Using a manufacturer submitted dossier and other clinical data, extensive research was performed to analyze the proper placement of Yervoy on a hypothetical health plan's formulary for treatment of unresectable metastatic melanoma. Pharmacoeconomic benefits and clinical efficacy were weighed heavily in decision making.

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Pitt Street Health Plan Formulary Monograph Template
Individual Drug Review
Generic Name: ipilimumab injection for intravenous infusion
Brand Name: Yervoy®
Manufacturer: Bristol-Myers Squibb
Date of Review: January 27th
, 2015
Available Therapeutic Alternatives:
Preferred/Formulary Non-Preferred/Non Formulary
aldesleukin (Proleukin®) ipilimumab (Yervoy®)
interferon alfa-2b (Intron-A®)
vemurafenib (Zelboraf®)
dabrafenib (Tafinlar®)
temozolomide (Temodar®) [oral capsules] – off label
imatinib (Gleevec®)
trametinib (Mekinist®)
peginterferon alfa-2b (Sylatron®)
pembrolizumab (Keytruda®)
dabrafenib/trametinib - combination therapy
dacarbazine
TABLE OF CONTENTS:
(Click on a link below to view the section.)
Executive Summary
Recommendations
Key Questions/Issues:
Issue 1: Efficacy
Issue 2: Comparative Effectiveness
Issue 3: Safety
Issue 4: Value Proposition
Issue 5: Cost-effective Patient Subgroups
Clinical Evidence Tables
Cost-effectiveness Evidence Tables
Background
Disease Background
Pharmacotherapy
Product Background
Methodology
References

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Abbreviations used in this monograph:
QALY- Quality adjusted life year OS-overall survival
PPHM- Price per member month BORR-Best Overall Response Rate
ICER- Incremental cost effectiveness ration DB-Double Blind
ICUR-incremental cost utility ratio PC- placebo controlled
AE-Adverse event EORTC-European Organization for
Researchand Treatment of Cancer
REASON FOR REVIEW:
To determine the formulary status for ipilimumab injection for intravenous infusion, FDA
approved for treatment of un-resectable or metastatic melanoma.
EXECUTIVE SUMMARY
Key Questions/Issues and Results of Investigation:
Issue 1: What is the evidence of efficacy from clinical trials?
The phase 3 CA184-024 trial was randomized, double-blind, and multinational. Patients received
Ipilimumab plus dacarbazine (n=250) was compared against dacarbazine plus placebo. The
primary endpoint of OS, ipilimumab plus dacarbazine produced a statistically significant
increase when compared to dacarbazine alone. At the 3year mark, a post-hoc showed 20.8%
survival rates for ipilimumab plus dacarbazine, compared to 12.2% for dacarbazine alone.
Issue 2: Is there sufficient evidence to assessreal world comparative effectiveness?
Based on the ICER matrix assessment of the MDX-010-20 trail it was determined that there was
sufficient evidence of real world comparative effectiveness. The study received a B+ rating.
CA184-024 trial revieved a “C” rating.
Issue 3: What is the evidence of safety?
In regards to adverse reactions for MDX-010-20, Arm A, Arm B, and Arm C were 88.9% 80.2%,
and 78.8% respectively. Immune-related adverse events for Arm A, Arm B, and Arm C were
58.2%, 61.1%, and 31.8% respectively.
Issue 4: What is the value proposition for this product?
Over the 30 year lifetime time horizon, it was estimated that the average ipilimumab patient
would live 2.88 years which was 1.8 years longer than patients receiving BSC. The BSC was the
experimental gp100 vaccine which has been shown to have similar efficacy to dacarbazine and
temozolomide. The scale used to determine the quality adjusted life year was the EORTC QLQ-
C30 version 3.0. The average ipilimumab patient gained 1.76 QALYs, 1.14 QALYs more than

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the average BSC patient. The total cost associated with ipilimumab therapy was greater than
BSC. The base case ICER was $78,218 per life-year gained and the ICUR was $128,656 per
QALY gained. Yervoy cost $120,000 per course of therapy
Issue 5: Are there identifiable patient subgroups in which this treatment will be most cost-effective?
The patient subgroups that the treatment would be most cost effective is patients who have
already undergone unsuccessful treatment with dacarbazine or temozolomide and do not have a
BRAF mutated melanoma and can’t be treated with vemurafanib or dabrafenib.
RECOMMENDATIONS TO THE COMMITTEE
Therefore, the following P&T action is recommended:
We recommend placing Yervoy on the specialty 4th tier of the Pitt Street Health plan with a
prior authorization along with verumafenib and dabrafanib. It is recommended to place
dacarbazine and temozolomide on tier one preferred on the formulary. It was found that
Yervoy did increase length of life but being the drug is much more expensive than the
other medications it was decided to prefer it to be 2nd line therapy. There was not enough
long term survival data to justify placing Yervoy as a tier one medication over medications
that are a fraction of the cost. We recommended implementing prior authorization criteria
such as undergoing a Braf mutation test, clinically diagnosed Stage III/IV unresectable or
metastatic melanoma, life expectancy of at least 4 months, Baseline Liver function tests
included total bilirubin/ALT/AST, baseline thyroid function test(TSH). Approval will be
for a maximum of 16 months of therapy or 4 cycles of Yervoy treatment.

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ISSUE DETAILS
ISSUE 1: What is the level and quality of evidence for efficacy from clinical trials?
The MDX-010-20 was a placebo controlled, double-blind, phase 3 clinical trial to evaluate safety
and efficacy between ipilimumab plus gp100, ipilimumab alone, and gp100 alone. A total of 676
patients were assigned randomly in a 3:1:1 ratio with 403 patient’s ipilimumab plus gp100, 137
patients ipilimumab alone, and 137 patients gp100 alone. Ipilimumab was dosed at 3mg/kg every
3 weeks plus (Q3W) x 4 doses. The gp100 peptide vaccine was also used. The trial showed that
both ipilimumab with or without gp100 improved overall survival compared to gp100 alone in
patients with metastatic melanoma. The primary endpoint was OS between ipilimumab plus
gp100 (Arm A) and gp100 (Arm B).
The phase 3 CA184-024 trial was randomized, double-blind, and multinational. Ipilimumab plus
dacarbazine was compared against dacarbazine plus placebo. When looking at the primary
endpoint of OS, ipilimumab plus dacarbazine produced a statistically significant increase when
compared to dacarbazine alone. At the 3year mark, a post-hoc showed 20.8% survival rates for
ipilimumab plus dacarbazine, compared to 12.2% for dacarbazine alone.
ISSUE 2: Is there sufficient evidence to assess real world comparative effectiveness?
Based on the ICER matrix assessment of the MDX-010-20 it was determined that there was sufficient
evidence of realworld comparative effectiveness. The study received a B+ rating.
The trail did not receive an “A” rating because it did not fully reflect a realworld diverse population.
Additionally, the trail was pitted against just an experimental vaccine that has no proven clinical efficacy.
The trial last only 4.5 years but projected a 30 year lifetime horizon which was found to be too much of
stretch. The survival benefit was demonstrated for the length of the trial, but that there was uncertainty
about continuing benefit thereafter. The clinical specialists indicated that melanoma may have an
unpredictable clinical course and that late recurrences are well recognized. The positives were the study
and trial was well done in terms of data analysis and testing clinical significance. It also did not have any
conflict of interests. The cost effectiveness 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 (unrespectable or metastatic) melanoma.
Additionally in this trial there were only 36 chemotherapy naive patients treated which is too
small of a number. Additionally, in the CA184-024 trial, ipilimumab was dosed at 10 mg/kg
rather than 3 mg/kg, which is the current recommended dose. It is important to note that this was
still a phase 3 trial and the dosing was still not finalized Additionally, the manufacturer did not
test for the BRAF mutation in patients and just used assumptions to project efficacy in these
patients. It was determined this study would receive a “C” grade
.
ISSUE 3: What is the level and quality of evidence for safety?
In regards to adverse reactions for MDX-010-20, Arm A, Arm B, and Arm C were 88.9% 80.2%,
and 78.8% respectively. Immune-related adverse events for Arm A, Arm B, and Arm C were
58.2%, 61.1%, and 31.8% respectively. High grade (3 or 4) immune-mediated adverse reactions

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occurred in 10.2%, 14.5%, and 3% in Arm A, Arm B, and Arm C respectively. Dermatologic
adverse events were the most common with 40.0% in Arm A, 43.5% in Arm B, and 16.7% in
Arm C. Gastrointestinal tract adverse events occurred in 32.1%, 29.0%, and 14.4% of Arms A,
B, and C respectively. There were found to be 7 deaths associated with immune-mediated
adverse reactions. Of these, 5 deaths were in Arm A, and 2 were in Arm B. In CA184-024,
Grade 3 or 4 adverse events occurred in 98.8% and 94.0% of Arm A and Arm B respectively.
The most common adverse event was gastrointestinal: diarrhea, which was present in 36.4% and
24.7% of Arm A and Arm B respectively. Immune related adverse events occurred in 77.7% and
38.2% of Arm A and Arm B respectively. In the extended follow-up of the BRIM-3 trial, it was
found that the most common low-grade adverse events for dacarbazine were fatigue (34%) and
nausea (43%). The most common low-grade adverse events for vemurafenib were arthralgia
(50%), rash (32%), fatigue (43%), photosensitivity (37%), increased LFTs (25%), skin papilloma
(28%), and nausea (36%). The most common high-grade adverse events for vemurafenib was
cutaneous squamous-cell carcinoma (19%) followed by increased LFTs (10%) and
keratoanthoma (10%). Treatment was discontinued in 24 (7%) of patients receiving vemurafenib
and six (2%) of patients receiving dacarabazine. A REMS program also needs to be implemented
and followed to monitor immune-mediated enterocolitis (including gastrointestinal perforation),
immune-mediated hepatitis (including hepatic failure) , immune-mediated dermatitis (including
toxic epidermal necrolysis), immune-mediated neuropathies and immune-mediated
endocrinopathies
ISSUE 4: What is the value proposition for this product?
Summary of Product Value
Over the 30 year lifetime time horizon, it was estimated that the average ipilimumab patient
would live 2.88 years which was 1.8 years longer than patients receiving BSC. The mean
survival durations in the first year of treatment (ipilimumab: 8.5 months; comparators: 7.2
months [BMS BIM DoF 003]86
The average ipilimumab patient gained 1.76 QALYs, which was 1.14 QALYs more than the
average BSC patient. . This result showed an improvement in the length of the patient’s life but
also an increase in cost to the payer. The BSC was the experimental gp100 vaccine which was
used because it was a non-chemotherapy agent .The difference in QALYs was influenced by the
differences in life years gained, PFS, and proportion of responders. Difference in QALY and
life-years between ipilimumab and BSC was statistically significant.
The total cost associated with ipilimumab therapy was greater than BSC. The base case
ICER was $78,218 per life-year gained and the ICUR was $128,656 per QALY gained
Yervoy cost $120,000 per course of therapy (conflicting cost value, other source states
$150,000), Proleukin costs $110,000 per course of therapy, Intron-A- cost 47,000 per course of
therapy, vemurafenib cost $56,400 per course of therapy (conflicting cost values other source
says 78,000 for 6 months tx) , dabrafenib costs 45,600 per course of therapy, dacarbazine $1,870,
and Temozolomide $11,065 The manufacturer derived efficacy data primarily from the
MDX010-20 trial, which showed that treatment with ipilimumab led to a statistically significant
median overall survival gain of approximately 3.7 months (HR 0.66; 95% CI 0.51 to 0.87;
p=0.0026) compared with gp100 for. It was determined form the MDX010-20 trial that only 10%
of people may experience long term survival benefits.

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Manufacturer-Submitted Modeling
Budget Impact Analysis:
The cost of adding YERVOY to a health plan formulary is moderated by: 1) the relatively
small patient population with unresectable or metastatic melanoma, and 2) the widespread use of
systemic treatments prior to YERVOY approval, which themselves have an associated cost.
Based on a budget impact model comparing the cost of current treatment to forecasted use of
YERVOY and other regimens in patients with unresectable or metastatic melanoma over the
three years after approval, the estimated incremental cost per member per month of adding
YERVOY to a health plan formulary is $0.051 (USD), assuming the modeling assumptions hold
over time. If accounting for drug wastage the incremental cost increase will be $0.055. The
annual budget without ipilimumab is just under $1 million ($907,574). With an initial market
share of 7%, the addition of ipilimumab to the health plan adds $206,025 in Year 1; $638,322 in
Year 2 (21% share), and $1,057,411 in Year 3 (35% share) for a plan with 1 million members. If
the projected market share of yervoy is projected correctly for 2014, which is 35%, the increased
cost to the Pitt street health plan would be $3,172,233 for 2014 with their being an average of 85
new cases per year.
The incremental cost per member per month (PMPM) ranges from $0.017, in Year 1, to $0.088 in Year 3 (Table 4.2.4.1-1). The average
incremental cost PMPM over the 3-year horizon was estimatedto be $0.053.
Table 4.2.4.1-1: Overall Cost to Plan
Base Year,
Pre-ipilimumab
With Ipilimumab Incremental
Year 1 Year 2 Year 3 Year 1 Year 2 Year 3 3-year
Average
Cost
PMPM
$0.076 $0.093 $0.129 $0.164 $0.017 $0.053 $0.088 $0.053
Cost
PTMPM
$2,570 $3,153 $4,377 $5,563 $583 $1,807 $2,994 $1,795
1: Epidemiology Data (Privately Insured Population)
% of Populationa
Number of New Cases
per 100,000a
Number of New Cases per
Plan 1M
Age < 18 27.7% 0 -
Age 18-64 65.0% 2.51 16.3
Age 65-74 4.4% 9.55 4.2
Age 75+ 2.9% 14.77 4.3
TOTAL cases 25

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%b
Number of New Cases per
Plan 1M
% of new cases receiving initial treatment 92.5% 23
% of new cases receiving second-line treatment 21.0% 5
% of new cases receiving third-line treatment 5.2% 1
Cost-Utility Analysis:
As per the cost‑effectiveness analyses published by Barzey, et al, treatment with ipilimumab
compared with BSC is estimated to result in significant difference in life years gained (mean
1.88; 95% CI: 1.62 to 2.20) and a mean gain of 1.14 (95%CI: 1.01 to 1.34) quality-adjusted life
years (QALYs) over lifetime.20 The cost of treating with ipilimumab vs BSC was $146,176
(95% CI: $130,992 to $164,025) with an ICER $128,656 per QALY gained. The ICER of
128,656 is above the average payer threshold of $100,000 per QALY gained as determined by
the World Health Organization. Ipilimumab requires one and half hours for infusion, somewhat
longer than for other drugs infused in an outpatient setting, with a consequent elevation in
administration cost. The other regimens are all assumed to be given as 1 hour intravenous
infusions, with the exception of IFN-alpha, which is given by subcutaneous injection. Yervoy
had cost of infusion of $504 compared to Intron-A at $163 and Proleuken at $945. Dabrafinib
and Vemurafenib are taken orally. The treatment duration for yervoy is 12 weeks, Intron-A 13.4
weeks, Proleukin 13.4 weeks, dabrfinib and vemurafenib typically 26-30 weeks.
Cost of treating toxicities for yervoy were $936, proleukin $457, Intron A $1,195 and the
other regimens average $593.
ISSUE 5: Are there identifiable patient subgroups in which this treatment will be most
cost-effective?
The patient subgroups that the treatment would be most cost effective is patients who have
already undergone unsuccessful treatment with dacarbazine or temozolomide and do not
have a BRAF mutated melanoma and therefore can’t be treated with verumafanib or
dabrafenib.

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effectivenessevidence summary (Reviewers may change this table format to better fit the economic study methodology)
Ref. and
Evidence
Grade
Drug Regimens N Time Demographics Design* End Points/Results/Comments NNT
MDX010-20
B
1. Arm A: ipilimumab
3mg/kg every 3
weeks + (Q3W) x 4
doses gp100 peptide
vaccine every 3
weeks (Q3W) x 4
doses
2. Arm B: ipilimumab
3mg/kg every 3
weeks (Q3W) x 4
doses + placebo
every 3 weeks
(Q3W) X 4 doses
3. Arm C: gp100
peptide vaccine
every 3 weeks
(Q3W) x 4 doses
676 (need to
find)
Mean age = 56.2
Male – 59.3%
Female – 40.7%
M Stage:
M0 – 1.5%
M1a – 9.2%
M1b – 17.9%
M1c – 71.4%
Inclusion Criteria: age
18 or older, unresectable
Stage III or IV
melanoma, HLA-*0201
positive, received
previous treatment with
a regimen containingat
least one of the
following: IL-2,
dacarbazine,
temozolomide,
carboplatin, or
fotemustine; at least 4
weeks since prior
systemic treatment
Phase 3, DB, , MC, 125 treatment
centers encompassing 13 countries
in North America, South America,
Europe, and Africa
End Points:
Primary endpoint: comparison of survival between
ipilimumab plus gp100 and gp100
Secondary endpoints: Best overall response rate (BORR)
at Week 24; duration of response; progression free
survival (PFS)
Results:
Primary endpoint: Median overall survival (OS) for
ipilumab+gp100 arm was 10 months andgp100 arm was
6.4 months; the combination provedto be a statistically
improvement
Secondary endpoints:
 OS for Arm A, Arm B, and Arm C were 43.6%,
45.6%, and 25.3% respectively; Arm B had a
statistically significant increase in OS when compared
to Arm C
 The BORR for Arm A, Arm B, and Arm C were
5.7%, 10.9%, and 1.5% respectively
 Risk of PFS was reduced in Arm A compared to Arm
C
Ipilimumab
+gp100 vs
gp100
N=13
Ipilimumab vs
gp100
N=10

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Robert, et al.
2011
CA184-024
B
Induction:
1. Ipilimumab 10
mg/kg Q3W x 4
doses + dacarbazine
850 mg/m2
2. Placebo +
dacarbazine 850
mg/m2
x 8 doses
Maintenance:
1. Ipilimumab 10
mg/kg Q12W
2. Placebo x Q12W
502 (need to
find)
Ipilimumab plus
dacarbazine:
 Mean age = 57.5
years
 Sex
- Male: n=152 (60.8)
- Female: n=98
(39.2)
 Metastasis stage
- M0 = 6 (2.4)
- M1a = 37 (14.8)
- M1b = 64 (25.6)
- M1c = 143 (57.2)
Placebo plus
dacarbazine:
 Mean age = 56.4
years
 Sex
- Male: n=149 (59.1)
- Female: n=103
(40.9)
 Metastasis stage
- M0 = 8 (3.2)
- M1a = 43 (17.1)
- M1b = 62 (24.6)
- M1c = 139 (55.2)
Phase 3, DB, PC, MC End Points:
Primary endpoint: OS
Secondary endpoints: PFS, BORR, disease control rate
(DCR), time to response, duration of response, and safety
Results:
Primary endpoint: statistically significant increase in OS
when comparing ipilimumab plus dacarbazine to
dacarbazine; OS at 3 years for ipilimumab plus
dacarbazine and dacarbazine was 20.8% and 12.2%
respectively
Secondary endpoints:
 The HR for disease progression was 0.76
 BORR observed in 15.2% and 10.3% of patients in
ipilimumab plus dacarbazine and dacarbazine
respectively.
 Progressive disease was observed in 44.4% of the
combination group and 52% of the dacarbazine group.
Not provided

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Lancet Oncol
2014; 15:
323–32
BRIM-3
Grade B
1. vemurafenib 960 mg
PO BID
2. dacarbazine 1000
mg/m² IV Q3W
675 18
months
Inclusion criteria: 18
years of age or older,
presence of BRAFV600
mutation, metastatic
melanoma, life
expectancy of 3 months
or longer, an ECOG
performance status of 0
or 1, and adequate renal,
hepatic, and hematologic
status
BRAFV600E
:
 Median age = 53.0
 Australia/New
Zealand (n=72) (12%)
 North America
(n=144) (24%)
 Other (n=18) (3%)
 Western Europe
(n=364) (61%)
BRAFV600K
:
 Median age = 63.0
 Australia/New
Zealand (n=5) (9%)
 North America (n=23)
(40%)
 Other (n=0)
 Western Europe
(n=29) (51%)
Phase 3, DB, MC, 104 centers in
12 countries worldwide
INITIAL
End Points:
Primary endpoints: OS and progression-free survival (Dec
30, 2010 cutoff) for the BRAFV600
mutation
Secondary endpoints: the proportionof patients with a
confirmedor partial response on RECIST , time to
response, duration of response, time to treatment failure,
the PK profile of vemurafenib, and validation of the cobas
test
Results:
Primary endpoint:
Secondary endpoints:
Comments:
 Median follow of 12.5 months for vemurafenibgroup
and 9.5 months for dacarbazine group
 Of the 675 patients, 673 hadSanger/454 sequencing
performed; of those 673 patients 657 tumors were able
to have the BRAFV600
mutation determined:
- 91% BRAFV600E
mutation, 9% BRAFV600K
mutation,
and <1% BRAFV600D
mutation
FOLLOW UP
End Points:
Primary endpoints: Primary endpoints: OS and
progression-free survival (Dec 30, 2010 cutoff) for the
BRAFV600E
and mutation BRAFV600K
mutation
Secondary endpoints:
Results:
Primary endpoint: median OS (censoredat crossover) was
significantly longer in the vemurafenib group for both
BRAFV600E
and BRAFV600K
mutations; 13.3 months versus
10.0 months in vemurafenib and dacarbazine respectively;
At 18 month follow up there was minimal difference in
OS between both groups
Secondary endpoints: progression free-survival was 6.9
months versus 1.6 months in vemurafenib and dacarbazine
respectively
Mutation-postitive disease: 5.9 months versus 1.7 months
in vemurafenib and dacarbazine respectively
Comments:
 7% of vemurafenib comared to 2% of dacarbazine
discontinued therapy due to adverse events
Not provided

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Ref. and
Evidence
Grade
Study design and
treatments
compared
Time
Horizons
and
Demograp
hics
Model input and data sources
Results
Base case, sensitivity analysis and limitations
Cost-
effectiveness
of treatment
strategies for
BRAF-
mutated
metastatic
melanoma.
Grade B
AMCP
eDossier
Dacarbazine alone verses
Vemurafenib alone
verses vemurafenib
followed by ipilimunab.
Study was done from a
societal perspective with
a discount rate of 3%. A
expectedvalue cost-
utility model was used to
calculate the present
value of all expected
lifetime costs and all
expectedlife QALY’s. a
decision tree model was
performed.
Baseline
analysis
considered
a
population
of treatment
naïve
patients
with the
BRAF
mutated
metastatic
or
unresectabl
e
melanoma.
The
remaining
life
expectance
of the
patients
A one way sensitivity analyses
was performed on all variables
and a multi way sensitivity
analysis was performedfor several
clinical efficacy values
simultaneously for both
vemurafenib and ipilimumab.
-Dacarbazine Only resulted in a QALY of 0.30 with a
cost of $8,391 comparedto Vemurafenib Only with a
QALY of 0.72 with a cost of $156,831. The ICER of
vemurafenib only compared to dacarbazine only was
$353,993. Vemurafenib only increased QALYs by 0.42
over Dacarbazine only
-Vemurafenib + Ipilimumab resulted in a QALY of 1.34
with a cost of $254,695 andICER of $158,139 compared
to vemurafenib alone which resulted in a QALY of 0.72
with a cost of $156,831. Vemurafenib + ipilimumab
increased QALY’s by 0.62 over just using vemurafenib
only. Vemurafenib + ipilimumab resulted in an increase in
cost of $97,864
- For ipilimumab, a sensitivity analysis assuming a patient
age of 50 and allowing for an average life expectancy in
patients with a complete response reduced the ICER to
$90,000 for vemurafenibfollowed by ipilimumab
compared with vemurafenib alone.
Ipilimumab resulted in a cost of $102,000 per QALY
gained
Compared to vemurafenib alone, the addition of
ipilimumab demonstrates a clear benefit in both quality
and duration of life, and provedto be more cost-effective
than the comparison between dacarbazine and
vemurafenib but still above most desirable thresholds for
cost-effectiveness. Despite the high initial treatment cost
of ipilimumab, what drives the difference in cost-
effectiveness of this strategy is the potential for a durable
response which does not require continuous lifetime
treatment.
In the base case, the incremental cost-effectiveness ratio
(ICER) for vemurafenib compared with dacarbazine was
$353,993 per QALY gained (0.42 QALYs added,
$156,831 added). The ICER for vemurafenib followed by
ipilimumab compared with vemurafenib alone was
$158,139. In sensitivity analysis, treatment cost hadthe
largest influence on results: the ICER for vemurafenib
versus dacarbazine dropped to $100,000 per QALY
gained with a treatment cost of $3600per month.

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CA184-024
Ipilimumab in
2nd line
treatment of
patients with
advanced
melanoma: a
cost-
effectiveness
analysis.
Pubmed
Grade C
A three state markov
model was developed
representingclinical
outcomes, quality of life,
and healthcare recourse
use of patients treated
with ipilimumab and
BSC.
30 year
time
horizon
Traansisitions between states were
modeled using overall and
progression-free survival data
from the MDX0101 trial. Utility
data were from a melanoma –
specific study of the helath state
prefere3nces of the general
population. Disease management
costs were based on healthcare
resource se observed in a US
retrospective medical chart study.
Uncertainty was analyzed using
one-way and probabilistic
sensitivity analyses.
The gain in life years and QALYs from introducing
ipilimumab over BSC were 1.88 years (95% CI = 1.62-
2.20) and 1.14 (95% CI = 1.01-1.34) QALYs,
respectively, over the lifetime time horizon. The estimated
incremental cost of treatingwith ipilimumab vs BSC was
$146,716 (95% CI = $130,992-$164,025).The estimated
incremental cost-effectiveness ratios were $78,218 per life
year gained and $128,656 per QALY gained. Ipilimumab
was 95% likely to be cost-effective at a willingness-to-pay
of $146,000/QALY.
Limitations:
Ipilimumab's methodof action causes a tumor response
pattern that differs from the Response Evaluation Criteria
in Solid Tumors upon which the model is based, leading
to a potential under-estimate of quality-of-life of
ipilimumab patients. Survival and QALY gains were
related to the time horizon of the analysis. Sensitivity
analyses indicated that qualitative conclusions regarding
the cost-effectiveness of ipilimumab were unchanged
when the methodof quality adjustment and the time
horizon were varied.
Dose rounding
of ipilimumab
in adult
metastatic
melanoma
patients
results in
significant
cost savings.
Pubmed
Grade C
Not provided Not
provided
METHODS:
All patients with a diagnosis of
metastatic melanoma andwho
received at least one dose
ipilimumab were included for
analysis. Doses of ipilimumab
were calculated based upon the
actual body weight (in kg) of the
patient at the FDA approved
regimen of 3 mg/kg every 21
days × 4 doses. The exact total mg
dose was then rounded to the
nearest 50 mg vial size. The
potential effect on cost was
calculated in
22 patients have received at least one dose of ipilimumab.
11 patients have completedtherapy andreceived all four
induction doses. 9 patients discontinued therapy early and
2 patients were still actively receiving induction at the
time of this analysis. A total of 63 doses were given. The
maximum potential cost savings by giving ipilimumab to
the nearest 50 mg over the periodwas 155,400.

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Cost
Effectiveness
of Dabrafenib
as a First-Line
Treatment in
Patients with
BRAF V600
Mutation-
Positive
Unresectable
or Metastatic
Melanoma in
Canada
.
Grade B
Pubmed
partitioned-survival
analysis model with three
mutually exclusive health
states (pre-progression,
post-progression, and
dead) was used.
dabrafenib
and
vemurafeni
b
5 year time
horizon
The proportionof patients in each
state was calculated using survival
distributions for progression-free
and overall survival derived from
pivotal trials of dabrafenib and
vemurafenib. For each treatment,
expectedprogression-free, post-
progression, overall, and quality-
adjusted life-years (QALYs), and
costs were calculated. Costs were
based on list prices, a clinician
survey, and published sources
Dabrafenib was estimated to yield 0.2055 more QALYs at
higher cost than dacarbazine. The incremental cost-
effectiveness ratio was CA$363,136/QALY. In
probabilistic sensitivity analyses, at a thresholdof
CA$200,000/QALY, there was an 8.2 % probability that
dabrafenib is cost effective versus dacarbazine. In
deterministic sensitivity analyses, cost effectiveness was
sensitive to survival distributions, utilities, and time
horizon, with the hazard ratio for overall survival for
dabrafenib versus dacarbazine being the most sensitive
parameter. Assuming a class effect for efficacy of BRAF
inhibitors, dabrafenib was dominant versus vemurafenib
(less costly, equally effective), reflectingits assumed
lower daily cost. Assuming no class effect, dabrafenib
yielded 0.0486 more QALYs than vemurafenib.

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BACKGROUND INFORMATION
DISEASE BACKGROUND
What is the disease?
Skin cancer can occur anywhere on the body, but it is most common in skin that is often
exposed to sunlight, such as the face, neck, hands, and arms. There are different types of cancer
that start in the skin. Melanoma is a disease in which malignant (cancer) cells form in the skin
cells called melanocytes (cells that color the skin). Melanocytes are found throughout the lower
part of the epidermis. They make melanin, the pigment that gives skin its natural color.
The most dangerous form of skin cancer, these cancerous growths develop when unrepaired
DNA damage to skin cells (most often caused by ultraviolet radiation from sunshine or tanning
beds) triggers mutations (genetic defects) that lead the skin cells to multiply rapidly and form
malignant tumors. These tumors originate in the pigment-producing melanocytes in the basal
layer of the epidermis. Melanomas often resemble moles; some develop from moles. The
majority of melanomas are black or brown, but they can also be skin-colored, pink, red, purple,
blue or white. Melanoma is caused mainly by intense, occasional UV exposure (frequently
leading to sunburn), especially in those who are genetically predisposed to the disease. This may
include people with fair complexion that typically burn easily, and those with increased UV light
exposure or radiation exposure. The disease presents with a bimodal age distribution (early
adulthood and older age, 62 years old is the median age).
Melanoma kills an estimated 9,710 people in the US annually. If melanoma is recognized and
treated early, it is almost always curable, but if it is not, the cancer can advance and spread to
other parts of the body, where it becomes hard to treat and can be fatal. While it is not the most
common of the skin cancers, it causes the most deaths. The American Cancer Society estimates
that at present, more than 120,000 new cases of melanoma in the US are diagnosed in a year. In
2014, an estimated 76,100 of these will be invasive melanomas, with about 43,890 in males and
32,210 in women. Aggressive local growth and metastasis are common features of malignant
melanoma, which accounts for 75 percent of all deaths associated with skin cancer. The median
survival for advanced melanoma is 6 months.
The prognosis (chance of recovery) and treatment options depend on the following:
 The thickness of the tumor and where it is in the body.
 How quickly the cancer cells are dividing.
 Whether there was bleeding or ulceration at the primary site.
 Whether cancer has spread to the lymph nodes or to other places in the body.
 The number of places cancer has spread to in the body and the level of lactate dehydrogenate
(LDH) in the blood.
 Whether the cancer has certain mutations (changes) in a gene called BRAF.
 The patient’s general health.

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DISEASE BURDEN
The burden of disease is similar to most metastatic cancers. The patient will go through
treatments in order to extend their life which will be very time consuming. The patient will most
likely also experience pain and have the constant thought of there being a time frame on the rest
of their life. The patient may also be insecure about the way that they look if they have visible
lesions. The thought of making the choice of paying/affording more expensive treatments that
may extend life vs. choosing the less expensive treatment that will most likely not extend life as
long as the other, more expensive agent
Healthcare costs for unresectable or metastatic melanoma, from diagnosis to death or the end of
the follow-up period of the retrospective chart review study, were estimated to have a mean of
$53,229 per patient (SD=$71,411; 10th and 90th percentile: $8,863 and $104,559, respectively);
over half (51.4%) of this cost was for drug therapy to treat the disease (BMS DoF, OR YERV
00216).
A recent study of insurance claims projected the annual cost of healthcare use for US patients
with unresectable or metastatic melanoma to be approximately $1.2 billion in 2008 (BMS DoF,
OR YERV 0014).
PATHOPHYSIOLOGY
Skin cancer can occur anywhere on the body, but it is most common in skin that is often exposed
to sunlight, such as the face, neck, hands, and arms. There are different types of cancer that start
in the skin. Melanoma is a disease in which malignant (cancer) cells form in the skin cells called
melanocytes (cells that color the skin). Melanocytes are found throughout the lower part of the
epidermis. They make melanin, the pigment that gives skin its natural color. When these cells
undergo DNA damage that remains unrepaired they have the ability to proliferate and
differentiate into cancerous cells. Eventually these cells can increase in size, become invasive,
and recruit blood vessels to gain needed nutrients for proliferation. Metastasis occurs once these
cells leak contents into the blood stream where they next move on to infect the lymph nodes.
Progression can then expand to other organs.
STAGING:
Stage 0: This stage represents the finding of abnormal melanocytes in the epidermis that are not
considered cancer, but may become cancerous and spread. This stage is also referred to as
“melanoma is situ”.
Stage Ia: The tumor is not more than 1 mm thick and without ulceration.
Stage Ib: The tumor is either not more than 1 mm thick, but has ulceration; or is between 1-2 mm
thick without ulceration.
Stage IIa: Stage II melanoma. In stage IIA, the tumor is either more than 1 but not more than 2
millimeters thick, with ulceration (break in the skin), OR it is more than 2 but not more than 4
millimeters thick, with no ulceration
Stage IIb: In stage IIB, the tumor is either more than 2 but not more than 4 millimeters thick,
with ulceration, OR it is more than 4 millimeters thick, with no ulceration.

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Stage IIc: In stage IIC, the tumor is more than 4 mm thick, with ulceration. Skin thickness is
different on different parts of the body.
Stage IIIa: The tumor may be any thickness, with or without ulceration (a break in the skin), and
(a) cancer has spread to one or more lymph nodes; (b) lymph nodes with cancer may be joined
together (matted); (c) cancer may be in a lymph vessel between the primary tumor and nearby
lymph nodes; and/or (d) very small tumors may be found on or under the skin, not more than 2
centimeters away from the primary tumor.
Stage IV: the cancer has spread to other places in the body, such as the lung, liver, brain, bone,
soft tissue, or gastrointestinal (GI) tract.
Preferred Existing Therapy
Treatment for unresectable Stage III, Stage IV, and Recurrent Melanoma Treatment
Preferred treatment options include Immunotherapy, signal transduction inhibitors, and
chemotherapy.
Immunotherapy:
The Anti-PD-1 agent, Pembrolizumab, targets the PD-1 pathway that many tumors utilize to
attenuate T-cell proliferation. By blocking this pathway, T-cell activation, expansion, and
enhanced effector functions such as increased IL-2 production can be achieved.
High dose IL-2[Aldesleukin (Proleukin)] is another treatment option utilized to enhance immune
system effects against the tumor through modified and enhanced cellular signaling.
Signal Transduction inhibitors:
This treatment category includes the targets, BRAF and MEK. These proteins are responsible for
direct involvement with tumor growth through signal transduction protein kinases affecting cell
division and differentiation. BRAF activates MEK1 and MEK2 proteins that activate the MAP
kinases responsible for the effects on tumor growth.
Vemurafenib and Dabrafenib are the suggested BRAF inhibitors for use in unresectable or
metastatic melanoma, however their use in limited to those patients with the BRAF V600E
mutation. Vemurafenib can also be used in patients with V600K mutation.
Trametinib is the suggested MEK inhibitor selective for MEK1 and MEK2. The agent is
approved for unresectable or metastatic melanoma with BRAF V600E or K mutations.

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Chemotherapy:
DTIC (dacarbazine) is the approved and suggested chemotherapy for metastatic melanoma. TMZ
(temozolomide), another alkylating agent, has also been an explored option for use in metastatic
melanoma.
Other Therapeutic Alternatives
The use of regional lymphadenectomy and radiation are used only for the relief of pain and
complications associated with symptoms. Examples where regional resections may be useful are
metastatic sites in the lung, gastrointestinal tract, bone, and sometimes the brain. Use of
palliative radiation in metastatic melanoma includes patients with multiple brain metastases,
bone metastases, and spinal cord compression.
Antiangiogenesis agents are being explored for those who are resistant to BRAF inhibitors. This
therapy aims to reduce the growth of the disease by cutting off its highway of nutrient supply, the
blood vessels.
PRODUCT BACKGROUND
PHARMACOLOGY
Ipilimubab may indirectly mediate T-cell immune response against tumors in melanoma patients.
Ipilimubab is a monoclonal antibody that binds to CTLA-4 (cytotoxic T-lymphocyte associated
antigen 4) blocking CTLA-4 from binding to its ligand CD 80/86. CTLA-4 is a downregulator
of T-cell activation pathways. Thus by blocking CTLA-4 enhances T-cell activation and
proliferation.
PHARMACOKINETICS
Route of
Administration:
Intravenous
Bioavailability: 100% due to all administrations via intravenous route.
Time to Peak: Achieved by the 3rd dose.
Multiple dosing:
Clearance has been found to be time-invariant. Minimal
systemic accumulation was absorbed by obtaining an
accumulation index of 1.5 or less.
Clearance: 16.8 mL/ h
ADVERSE EFFECT PROFILE

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Pruritis (any grade) 21% to 31%
Pruritis (grade 3-5) < 1%
Rash (any grade) 25% to 29%
Rash (grade 3-5) 2%
Colitis (any grade) 5% to 8%
Colitis (grade 3-5) 3% to 5%
Diarrhea (any grade) 32% to 37%
Diarrhea (grade 3-5) 3% to 5%
Fatigue (any grade) 34% to 41%
Fatigue (grade 3-5) 5% to 7%
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only;
intervention not indicated.
Grade 2: Moderate; minimal, local or noninvasive interventionindicated;
Grade 3:Severe or medically significant but not immediately life-threatening;hospitalizationor
prolongation of hospitalization indicated; disabling;
Grade 4: Life-threateningconsequences; urgent intervention indicated.
Grade 5: Death related to AE.
DRUG INTERACTIONS
According to the package insert, no formal pharmacokinetic drug interaction studies have been
conducted with Yervoy. Yervoy does not appear to involve the cytochrome P450 System.
CONTRACTING AND SITE OF CARE
The average sale price for Yervoy is $133.66 per 1mg of drug. The average wholesale
acquisition price is $6,463 for a 50mg/ml package Therefore one infusion based on
recommended dose would cost $32,078 (cms.gov). The administration fee per infusion is $504. .
Reimbursement decisions were based off of 2015 center of Medicare services price. The
recommended site of infusion is in an outpatient infusion center setting.
METHODOLOGY OF THIS REVIEW
DATABASES SEARCHED:
PubMed
Google Scholar
eDossier
SECONDARY SOURCES:
1. NICE, http://www.nice.org.uk/guidance/ta319/resources/guidance-ipilimumab-for-
previously-untreated-advanced-unresectable-or-metastatic-melanoma-pdf, July 2014.

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SEARCH STRATEGY:
Searched for studies that compared drugs in the use of unrespectable metastatic melanoma in
cost and clinical effectiveness.
INCLUSION CRITERIA:
Databases such as Pubmed and Google Scholar were used to search for clinical efficacy and cost
effectiveness. Information in the Yervoy Dossier was also included. The studies must of included
metastatic melanoma patients and had a sufficient patient population. The studies also had to
include short term and longer term endpoints.
Search Results:
Study Type N
Randomized controlled trials (RCT) 3
Meta-analyses
Indirect Comparison studies
Prospective observational studies
Retrospective observational studies
Economic or QALY modeling studies 3
Case Series
RCT abstracts, not peer-reviewed
Other abstracts, posters, etc., not peer-reviewed
Articles Excluded from Evidence Synthesis:
1. “Dose rounding of ipilimumab in adult metastatic melanoma patients results in significant cost
savings”
Reasonfor Exclusion N
There wasn’t enough comparison to other medications to warrant its inclusion
in pharmacoeconomic analysis
1
REFERENCES
1. Yervoy eDossier AMCP, accessed November 2014
2. Barzey V, Atkins MB, Garrison LP, Asukai Y, Kotapati S, Penrod JR. Ipilimumab in 2nd
line treatment of patients with advanced melanoma: a cost-effectiveness analysis. J Med
Econ. 2013; 16:202-212.
3. 21. Red Book Database. Greenwood Village, Colorado: Thomson Micromedex. 2013.
4. Curl P, Vujic I, van 't Veer LJ, Ortiz-Urda S, Kahn JG. Cost-effectiveness of treatment
strategies for BRAF-mutated metastatic melanoma.. PLoS One. 2014 Sep 8;9(9):e107255.
doi: 10.1371/journal.pone.0107255. eCollection 2014.

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5. Centers for Medicaid and Medicare Services
6. Delea TE1, Amdahl J, Wang A, Amonkar MM, Thabane M. Delea TE1, Amdahl J, Wang A,
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http://www.cms.gov/McrPartBDrugAvgSalesPrice/01a18_2011ASPFiles.asp#TopOfPage.
Accessed March 24, 2011.
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Glover D, Ibrahim J, Kirkwood J, et al. Phase II randomized trial of cisplatin and WR-2721
versus cisplatin alone for metastatic melanoma: an Eastern Cooperative Oncology Group
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Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for
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Danson S, Lorigan P, Arance A, et al. Randomized phase II study of temozolomide given
every 8 hours or daily with either interferon alfa-2b or thalidomide in metastatic malignant
melanoma. J Clin Oncol. 2003;21(13):2551-2557.
12. Data on File (OR YERV 002) The Epidemiology and Clinical and Demographic
Characteristics of Advanced Melanoma Patients in the US: Evidence from a Retrospective
Medical Chart Review. Bristol-Myers Squibb. Princeton, NJ. 2011.
13. Physicians' Fee and Coding Guide Duluth, GA: Mag Mutual Healthcare Solutions; 2010.
14. http://www.skincancer.org/skin-cancer-information/melanoma, January 20th
15. Jerant, Anthony “Early Detection and treatment of skin cancer
http://www.aafp.org/afp/2000/0715/p357.html Am Fam Physsician, 2000 Jul 15.
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http://www.cancer.gov/cancertopics/pdq/treatment/melanoma/HealthProfessional/page9
January 20th
17. EORTC QLQ-C30 Version 3.0
http://www.trialsjournal.com/content/10/1/8/figure/F1?highres=y January 21st
18. http://www.nice.org.uk/guidance/ta319/resources/guidance-ipilimumab-for-previously-
untreated-advanced-unresectable-or-metastatic-melanoma-pdf
19. Hans-Georg Eichler, MD, MS,1,2 Sheldon X. Kong, PhD,2 William C. Gerth, MBA,2
20. Panagiotis Mavros, PhD,2 Bengt Jönsson, PhD3. “Use of Cost-Effectiveness Analysis in
Health-Care ResourceAllocation Decision-Making: How Are Cost-Effectiveness.Thresholds
Expected to Emerge?” Volumne 7, November 5th, 2004
21. NICE, http://www.nice.org.uk/guidance/ta319/resources/guidance-ipilimumab-for-
previously-untreated-advanced-unresectable-or-metastatic-melanoma-pdf, July 2014.

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