumed to have zero (incremental)
costs/effects. The PBAC noted that no studies identifying utility
weights in CTCL health states were identified and that
consequently, a cost-utility analysis could not be performed. The
costs of vorinostat are modelled on the basis that patients without
a 50% improvement in mSWAT will stop vorinostat treatment after 12
weeks (consistent with the requested restriction). The trial-based
outcome (proportion of patients with response) is incorporated into
the ICER. The ICER is calculable only for surrogate outcome
measures of response and response duration and was therefore
considered to be highly uncertain. The ICER was estimated by the
submission to be in the range $75,000 to $105,000 per additional
responder (surrogate outcome number of patients with response
(≥25% decrease in SWAT) in patients with stage IIB or greater
disease) to greater than $200,000 per additional year of response
(years with response (≥50% decrease in SWAT) in patients with
stage IIB or greater disease).
The PBAC noted that the total cost to the PBS was relatively low,
however, the clinical place of the drug was uncertain and there was
potential for use beyond the requested restriction. Therefore, the
financial estimates were considered to be uncertain.
The PBAC acknowledged that that there was a high clinical need for
vorinostat and a treatment benefit of around 30% in patients with
cutaneous T-cell lymphoma. However, the incremental costs for
measurable health gains far exceeded those accepted for other
chronic, intractable diseases and other cancers. Cost offsets and
toxicities of chemotherapies in the comparator arm may help improve
the ICER, although some reduction in the treatment benefit would
also need to be assumed.
The PBAC therefore rejected the submission on the basis of
unacceptably high and uncertain cost-effectiveness ratios.
The PBAC also acknowledged and noted the consumer comments on this
item.
Recommendation:
Reject
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
Vorinostat fulfils an unmet medical need by providing a treatment
option for patients who have exhausted other effective systemic
treatments. The negative impact of the disease on patient's quality
of life and survival is significant and patients who respond to
treatment with vorinostat experience significant relief from their
symptoms.
The sponsor acknowledges that the data provided was limited. This
is because the rareness of the disease and the individualised
approach to treatment makes it difficult to conduct randomised
controlled trials (RCT's) in this population.
