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Pitt Street Health Plan Formulary Monograph TemplateIndividual 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 Formularyaldesleukin (Proleukin®) ipilimumab (Yervoy®)interferon alfa-2b (Intron-A®)vemurafenib (Zelboraf®)dabrafenib (Tafinlar®)

temozolomide (Temodar®) [oral capsules] – off labelimatinib (Gleevec®)trametinib (Mekinist®)peginterferon alfa-2b (Sylatron®)pembrolizumab (Keytruda®)dabrafenib/trametinib - combination therapydacarbazine

TABLE OF CONTENTS:(Click on a link below to view the section.)

Executive SummaryRecommendations Key Questions/Issues:

Issue 1: EfficacyIssue 2: Comparative EffectivenessIssue 3: SafetyIssue 4: Value PropositionIssue 5: Cost-effective Patient Subgroups

Clinical Evidence TablesCost-effectiveness Evidence TablesBackground

Disease BackgroundPharmacotherapyProduct Background

MethodologyReferences

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Abbreviations used in this monograph:

QALY- Quality adjusted life year OS-overall survivalPPHM- Price per member month BORR-Best Overall Response RateICER- Incremental cost effectiveness ration DB-Double BlindICUR-incremental cost utility ratio PC- placebo controlledAE-Adverse event EORTC-European Organization for

Research and 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 assess real 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 real world comparative effectiveness. The study received a B+ rating. The trail did not receive an “A” rating because it did not fully reflect a real world 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]86The 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 gainedYervoy 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 estimated to 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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effectiveness evidence summary (Reviewers may change this table format to better fit the economic study methodology)

Ref. andEvidence

GradeDrug Regimens N Time Demographics Design* End Points/Results/Comments NNT

MDX010-20B

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 = 56.2Male – 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 containing at 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 gp100Secondary 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 and gp100 arm was 6.4 months; the combination proved to be a statistically improvementSecondary 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 gp100N=13

Ipilimumab vs gp100N=10

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Ref. andEvidence

GradeDrug Regimens N Time Demographics Design* End Points/Results/Comments NNT

Robert, et al. 2011

CA184-024B

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 Q12W2. 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: OSSecondary 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% respectivelySecondary 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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Ref. andEvidence

GradeDrug Regimens N Time Demographics Design* End Points/Results/Comments NNT

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 statusBRAFV600E: 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

INITIALEnd Points:Primary endpoints: OS and progression-free survival (Dec 30, 2010 cutoff) for the BRAFV600 mutationSecondary endpoints: the proportion of patients with a confirmed or partial response on RECIST, time to response, duration of response, time to treatment failure, the PK profile of vemurafenib, and validation of the cobas testResults:Primary endpoint:Secondary endpoints:Comments: Median follow of 12.5 months for vemurafenib group

and 9.5 months for dacarbazine group Of the 675 patients, 673 had Sanger/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 UPEnd Points:Primary endpoints: Primary endpoints: OS and progression-free survival (Dec 30, 2010 cutoff) for the BRAFV600E and mutation BRAFV600K mutationSecondary endpoints:

Results:Primary endpoint: median OS (censored at 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 groupsSecondary endpoints: progression free-survival was 6.9 months versus 1.6 months in vemurafenib and dacarbazine respectivelyMutation-postitive disease: 5.9 months versus 1.7 months in vemurafenib and dacarbazine respectivelyComments: 7% of vemurafenib comared to 2% of dacarbazine

discontinued therapy due to adverse events

Not provided

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Ref. andEvidence

Grade

Study design and treatments compared

Time Horizons

and Demograp

hics

Model input and data sources ResultsBase 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 expected value cost-utility model was used to calculate the present value of all expected lifetime costs and all expected life QALY’s. a decision tree model was performed.

Baseline analysis considered a population of treatment naïve patients with the BRAF mutated metastatic or unresectable 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 performed for 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 compared to 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 and ICER 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 vemurafenib followed 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 proved to 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 had the largest influence on results: the ICER for vemurafenib versus dacarbazine dropped to $100,000 per QALY gained with a treatment cost of $3600 per month.

CA184-024Ipilimumab in 2nd line treatment of patients with advanced melanoma: a cost-effectiveness analysis.

PubmedGrade C

A three state markov model was developed representing clinical 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 treating with 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 method of 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 method of quality adjustment and the time horizon were varied.

Dose rounding of ipilimumab in adult metastatic

Not provided Not provided

METHODS:All patients with a diagnosis of metastatic melanoma and who received at least one dose ipilimumab were included for

22 patients have received at least one dose of ipilimumab. 11 patients have completed therapy and received 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

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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 ulcerationStage 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 intervention indicated;

Grade 3:Severe or medically significant but not immediately life-threatening; hospitalization or

prolongation of hospitalization indicated; disabling;

Grade 4: Life-threatening consequences; 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:PubMedGoogle ScholareDossier

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 NRandomized controlled trials (RCT) 3Meta-analysesIndirect Comparison studiesProspective observational studiesRetrospective observational studiesEconomic or QALY modeling studies 3Case SeriesRCT abstracts, not peer-reviewedOther 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”

Reason for Exclusion NThere wasn’t enough comparison to other medications to warrant its inclusion in pharmacoeconomic analysis

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REFERENCES

1. Yervoy eDossier AMCP, accessed November 2014

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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, Amonkar MM, Thabane M. Pubmed. Pharmacoeconomics. 2014 Dec 9.

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10. 94 Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. Jul 1999;17(7):2105-2116.

11. 95 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 20th15. Jerant, Anthony “Early Detection and treatment of skin cancer

http://www.aafp.org/afp/2000/0715/p357.html Am Fam Physsician, 2000 Jul 15.16. National Cancer Institute

http://www.cancer.gov/cancertopics/pdq/treatment/melanoma/HealthProfessional/page9 January 20 th

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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,220. 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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