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Ipilimumab for previously untreated advanced (unresectable or metastatic) melanoma

Issued: July 2014
NICE technology appraisal guidance 319 guidance.nice.org.uk/ta319

NICE has accredited the process used by the Centre for Health Technology Evaluation at NICE to
produce technology appraisals guidance. Accreditation is valid for 5 years from September 2009 and
applies to guidance produced since June 2008 using the processes described in NICE’s ‘The guide to
the methods of technology appraisal’ (2008). More information on accreditation can be viewed at
www.nice.org.uk/accreditation
© NICE 2014
Contents
1 Guidance …………………………………………………………………………………………………………………. 3
2 The technology…………………………………………………………………………………………………………. 4
3 The manufacturer’s submission…………………………………………………………………………………… 5
Manufacturer’s original submission …………………………………………………………………………………………. 5
Manufacturer’s response to consultation………………………………………………………………………………….. 21
Evidence Review Group’s response to manufacturer’s consultation comments …………………………….. 24
4 Consideration of the evidence…………………………………………………………………………………….. 26
Summary of Appraisal Committee’s key conclusions…………………………………………………………………. 33
5 Implementation…………………………………………………………………………………………………………. 41
6 Recommendations for further research………………………………………………………………………… 42
7 Review of guidance …………………………………………………………………………………………………… 43
8 Appraisal Committee members and NICE project team………………………………………………….. 44
8.1 Appraisal Committee members…………………………………………………………………………………………. 44
8.2 NICE project team …………………………………………………………………………………………………………… 47
9 Sources of evidence considered by the Committee ……………………………………………………….. 48
About this guidance……………………………………………………………………………………………………… 51
Ipilimumab for previously untreated advanced (unresectable
or metastatic) melanoma
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1 Guidance
This guidance was developed using the single technology appraisal (STA) process.
1.1 Ipilimumab is recommended, within its marketing authorisation, as an option
for treating adults with previously untreated advanced (unresectable or
metastatic) melanoma, only if the manufacturer provides ipilimumab with the
discount agreed in the patient access scheme.
Ipilimumab for previously untreated advanced (unresectable
or metastatic) melanoma
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2 The technology
2.1 Ipilimumab (YERVOY, Bristol-Myers Squibb) is a fully human antibody that
binds to cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a molecule
expressed on T cells that plays a critical role in regulating natural immune
responses. Ipilimumab is designed to block the activity of CTLA-4 resulting in
augmentation and prolongation of the T-cell immune response, thereby
sustaining the immune attack on cancer cells. It has a UK marketing
authorisation ‘for the treatment of advanced (unresectable or metastatic)
melanoma in adults’. The recommended dose of ipilimumab is 3 mg per
kilogram of body weight (mg/kg) administered intravenously over a 90-minute
period every 3 weeks for a total of 4 doses.
2.2 The summary of product characteristics lists the following very common
adverse reactions for ipilimumab: diarrhoea, rash, pruritus, fatigue, nausea,
vomiting, decreased appetite and abdominal pain. For full details of adverse
reactions and contraindications, see the summary of product characteristics.
2.3 Ipilimumab is priced at £3750 per 10-ml vial (5 mg/ml) or £15,000 per 40-ml
vial (5 mg/ml) (excluding VAT; ‘British national formulary’ [BNF] edition 67). The
manufacturer of ipilimumab has agreed a patient access scheme with the
Department of Health, in which a confidential discount on the list price of
ipilimumab is offered. The Department of Health considered that this patient
access scheme does not constitute an excessive administrative burden on the
NHS.
Ipilimumab for previously untreated advanced (unresectable
or metastatic) melanoma
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3 The manufacturer’s submission
The Appraisal Committee (section 8) considered evidence submitted by the manufacturer of
ipilimumab and a review of this submission by the Evidence Review Group (ERG; section 9).
Manufacturer’s original submission
3.1 There were no trials directly comparing ipilimumab 3 mg/kg monotherapy with
the comparators specified in the scope (dacarbazine or vemurafenib). The key
clinical evidence came from 4 randomised controlled trials (CA184-024,
MDX010-08, BREAK-3 and BRIM-3) that were used in an indirect comparison
of the effectiveness of ipilimumab 3 mg/kg compared with dacarbazine,
vemurafenib or dabrafenib. In addition, the manufacturer presented data from
2 ongoing US retrospective, observational trials (CA184-332 and CA184-338)
because there was limited randomised controlled trial evidence directly
investigating the clinical efficacy of ipilimumab 3 mg/kg monotherapy in people
with previously untreated advanced (unresectable or metastatic) melanoma.
The manufacturer also presented a pooled analysis of patients who had not
had chemotherapy before (n=78), randomised to 3 mg/kg ipilimumab
monotherapy in 4 trials: MDX010-08, CA184-004, CA184-022 and
MDX010-020.
3.2 The CA184-024 trial was a multinational, randomised, double-blinded trial
observing adults with previously untreated advanced (unresectable or
metastatic) melanoma. The intervention was ipilimumab 10 mg/kg in
combination with dacarbazine 850 mg/m2 (n=250), and the comparator was
placebo plus dacarbazine alone 850 mg/m2 (n=252). Treatment with
ipilimumab or placebo was provided every 3 weeks for the first 10 weeks
followed by 1 dose every 12 weeks from week 24. Treatment with dacarbazine
was given once every 3 weeks for 22 weeks until disease progression,
unacceptable toxicity or withdrawal of consent. The median patient age was
57 years, 60% of patients were male and 40% had an elevated serum lactate
dehydrogenase level. The median time from first diagnosis to diagnosis of
advanced melanoma was 1.7 years.
Ipilimumab for previously untreated advanced (unresectable
or metastatic) melanoma
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3.3 The primary outcome of the CA184-024 trial was overall survival: median
overall survival differed by 2.1 months, from 9.1 months with dacarbazine
alone to 11.2 months with ipilimumab 10 mg/kg plus dacarbazine, and there
was a 5.7 month survival gain over the 5 year trial. The hazard ratio for death
was 0.72 (95% confidence interval [CI] 0.59 to 0.87; p statistically significant difference in the median progression-free survival
between ipilimumab 10 mg/kg plus dacarbazine and dacarbazine alone (2.8
compared with 2.6 months), but ipilimumab 10 mg/kg statistically significantly
increased progression-free survival compared with dacarbazine, with a hazard
ratio for progression of 0.76 (95% CI 0.63 to 0.93; p=0.0064). The response
rate was statistically significantly improved with ipilimumab 10 mg/kg plus
dacarbazine compared with dacarbazine alone (15.2% compared with 10.3%;
p=0.03) and the duration of response was statistically significantly longer
(median 19.3 compared with 8.1 months; p=0.03) in the ipilimumab group.
There were no statistically significant differences in disease control rate (which
included response and stable disease rates), time to response, or European
Organisation for Research and Treatment of Cancer questionnaire
(EORTC-QLQ-C30) functioning scales or symptom scales between treatment
arms.
3.4 Long-term safety data were available from the CA184-024 trial, which indicated
that the safety profile of ipilimumab was maintained throughout therapy.
Severe, serious, drug-related and adverse events leading to drug
discontinuation were all more frequent in the ipilimumab 10 mg/kg plus
dacarbazine group (46%) than in the group treated with dacarbazine alone
(18%). Discontinuations because of trial-drug toxicity led to 37% of patients not
receiving all 4 doses of ipilimumab 10 mg/kg. Of the patients receiving
ipilimumab, 77.7% experienced an immune-related adverse event (41.7% were
grade 3 or 4 events). The most commonly reported adverse events were
hepatic-related with 17.4% to 20.7% of patients experiencing grade 3 or 4
elevations in liver function values, but these reactions were generally
reversible. Other adverse events observed in the trial were dermatological
events, gastrointestinal events, pyrexia, chills and weight loss. The safety
profile of ipilimumab was similar in patients during the induction period and in
patients having treatment for longer than 2 years.
Ipilimumab for previously untreated advanced (unresectable
or metastatic) melanoma
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3.5 The MDX010-08 trial was a multicentre, randomised, open-label trial carried
out in the USA, including adults with advanced (unresectable or metastatic)
melanoma who had not received prior chemotherapy and had a life expectancy
of over 3 months. Treatment was either with the intervention, ipilimumab 3 mg/
kg plus dacarbazine 1000 mg/m2 (n=36), or the comparator ipilimumab 3 mg/
kg alone (n=40). The trial was randomised using a central randomisation
scheme with stratification by random block size, and because it was carried out
in the USA it did not contain any UK patients. The trial was also not designed
to detect differences in survival between the 2 treatment arms. The
manufacturer provided details of pre-specified subgroups of patients within the
trials including median age (60 years and 66 years for the ipilimumab plus
dacarbazine and ipilimumab groups respectively), sex (74.3% and 56.8% male
for the ipilimumab plus dacarbazine and ipilimumab groups respectively), stage
of metastasis, time since diagnosis and lactate dehydrogenase level.
3.6 The MDX010-08 trial demonstrated that no statistically significant difference
was observed for the primary outcome of objective response rate between
ipilimumab alone and ipilimumab plus dacarbazine. There was also no
statistically significant difference in overall survival between the ipilimumab
3 mg/kg plus dacarbazine group and the ipilimumab alone group. The results
appeared to favour ipilimumab plus dacarbazine over ipilimumab alone
(median overall survival of 14.3 months compared with 11.4 months with a
hazard ratio for overall survival of 0.75 [95% CI 0.45 to 1.24] and a 1-year
overall survival rate of 62% compared with 45%), but the trial was
underpowered to detect statistically significant differences in overall survival.
All patients in both treatment groups experienced at least 1 adverse event, with
65.7% in the ipilimumab plus dacarbazine group compared with 53.8% in the
ipilimumab alone group experiencing an immune-related adverse event.
Serious adverse events, drug-related adverse events and adverse events
leading to drug discontinuation were more frequent in the ipilimumab alone
group than in the ipilimumab plus dacarbazine group. One person died from a
suspected drug-related adverse event in the ipilimumab plus dacarbazine
group and 2 people died in the ipilimumab alone group.
3.7 The BRIM-3 trial was a multinational, randomised, crossover trial including
adults with previously untreated advanced (unresectable or metastatic)
Ipilimumab for previously untreated advanced (unresectable
or metastatic) melanoma
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melanoma that was also BRAF V600 mutation-positive, and who had a life
expectancy of over 3 months. People received either vemurafenib 960 mg
(n=337) twice daily or dacarbazine 1000 mg/m2 (n=338) every 3 weeks.
Randomisation was used to assign patients in a 1:1 ratio. The manufacturer
included details of sub-populations within the trial. These included the age
(median 56 years in the vemurafenib group and 52 years in the dacarbazine
group) and sex of patients (59.4% and 53.6% male respectively), their Eastern
Cooperative Oncology Group (ECOG) performance status (most patients in
both groups had a score of 0), their stage of metastasis (most patients in both
groups had metastases at the M1c stage; distant metastases were found) and
lactate dehydrogenase level (most patients in both groups had levels above
the upper limit of normal).
3.8 The BRIM-3 trial demonstrated that vemurafenib statistically significantly
increased overall survival in patients who had BRAF V600 mutation-positive
melanoma when compared with dacarbazine. Median overall survival was
increased by 3.6 months in the vemurafenib group (13.2 months compared
with 9.6 months; hazard ratio 0.62; 95% CI 0.49 to 0.77; p survival rates were higher with vemurafenib than dacarbazine at 6 months
(84% compared with 64%). Progression-free survival was also statistically
significantly increased for patients in the vemurafenib treatment group, with a
median progression-free survival of 5.3 months compared with 1.6 months and
a hazard ratio for progression of 0.26 (95% CI 0.20 to 0.33; p response rate was statistically significantly improved with vemurafenib
compared with dacarbazine (48.4% compared with 5.5%; p response was 1.5 months for vemurafenib compared with 2.7 months for
dacarbazine, although duration of response was not reported. The BRIM-3 trial
used the Functional Assessment of Cancer Therapy Melanoma (FACT-M)
questionnaire to measure health-related quality of life but the data were not
reported because of low completion rates.
3.9 The manufacturer also presented the BREAK-3 trial that compared dabrafenib
150 mg with dacarbazine 1000 mg/m2 in adults with advanced (unresectable or
metastatic) melanoma who tested positive for the BRAF V600 mutation. The
manufacturer included this trial as part of the mixed treatment comparison
described in section 3.15 but did not include it in the cost-effectiveness
Ipilimumab for previously untreated advanced (unresectable
or metastatic) melanoma
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analyses because it was not included in the NICE scope, had limited publicly
available data, and dabrafenib did not have a UK price.
3.10 Two ongoing US retrospective, observational studies (CA184-332 [n=61] and
CA184-338 [n=120]) for ipilimumab 3 mg/kg in people who had not previously
received treatment were also included in the manufacturer’s submission. The
median overall survival for ipilimumab 3 mg/kg monotherapy was 11.5 months
in the CA184-332 trial and 14.3 months in the CA184-338 trial. The
manufacturer reported that in the CA184-338 trial, 54.2% of people treated
with ipilimumab 3 mg/kg experienced a drug-related adverse event.
BRAF V600 mutation status data were available, and the manufacturer
suggested that a post-hoc analysis of CA184-338 supported the conclusion
from a previous post-hoc analysis of CA184-004 that tumour mutation status
does not impact on the clinical activity of ipilimumab with no differences in
survival observed between patients who have BRAF V600 mutation-positive
melanoma and those who have BRAF V600 mutation-negative melanoma.
3.11 The manufacturer presented a pooled analysis of patients (n=78) randomised
to 3 mg/kg ipilimumab monotherapy (MDX010-08, CA184-004, CA184-022 and
MDX010-020). It was noted that 43 out of 78 patients had received prior
immunotherapy. The manufacturer stated that CA184-004 and CA184-022
were not included as stand-alone trials because the patient numbers were too
small but stated that they demonstrated the clinical equivalence between 3 mg/
kg and 10 mg/kg doses of ipilimumab and supported the extrapolation of the
CA184-024 data. The MDX010-020 trial was a double-blind trial including
patients with advanced (unresectable or metastatic) melanoma who had
previously been treated with regimens containing 1 or more of the following:
interleukin-2, dacarbazine, temozolomide or other chemotherapies. Patients
were randomised into 3 groups (in a ratio of 3:1:1) who received either 3 mg/kg
ipilimumab plus an investigational gp100 peptide vaccine (n=403), 3 mg/kg
ipilimumab alone (n=137) or gp100 alone (n=136). Patients were enrolled
regardless of BRAF V600 mutation status. Follow-up was up to 55 months.
The hazard ratio for comparison of overall survival between 3 mg/kg
ipilimumab alone and gp100 was 0.66 (95% CI 0.51 to 0.87; p=0.0026). The
median overall survival for ipilimumab 3 mg/kg monotherapy in this pooled
analysis was 13.5 months (95% CI 11.2 to 19.6).
Ipilimumab for previously untreated advanced (unresectable
or metastatic) melanoma
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3.12 The manufacturer made several assumptions to support the clinical and cost
effectiveness of 3 mg/kg ipilimumab monotherapy. The first key assumption
was that ipilimumab 3 mg/kg and 10 mg/kg were clinically equivalent. Data
from 2 trials (CA184-004, 36 chemotherapy-naive patients and CA184-022, 18
chemotherapy-naive patients) comparing ipilimumab 3 mg/kg and 10 mg/kg
were presented in support of this assumption. The manufacturer highlighted
that the trials indicated that the survival associated with ipilimumab 3 mg/kg
and 10 mg/kg was similar, with median overall survival of 14.3 and 11.2 months
respectively. The manufacturer also provided pooled data comparing overall
survival profiles of ipilimumab 3 mg/kg (MDX010-020 and CA184-022) and
10 mg/kg (CA184-007, CA184-008 and CA184-022) for a mixed population.
The manufacturer stated that no statistically significant difference in survival
was observed between the 3 mg/kg and 10 mg/kg treatment arms across the
whole population. The European Medicines Agency’s (EMA) Committee for
Medicinal Products for Human Use (CHMP) has requested that the
manufacturer conduct a study on any relevant difference in efficacy between
3 mg/kg and 10 mg/kg.
3.13 The second key assumption made by the manufacturer was that ipilimumab
plus dacarbazine was equivalent to ipilimumab alone. The manufacturer stated
that this was demonstrated in the MDX010-08 trial in which ipilimumab 3 mg/kg
plus dacarbazine (n=32) provided comparable survival times to ipilimumab
3 mg/kg monotherapy (n=32) after a median follow-up of 20.9 and 16.4 months
respectively. Median overall survival times were 14.3 months and 11.4 months,
and 1-year survival rates were 62% and 45% in the ipilimumab 3 mg/kg plus
dacarbazine and ipilimumab 3 mg/kg alone groups respectively. This difference
was not statistically significant. The median overall survival with ipilimumab
3 mg/kg alone was directly comparable with that observed with ipilimumab
10 mg/kg plus dacarbazine in CA184-024. The CHMP concluded that
ipilimumab pharmacokinetic data were not significantly affected by concomitant
dacarbazine.
3.14 The manufacturer provided information to demonstrate that ipilimumab efficacy
is similar in patients with previously untreated and previously treated
melanoma. The manufacturer stated that the results of the MDX010-020
(previously treated melanoma) and CA184-024 trials (previously untreated
Ipilimumab for previously untreated advanced (unresectable
or metastatic) melanoma
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melanoma) demonstrated similar 2-year overall survival rates: 24% and 29%
respectively. Although these trials used different regimens (3 mg/kg ipilimumab
and 10 mg/kg ipilimumab plus dacarbazine respectively), the manufacturer
stated that the CHMP accepted this evidence from the MDX010-020 trial
supported by high-level results from the CA184-024 trial as part of the
marketing authorisation granted in 2011 for ipilimumab for the treatment of
adults with previously treated advanced (unresectable or metastatic)
melanoma. The CHMP commented in the licensing assessment report that
ipilimumab 3 mg/kg alone could be supported on the basis of the following
considerations:
The efficacy of 3 mg/kg ipilimumab alone has been established in patients with
previously treated melanoma and the baseline characteristics of the patients
included in the pivotal studies in previously treated and previously untreated
subpopulations were similar.
Ipilimumab pharmacokinetic data were not substantially affected by concomitant
dacarbazine.
There is no biological rationale to suspect a different activity for ipilimumab
treatment in the first- or next-line setting.
The CHMP also requested that the manufacturer conduct a study on any relevant
difference in efficacy between 3 mg/kg and 10 mg/kg.
3.15 Data from 3 (CA184-024, BREAK-3 and BRIM-3) of the 4 randomised
controlled trials identified were analysed as a mixed treatment comparison to
provide a comparison between ipilimumab 10 mg/kg and BRAF inhibitors. The
manufacturer stated that given that ipilimumab 3 mg/kg and ipilimumab 10 mg/
kg could be considered equivalent, the results of the mixed treatment
comparison would also hold for a comparison of ipilimumab 3 mg/kg with
BRAF inhibitors. The manufacturer stated that hazard ratios of death from the
trials were used to populate the mixed treatment comparison analysis because
there were different follow-up times and event numbers across trials. The
manufacturer constructed a forest plot of overall survival which demonstrated
that although ipilimumab plus dacarbazine was associated with a statistically
significant improvement in survival compared with dacarbazine alone (hazard
Ipilimumab for previously untreated advanced (unresectable
or metastatic) melanoma
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ratio [HR] 0.72; 95% CI 0.55 to 0.95), there were no statistically significant
differences for ipilimumab plus dacarbazine compared with vemurafenib (HR
1.16) or dabrafenib (HR 1.19). Indirect comparisons using the Bucher equation
showed that there was no statistically significant difference in efficacy for
ipilimumab plus dacarbazine compared with vemurafenib (HR 1.16; 95% CI
0.86 to 1.56) and dabrafenib (HR 1.18; 95% CI 0.48 to 2.93). The
manufacturer commented that the main difference in patients enrolled in the
clinical trials was their BRAF V600 mutation status and previous treatment.
3.16 The manufacturer conducted a de novo analysis to estimate the cost
effectiveness of ipilimumab compared with dacarbazine in patients who have
BRAF V600 mutation-negative melanoma, and of ipilimumab compared with
dacarbazine and vemurafenib in patients who have BRAF V600
mutation-positive melanoma. The manufacturer developed a semi-Markov
partitioned survival model with health states used to represent tiers of
treatment, incorporating second-line active treatment and third-line best
supportive care. The proportion of patients moving between health states was
derived by initially calculating the number of patients who died and then
adjusting the proportion of patients at each line of treatment by those who
would be expected to receive palliative care (defined as 12 weeks before
death). The model assumes the per-cycle risk of death to be equal for
ipilimumab, dacarbazine and vemurafenib and for the patients entering
palliative care to be a proportion of patients in each treatment group.
3.17 The manufacturer distributed patients across 6 health states, each associated
with a utility value, and 6 time-to-death sub-health states, to capture quality of
life as a function of time to death. In the base-case model, a utility decrement
for people treated with ipilimumab or vemurafenib was included to account for
treatment-related adverse events. Patients’ health-related quality of life was
estimated from time to death as an intermediate outcome because the
manufacturer determined that disease progression was the most meaningful
way of estimating health-related quality of life. The proportion of patients
receiving each of the 4 doses needed during the induction phase of the trial
was used within the model to predict how many patients would receive each
dose in clinical practice. The number of patients receiving subsequent
re-inductions was estimated from the MDX010-020 clinical trial.
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or metastatic) melanoma
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3.18 To add to the manufacturer’s previous assumptions about dose equivalence
and that ipilimumab plus dacarbazine and ipilimumab alone were equally
effective, the manufacturer also assumed that the efficacy of ipilimumab in
patients with and without the BRAF V600 mutation was equivalent. The
manufacturer justified this by stating that a post-hoc analysis of a subgroup
containing 69 people from the CA184-004 trial indicated there was no
difference in objective response and stable disease based on the BRAF V600
mutation status. The manufacturer also presented an analysis using the pooled
chemotherapy-naive dataset analysis (CA184-004, MDX010-08, CA184-022
and MDX010-020), stating that overall and progression-free survival outcomes
were similar using the 2 datasets. For vemurafenib, the manufacturer stated
that there was no difference between the dacarbazine arms of the CA184-024
and BRIM-3 trials and therefore data from the vemurafenib arm of the BRIM-3
trial were incorporated directly into the model.
3.19 The transition to second- and third-line treatment was modelled based on
progression-free survival data, whereas overall survival data were used to
model transition to death. For first-line treatment with ipilimumab or
dacarbazine, a 3-part curve fit for overall survival was used based on data from
CA184-024 and for vemurafenib a 5-part curve fit was used based on data
from the BRIM-3 trial. For second-line treatments, overall survival was based
on first-line survival curves but adjusted downwards to account for poorer
outcomes on second-line treatment using a constant proportional hazard
derived from expected survival with second-line ipilimumab. The duration of
response to second-line treatments was based on the number of
pre-progression life years for second-line ipilimumab. Third-line treatment was
assumed to be best supportive care, which consisted of a proportion of
patients on ‘no treatment’ and a proportion on commonly prescribed
chemotherapy drugs, including dacarbazine. The overall survival for patients
receiving third-line best supportive care was assumed to be the same as those
on first-line treatment who had not progressed to next line of treatment. The
manufacturer highlighted that for patients treated with ipilimumab, using
progression-free survival overestimates the number of patients moving to
second-line treatment because ipilimumab’s mode of action means it is
possible for a patient’s condition to initially progress and then become stable or
respond to treatment. This may overestimate the cost in the ipilimumab arm
Ipilimumab for previously untreated advanced (unresectable
or metastatic) melanoma
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because costs of first-line treatment with ipilimumab are almost static, whereas
the costs of second-line treatment depend on the duration of treatment.
3.20 The same ipilimumab patient access scheme will be in place as agreed in
Ipilimumab for previously treated advanced (unresectable or metastatic)
melanoma (NICE technology appraisal guidance 268; hereafter referred to as
TA268). The cost of vemurafenib was presumed to be 4 packs of tablets every
4 cycles as in Vemurafenib for treating locally advanced or metastatic BRAF
V600 mutation-positive malignant melanoma (NICE technology appraisal
guidance 269) and included the agreed patient access scheme. The costs of
dacarbazine and best supportive care were calculated based on an average
height (170 cm) and weight (78.65 kg) for the patients, taken from the
CA184-024 trial. Dosing schedules for the 2 drugs were taken from the specific
product characteristics. Second-line costs for ipilimumab were also taken from
the previous NICE appraisal, TA268. The administration and drug costs for
second-line vemurafenib treatment were assumed to be equal to first-line
costs. To account for the wastage incorporated in the costs for first-line
vemurafenib treatment, an additional 5.78% was added to the drug cost.
3.21 For patients who have BRAF V600 mutation-positive melanoma, base-case
results indicated that vemurafenib was dominated by (that is, was more
expensive and less effective than) ipilimumab because it was associated with
higher costs and fewer quality-adjusted life years (QALYs). A comparison of
ipilimumab with dacarbazine resulted in an incremental cost-effectiveness ratio
(ICER) of £31,559 per QALY gained using the CA184-024 results and £28,465
per QALY gained when using the pooled chemotherapy-naive data for
ipilimumab. For patients who have BRAF V600 mutation-negative melanoma,
the ICER for ipilimumab compared with dacarbazine was £16,958 per QALY
gained using the CA184-024 trial results and £17,866 per QALY gained using
the pooled chemotherapy-naive data.
3.22 The manufacturer conducted a one-way deterministic sensitivity analysis using
a tornado diagram to assess the impact of key uncertainties on the ICERs and
probabilistic sensitivity analyses using 1000 simulations. Sensitivity analysis
was only carried out for the BRAF V600 mutation-positive population because
the ICER for ipilimumab compared with dacarbazine was higher for this group
Ipilimumab for previously untreated advanced (unresectable
or metastatic) melanoma
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and was therefore considered the worst-case scenario. The deterministic
sensitivity analysis indicated that the model was most sensitive to the
parameters used to model overall survival for ipilimumab and dacarbazine, the
time spent on second-line treatment and the time spent on first-line treatment
with ipilimumab compared with dacarbazine. Data from the CA184-024 trial
were used to calculate ICERs for ipilimumab compared with vemurafenib and
dacarbazine. Ipilimumab dominated (that is, was less expensive and more
effective than) vemurafenib and the ICER was £31,619 per QALY gained
compared with dacarbazine. The manufacturer used 2 different maximum
acceptable ICERs to calculate the incremental net benefit: £30,000 per QALY
gained when comparing with vemurafenib and £50,000 per QALY gained when
comparing with dacarbazine. The manufacturer stated, after carrying out
probabilistic sensitivity analysis, that the probability of ipilimumab being cost
effective when compared with dacarbazine was 96%, using £50,000 per QALY
gained as the maximum acceptable ICER. There was a 40% probability of
ipilimumab being cost effective if the maximum acceptable ICER was £30,000
per QALY gained. The manufacturer suggested an ICER for ipilimumab
compared with dacarbazine of £49,579 per QALY gained as the most
pessimistic outcome, assuming a single parameter curve fit using a log-normal
distribution for overall survival, but it emphasised that single parametric curve
fits were a poor fit to the data.
3.23 The ERG stated that the manufacturer had identified all relevant randomised
controlled trials and that adequate trial details were included in the submission.
The ERG was satisfied that the CA184-024 trial was a large, good-quality trial
but stated that it did not provide direct evidence for the effectiveness of
ipilimumab 3 mg/kg monotherapy (without maintenance treatment) compared
with dacarbazine, vemurafenib or dabrafenib for treating previously untreated
advanced (unresectable or metastatic) melanoma. The ERG noted that the
MDX010-08 trial included treatment every 3 weeks rather than every 4 weeks
as per the marketing authorisation and also stated that the trial was
underpowered to detect a statistically significant difference in overall survival.
The ERG stated that the pooled analysis of chemotherapy-naive patients could
result in double counting because the MDX010-08 trial was also included
independently. The ERG highlighted that there were differences in
performance status, disease stage, presence of brain metastases, duration of
Ipilimumab for previously untreated advanced (unresectable
or metastatic) melanoma
NICE technology appraisal
guidance 319
© NICE 2014. All rights reserved. Last modified July 2014 Page 15 of 52
melanoma and prior immunotherapy

Escrito por Antonio Rondon Lugo el 29 de septiembre de 2014 con 0 comentarios.
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