milovac p&t competition monograph

Jennifer Baird, Janetta Geronian, Brent Milovac, and Vivan Nguyen

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 2015

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 Summary Recommendations

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

Abbreviations used in this monograph:

NCCN - National Comprehensive Cancer Network OS - Overall SurvivalREMS - Risk Evaluation and Mitigation Strategy ORR - Overall Response RateFDA - Food and Drug Administration BORR - Best Overall Response RateICER - Incremental Cost Effectiveness Ratio CI - Confidence IntervalQALY - Quality of Adjusted Life Years PMPM - Per-Member Per-MonthDTIC - Dacarbazine SD - Stable Disease

REASON FOR REVIEW:1


To determine the formulary status for ipilimumab injection for intravenous infusion, FDA approved for treatment of unresectable or metastatic melanoma.

EXECUTIVE SUMMARY

Key Questions/Issues and Results of Investigation:

Issue 1: What is the evidence of efficacy from clinical trials?

Despite the differences in dosing in the clinical trials and the use of other active agents along with ipilimumab, the monoclonal antibody is approved for single-agent use at a dose of 3 mg/kg. Efficacy was shown in the phase III Hodi et al study, the registration trial used for FDA approval, of ipilimumab 3 mg/kg plus gp100 melanoma vaccine versus ipilimumab 3 mg/kg alone and gp100 melanoma vaccine alone in patients with ECOG of 0-1 who had undergone previous therapy. OS was the primary end point, where there was a statistical significant difference (P<0.001) for ipilimumab plus gp100 versus gp100 alone. Efficacy in patients who were previously untreated was demonstrated in the phase III Robert et al study, in which ipilimumab 10 mg/kg plus dacarbazine was compared to placebo plus dacarbazine. Once again, the primary end point was OS. The results were statistically significant (P<0.001), since the median OS for ipilimumab plus dacarbazine was 11.2 months versus 9.1 months for placebo plus dacarbazine. There were multiple reports of phase II trials (O’Day 2010, Wolchok 2010, Hersh 2011, and Thompson 2012) that demonstrated the efficacy of ipilimumab in the treatment of unresectable or metastatic melanoma. Wolchock et al conducted a follow-up study in 2013 to determine the four-year survival rates for patients who received ipilimumab in phase II clinical trials. The study suggests that a large proportion of patients with metastatic melanoma survive long-term following the administration of ipilimumab monotherapy. Lastly, a phase II trial (Margolin 2012) studied the safety and efficacy of ipilimumab in patients with melanoma and brain metastases. The authors concluded that ipilimumab has activity in some patients with advanced melanoma and brain metastases, especially when the metastases are small and asymptomatic.

Issue 2: Is there sufficient evidence to assess real world comparative effectiveness?

The applicability of key findings in available trials is debatable. Very few studies exist that compare ipilimumab monotherapy directly to other standards of care. Combination therapy of ipilimumab and another agent compared to ipilimumab monotherapy is a somewhat common design within the evidence body. Many of the larger studies include patients from dozens of sites on multiple continents, while others are much smaller, more focused groups of individuals. Inclusion and exclusion criteria of the studies were similar, with a number of limiting factors for real-world patients. Among the most considerable threats to generalizability were the exclusion criteria of chronic corticosteroid use or concomitant immunosuppression, autoimmune disease, ocular or uveal melanoma, and central nervous system metastases. Also concerning is the recurring criterion of minimum life expectancy, with many requirements being at least 16 weeks. This limits the ability of reviewers to determine ipilimumab’s potential to improve outcomes for patients whose initial prognosis is not promising. Confounding also may have played an influential role in study bias. Within the evidence body, most enrolled patients had experienced

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treatment failure on at least one agent. The types of cytotoxic and immunogenic therapies previously used varied from one trial to the next. Differences in prior treatment regimens may have impacted ipilimumab response, potentially distorting results across studies. In summary, although existing data point toward favorable comparative efficacy for ipilimumab, more direct, comparative research should be conducted to confirm these findings as well as further establish the safety profile of the drug.

Issue 3: What is the evidence of safety?

Ipilimumab is a Pregnancy Category C medication, as animal reproduction studies have shown an adverse effect on the fetus but there are no adequate and well-controlled studies in humans. Safety and efficacy have not been established in the pediatric population. There is no clinical difference in safety or efficacy between the geriatric population and patients under the age of 65. Ipilimumab’s potential to result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation has necessitated the use of REMS criteria and a Boxed Warning to ensure that providers and patients are appropriately informed of the risks associated with ipilimumab use. These immune-mediated reactions were seen in all ipilimumab trials and may involve any organ system, but the most common severe adverse effects are enterocolitis, hepatitis, dermatitis, neuropathy, and endocrinopathy. More common, mild adverse reactions, as identified in the phase II and phase III trials, include fatigue, diarrhea, pruritus, rash, and colitis.

Issue 4: What is the value proposition for this product?

The costs incurred to a plan in order to manage patients with malignant melanoma are very high. However, this high cost is offset by low disease incidence and efficacy of the treatment in extending life. In modeling submitted in the e-Dossier, a QALY value of 1.14 (95% CI=1.01-1.34) was found by treating patients with ipilimumab over BSC. This was associated with an ICER of $128,656 per QALY. Depending on plan specific ICER values, it is predicted that ipilimumab is cost-effective. In Pitt Street Health, it is projected that out of 3.4M members covered, the number of members eligible to be treated with ipilimumab per predicted market share result in 30 courses of treatment. When considering other variables such as costs associated to treat toxicities and administration costs, the total impact was $0.090 PMPM. This cost does not reflect rebate contracting with the manufacturer and thus largely over-estimates the true impact. A more accurate PMPM cost could have been calculated had market share information been available to the P&T committee. The cost incurred to the plan is manageable. The additional 1.14 QALY generated by this drug necessitates that the plan include ipilimumab on the formulary. Thus, the recommendation is to add the agent despite the large acquisition costs. Issue 5: Are there identifiable patient subgroups in which this treatment will be most cost-effective?

At this time, it is inconclusive whether ipilimumab will be cost-effective in specific subgroups. Further research needs to be conducted focusing on longer term benefits and outcomes in patients with specific biomarkers and age grouping. In patients demonstrating long term survival, ipilimumab would be a cost-effective option; once the 12 week course is complete, re-induction is not necessary. BRAF inhibitors, while initially less expensive, require ongoing therapy in

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order to produce long-term survival. Thus, in patients with BRAF V600E mutations, ipilimumab is the cost effective agent. As new targeted therapies come to market, the cost effectiveness will need to be re-analyzed. It is recommended that all members have genomic testing for these mutations performed at diagnosis.

RECOMMENDATIONS TO THE COMMITTEE

The potential benefits, such as increased OS, outweigh the potential risks of adding ipilimumab to the formulary for metastatic melanoma. Ipilimumab should be added to the specialty medication tier. Rare but serious risks are associated with ipilimumab use, specifically a Boxed Warning for immune-mediated adverse reactions. However, these risks will be continually monitored through the REMS program. Ipilimumab must utilize a prior authorization and quantity limit utilization management program, since the medication has limited conditions for which it is prescribed in addition to an extremely high cost.

Therefore, the following P&T action is recommended:

The prior authorization criteria for approval of the drug is as follows:1. The prescribing physician is an oncologist and2. The individual is an adult (at least 18 years of age) with the diagnosis of unresectable

or metastatic melanoma and3. The individual has an Eastern Cooperative Oncology Group (ECOG) performance

status of 0 or 1 and4. The individual has satisfied all REMS requirements and5. The individual has documented testing for BRAFV600 mutations

If the above criteria are all met, ipilimumab would then be approved for twelve weeks with the following regimen:

3 mg/kg every 3 weeks for 4 doses

Patients may be eligible for maintenance therapy if they meet all previous prior authorization criteria and the following:

A Response Evaluation Criteria In Solid Tumors (RECIST) score of complete response, partial response, or stable disease upon evaluation occurring after the final dose of induction therapy

If the above criteria are all met, ipilimumab would be approved for one year with the following regimen:

3 mg/kg every 12 weeks for 4 doses

Formulary change recommendations:

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Proposed Tier 1 Proposed Tier 2 Proposed Non-FormularyIpilimumab (Yervoy®) Nivolumab (Opdivo®) Peginterferon alfa-2b (Sylaton®)Pembrolizumab (Keytruda®) Interferon alfa-2b (Intron-A®)Vemurafenib (Zelboraf®) Imatinib (Gleevec®)Aldesleukin (Proleukin®) Dabrafenib/Trametinib ComboDacarbazine (Dtic-Dome®) Dabrafenib (Tafinlar®)

Trametinib (Mekinist®)Temozolomide (Temodar®)

Justification:

We recommend moving all of these agents to the specialty tier due to their difficult dosing regimens, intensive monitoring parameters, high cost, and often injectable route of administration. Ipilimumab, pembrolizumab and vemurafenib all show increased overall survival and should be placed on tier 1. Dacarbazine and aldesleukin are inexpensive options which justifies their formulary placement. Nivolumab will be placed on tier 2 because while it shows increased overall survival, it has the same mechanism of action as pembrolizumab and comes at a higher cost. Temozolomide will be placed on non-formulary because is not FDA approved for metastatic melanoma. Similarly, imatinib is not cost effective and does not have significant increased overall survival. Dabrafenib/trametinib combination therapy shows increased overall survival when used together. However, these agents will not be added because of their significantly higher cost. Dabrafenib has the same mechanism of action as vemurafenib, but is not as efficacious when used alone. Trametinib is also not as efficacious when used alone despite its alternative mechanism of action.

ISSUE DETAILS

ISSUE 1: What is the level and quality of evidence for efficacy from clinical trials?

Ipilimumab has been proven in clinical trials to be more effective than placebo in ORR and OS in patients with unresectable or metastatic melanoma. The phase III, double-blind study used to gain FDA approval was conducted in patients with stage III or IV metastatic melanoma who had undergone previous therapy of one or more of the following: dacarbazine, temozolomide, fotemustine, carboplatin, or interleukin-2. In the Hodi et al study, patients were randomized (3:1:1) into three treatment groups: ipilimumab 3 mg/kg and gp100, ipilimumab 3 mg/kg alone, and gp100/placebo alone. The World Health Organization (WHO) criteria and Response Evaluation Criteria in Solid Tumors (RECIST) criteria are the standard criteria to assess tumor activity of cytotoxic drugs, but the standard criteria depend on tumor shrinkage. Additionally, the response criteria must be validated in prospective trials. Due to the issues with standard tumor shrinkage criteria, OS rate may better describe clinical effects from immune therapy. The primary end point was OS, where there were higher rates of OS in the ipilimumab (experimental) group opposed to those receiving gp100 (control). The median OS was 10 months for ipilimumab and gp100, 10.1 months for ipilimumab alone, and 6.4 months for gp100 alone. Ipilimumab, with or without gp100, improved OS in patients with previously treated metastatic melanoma. While HLA typing was required and only HLA-A

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positive patients were enrolled in the trial due to the gp100 vaccine requirements, a retrospective analysis of phase II trials that did not restrict enrollment based on HLA typing did not find a difference in survival between HLA-A positive and negative patients.

Robert et al conducted an additional phase III randomized clinical trial that included patients with previously untreated stage III or IV metastatic melanoma. This double-blind study showed an increased OS of 11.2 months with ipilimumab and dacarbazine compared to 9.1 months with placebo and dacarbazine. The phase III trials have been designed with peptide vaccine or dacarbazine comparators and established that patients given ipilimumab have improved survival.

There are also multiple reports of phase II clinical trials. In a non-randomized phase II study of patients with metastatic melanoma failing at least one prior line of systemic therapy, O’Day et al instituted treatment with single-agent ipilimumab at a dose of 10 mg/kg every 3 weeks for four doses, followed by a maintenance dose every 12 weeks beginning at week 24. This resulted in ORR of 5.8%, a mean OS of 10.2 months, and a 1-year OS of 47.2%. In the Hersh study, ipilimumab therapy resulted in clinically meaningful responses in advanced melanoma patients. The chemotherapy-naive patients in this multicenter, phase II study were treated with ipilimumab monotherapy or ipilimumab in combination with DTIC. The overall response rate was 5.4% with ipilimumab alone and 14.3% with ipilimumab and DTIC combination therapy, which supports the need for further research into the use of ipilimumab in combination with DTIC for advanced melanoma.

Similar efficacy was demonstrated in the Wolchok 2010 et al study, where the primary objective of the study was ORR, which is defined by the proportion of patients with complete or partial response. This phase II, cross-over study compared three ipilimumab doses in untreated stage 3 or 4 patients. The best overall response rates were 11.1% for 10 mg/kg, 4.2% for 3 mg/kg, and 0% for 0.3 mg/kg. There was a statistically significant p-value (P=0.0015) reported for the comparison of best overall response rate of low-dose vs. high-dose ipilimumab. The increased dose, unfortunately, resulted in an increased report of immune-related adverse effects. The incidence of adverse effects were 70% for 10 mg/kg, 65% for 3 mg/kg, and 26% for 0.3 mg/kg. The majority of patients did experience improvement of symptoms following administration of corticosteroid therapy. Hamid et al also compared low-dose to high-dose ipilimumab and found that 10 mg/kg compared with 3 mg/kg gave a better ORR of 11.9% versus 7.5%, respectively. Unfortunately, the ORR results did not translate into a survival benefit with OS at 12 months of 44.2% in the 10 mg/kg cohort compared with 60.9% in the 3 mg/kg cohort.

Thompson et al conducted a retrospective analysis of the first ever trial that compared the safety and efficacy of ipilimumab in treatment-naïve with previously-treated patients with metastatic melanoma. The clinical study examined the randomized, double-blind, placebo-controlled, phase II Weber et al study, where the patients received ipilimumab 10 mg/kg with prophylactic budesonide or placebo were retrospectively analyzed.

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Wolchok et al conducted a 2013 follow-up study for which patients from three previous trials were eligible. Individuals with an objective response or SD when the initial phase of each study closed, including those who eventually progressed, were eligible to receive maintenance therapy at their assigned dose every 12 weeks or complete re-treatment with ipilimumab, respectively. In the first trial, survival rates at years 3 and 4 for patients given ipilimumab 10 mg/kg were 23.3% and 19.7%. Patients from the second trial who were given ipilimumab at 0.3 mg/kg, 3 mg/kg, or 10 mg/kg had 3-year survival rates of 13.8%, 19.7%, and 24.8%, respectively, and 4-year survival rates of 13.8%, 18.2%, and 21.5%. Patients from the third trial who were given ipilimumab 10 mg/kg had survival rates at years 3 and 4 of 34.4% and 32%.

The Margolin et al study is the first study to investigate the safety and efficacy of ipilimumab in individuals with melanoma and brain metastases. The subjects were divided into two parallel cohorts, where cohort A included individuals that were neurologically asymptomatic and not receiving corticosteroid treatment and cohort B included individuals that were symptomatic and on a stable dose of corticosteroids. While all patients received 10 mg/kg ipilimumab every three weeks for a total of four doses, the median OS was 7.0 months in cohort A and 3.7 months in cohort B.

The studies reviewed exhibited an increased OS in patients with metastatic melanoma treated with ipilimumab. The data is not sufficient to prove the statistical significance of ipilimumab as first-line treatment for advanced melanoma. There is also a lack in continuity, since the experimental and control groups chosen in each study were different. The studies also measured progression or OS but used different means for assessment, which creates difficulty in comparison. Additional research is required with statistically significant p-values to determine the optimal dose that would reduce adverse effects and maximize efficacy.

ISSUE 2: Is there sufficient evidence to assess real world comparative effectiveness?

Ipilimumab has shown a statistically significant benefit in survival prolongation and disease control capability in multiple trials. However, very few studies exist that have directly compared ipilimumab to other agents as monotherapy. Designing these types of trials would be a difficult decision at this point, since OS rates can be improved substantially with ipilimumab. Currently, an ongoing trial is comparing ipilimumab to high-dose interferon alfa-2b in high-risk patients, as well as a study comparing ipilimumab monotherapy to ipilimumab plus sagramostim. These will help to further elucidate the true comparative effects and safety concerns of ipilimumab. Existing data shows a notably high incidence of immune-related side effects, particularly when an ipilimumab-containing regimen is compared with another existing therapy not containing ipilimumab. Most alarming of these may be Robert et al's comparison of ipilimumab plus dacarbazine vs dacarbazine alone, in which the rate of immune-related adverse events for the former nearly exceeded the latter by 40%. These events, especially when grades 3 and above, create extreme patient discomfort as well as additional expenditure for health plans and hospital systems. Nevertheless, ipilimumab's potential to increase survival rates so significantly cannot be ignored, but neither can its

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somewhat glaring lack of robust comparative trials. Ultimately, more research is necessary in order to interpret ipilimumab’s real-world comparative effectiveness.

ISSUE 3: What is the level and quality of evidence for safety?

Although there is clinical benefit with ipilimumab, increasing doses are associated with increasing immune-mediated effects and more severe adverse reactions. Clinical trials have shown ipilimumab to exhibit common adverse side effects, such as fatigue, diarrhea, pruritus, rash, and colitis. There are no adequate and well-controlled clinical trials of ipilimumab in pregnant women, so ipilimumab is a Pregnancy Category C medication. Additionally, it is unknown if ipilimumab is secreted into human breast milk. There are no studies testing the safety and efficacy of ipilimumab in the pediatric population. As noted in the clinical trials, there are no overall differences in safety and efficacy between the geriatric population and patients under the age of 65.

Ipilimumab carries a Boxed Warning for serious and potentially life-threatening immune-mediated adverse reactions. Due to T-cell activation and proliferation, ipilimumab can result in severe and fatal immune-mediated adverse effects that may involve multiple organ systems. Severe-to-fatal immune-mediated adverse effects include enterocolitis, hepatotoxicity, dermatitis, neuropathy, and endocrinopathy. In the Hodi et al study, there were serious adverse effects reported in 41% of patients in the ipilimumab and gp100 group, 42% of the ipilimumab alone group, and 39% of the gp100 alone group. In the Robert et al study, ipilimumab and dacarbazine greatly increase the risk for developing immune-mediated hepatitis when compared to dacarbazine alone. Patients should be assessed for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy. Liver function and thyroid function tests must be monitored at baseline and before each dose.

The REMS for ipilimumab is required to ensure that the benefits outweigh the risks of ipilimumab use. The REMS includes an informational booklet that highlights the signs, symptoms, and management of ipilimumab immune-mediated adverse reactions. Additionally, there is a nursing checklist with key questions to ask patients. The yes/no questions are separated into four categories: general, gastrointestinal, skin, and neurologic. Lastly, the REMS includes a wallet card for patients that lists the symptoms associated with ipilimumab adverse reactions and their prescribing healthcare providers’ contact information.

ISSUE 4: What is the value proposition for this product?

Summary of Product Value

Ipilimumab was FDA-approved in March 2011 and is the first drug to ever show a survival advantage in a phase III, randomized, controlled trial. The medication was approved for single-agent use at a dose of 3 mg/kg. The NCCN Melanoma Guidelines (V3. 2014) include ipilimumab as a category 1 recommendation for the treatment of unresectable or metastatic melanoma. Only 25.5% of patients diagnosed with unresectable metastatic melanoma survive beyond 1 year. Hence, the clinical benefit of ipilimumab is demonstrated in the pivotal Hodi, et al Phase 3 RCT. Ipilimumab is associated with a 10-month OS as compared to 6 months for

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treatment with gp100 vaccine alone. Additional benefit of ipilimumab stems from its non-selectivity for BRAF mutations. In comparison to the other NCCN category 1 recommendations, it is the only agent to show improvement in overall survival regardless of BRAFV600 mutational status.

The costs associated with treating unresectable or metastatic melanoma are inherently high despite the lack of efficacy in agents prior to ipilimumab approval. The costs associated with ipilimumab drug administration are justified due to the survival benefit and the fact that only 25 patients per million will present with this diagnosis.

Manufacturer-Submitted Modeling

Budget Impact Analysis:

The budget impact model submitted by BMS shows an average PMPM incremental cost of $0.05 USD associated with the additional of ipilimumab to the formulary. The model assumes 25 enrollees per 1 million will have the appropriate diagnosis and that the incidence rates will remain the same over the three year analysis period. Drug costs were calculated using ASP + 10.3% for IV comparators, AWP – 13.1% for oral comparators, and WAC + 10.3% for ipilimumab. This criteria is consistent with epidemiological data and AMCP’s Guide to Pharmaceutical Payment Methods.

Comparators measured in the model were chosen based on the top prescribed therapy regimes and included temozolomide, dacarbazine, carboplatin/paclitaxel, paclitaxel, cisplatin, interleukin-2, interferon alfa-2b, thalidomide. One downside is that the analysis did not include newer NCCN category 1 recommended agents such as vemurafenib, dabrafenib, and trametinib. They also failed to stratify PMPM costs based on age or mutation type.

The model uses projected market share data obtained from BMS market research. Market share estimates are expected to be 7% in year one, 21% in year two, and 35% by year three. The basis for obtaining this data was from physician consultations. The utilization increase reflects the lack of approved agents with clinical benefit. However, this model does not include other standards of care such as vemurafenib, dabrafenib, and trametinib. As new treatments are approved, this extrapolated market share will change.

The budget impact model sensitivity analysis was conducted very thoroughly. Factors taken into consideration included drug waste based on weight, fluctuation in market share forecast, and number of patients treated. There was a small variation in PMPM in the latter two parameters; $0.040 lower limit, $0.066 upper limit, base case of $0.053. However, the changes seen in the sensitivity analysis were not widely different from the base case. Overall, the budget impact was well executed to reflect expected trends.

Cost-Utility Analysis:

The cost effectiveness analysis model depicted in the dossier was published by Barzey et al. This was a Markov economic model conducted from a third party perspective which compared

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ipilimumab to best supportive care (BSC), gp100. Overall, the analysis found that patients treated with ipilimumab would have an average survival of 2.88 life years. The benefit of this agent is a gain of 1.88 life years and 1.14 quality of life years (QALY) compared to those treated with BSC alone. This was associated with an ICER of $78,218 per LY and an ICUR of $128,656 per QALY. While an ICER per QALY threshold of less than $50,000 has been accepted, this value was set in 1982 and does not reflect 5.5% annual inflation rate. Today, the value would be closer to $197,000 per QALY. Overall, ipilimumab was cost-effective for treating patients with metastatic melanoma based on comparison of the results to the set willingness-to-pay of $146,000 per QALY in 95% of scenarios. The sensitivity analysis found that cost effectiveness for ipilimumab would increase if the cost for alternative therapies were incorporated as a comparator rather than gp100. On the other hand, reducing the time horizon represented the largest decrease in cost effectiveness.

Gp100 is an experimental cancer vaccine and was chosen as the comparator because at the time of the study, no other agent showed a statistically significant increase in overall survival. The comparator was not appropriate because despite lack of clinical efficacy, patients still received treatment with other chemotherapy agents prior to ipilimumab approval. This model also failed to address new medications which have shown overall survival benefit in patients such as pembrolizumab, trametinib, and vemurafenib. Probabilities used in this model predominantly came from the Hodi et al trial. Due to lack of long-term efficacy, overall survival was extrapolated from 4.5 years to a 30 year lifetime time horizon. The model assumes that a durable long-term response would occur in 20% of patients treated with ipilimumab. This assumption is a downfall to this analysis because no studies have demonstrated this claim. Resistance to the mechanism of action over time could lead to a diminished response rate, making the drug much less cost effective.

Investigators were transparent when referencing the input sources used in this model which is a strength of this analysis. Cost inputs included drug costs, disease management, and toxicity management. Utility inputs were derived from Societal preference values for advanced melanoma health states in the United Kingdom and Australia. This study may have underestimated the quality of life in patients treated with ipilimumab because disease response to the drug does not follow typical Response Evaluation Criteria in Solid Tumors. Thus, using a different criteria for modeling would result in a more accurate cost analysis. Additionally, further studies should be performed examining the long-term benefits of ipilimumab along with other available NCCN category 1 treatment options for patients with advanced melanoma.

Another cost effectiveness analysis was evaluated in BRAF mutated patients treated with vemurafenib, dacarbazine, or subsequently with ipilimumab if treatment failure was seen with vemurafenib. The decision analysis model found that treatment costs of vemurafenib, which is associated with 15.9 months of median survival, were higher than desirable cost-effectiveness thresholds. However, adding ipilimumab after vemurafenib disease progression was more cost effective yet still above desirable thresholds. The benefit of ipilimumab lies within its ability to create a durable response without the need for ongoing monthly therapy.

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Drug Recommended Dose and Duration

Dose Assumptions 50kg, 160 cm, 1.5 m2

AWP per day

Drug cost for 12 weeks of treatment

Drug cost for 48 weeks

Ipilimumab (Yervoy®)

3mg/kg Q3W x 4 doses

150mg 23,269.32 93,077.28 93,077.28

Pembrolizumab (Keytruda®)

2mg/kg Q3W 100mg 5,179.20 20,717.16 82,867.20

Dabrafenib/Trametinib Combo

D:150mg BIDT: 2mg QD

See below 754.77 63,400.68 253,602.72

Nivolumab (Opdivo®) 3mg/kg Q2W 160mg (10mg of waste)

4,604.16 27,624.96 110,499.84

Aldesleukin (Proleukin®)

720,000 units/kg TID x 4-5 days; repeat once

1,080,000 units

693.01 5,544.08- 6,930.10

5,544.08- 6,930.10

Vemurafenib (Zelboraf®)

960mg BID 8 x 240mg tabs

434.03 36,458.52 145,834.08

Dabrafenib (Tafinlar®)

150mg BID 4 x 75mg tabs

351.92 29,561.28 118,245.12

Temozolomide (Temodar®)- Off Label

200 mg/m2/day for 5 days every 28 days (for up to 12 cycles)

3 x 100mg tabs

960.26 2,880.78 34,569.36

Imatinib (Gleevec®) 400 mg BID 2 x 400mg tabs

736.85 61,895.12 247,580.47

Trametinib (Mekinist®)

2mg QD 1 x 2mg 402.85 33,839.4 135,357.60

Dacarbazine (Dtic-Dome®)

250 mg/m2/dose x 5 days every 3 weeks

400mg (25 mg of waste)

25.42 508.40 2,033.60

*AWP information was obtained from UpToDate. *This table does not include costs associated with administration or treating adverse events. *12 weeks was chose based on the ipilimumab treatment regime*48 weeks corresponds with the drug’s overall survival benefit *Orange shading indicates NCCN category 1 preferred agents*Green shading indicates NCCN therapeutic alternative agents

Pitt street plan:3,400,000 lives covered 27/100,000 = x/3,400,000 x = 918 estimated new cases

25 per million = x/3.4 million x = 85 estimated cases qualifying for treatment Predicted market share of ipilimumab:

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2014- 35.1% as per BMS impact modelCan expect 30 members to be treated with ipilimumab 30 x $120,000 = $3,600,000 therapy regime90 x $504 = $45,360 for administration costs 30 x $936 = $28,080 cost to treat toxicities assuming 1 episode per member Total annual cost of ipilimumab = $3,673,440$3,673,440M/3.4M = $1.080 per member per year$1.080/12months = $0.090 PMPM

Cost does not factor in the savings associated with increased qualify of life, the cost shift from other agents (market shares not available), or rebates from the manufacturer. This pricing reflects the assumption that all members will complete their full course of treatment, thus largely over-estimating the cost burden.

ISSUE 5: Are there identifiable patient subgroups in which this treatment will be most cost-effective?

Biomarkers and intrinsic patient or tumor characteristics associated with clinical activity are increasingly demonstrating value toward the goals of personalized medicine. Promising biomarkers for melanoma include KIT and BRAF gene mutations. BRAF mutations can be tested via cobas® 4800 BRAF V600 Mutation Test at $150 per test. When considering the cost associated with treatment failure, genetic testing is recommended to guide patient specific therapy. 50-70% of melanoma tumors have a BRAF mutation. 80% are positive for BRAFV600E and 16% are positive for BRAFV600K. Using BRAF inhibitors in this patients with BRAFV600E results in a response rate of around 45-60%. However, BRAF inhibitor benefits have been negligible in patients with BRAFV600K mutation or absence of BRAF mutations. This is where ipilimumab has shown a particular benefit. In the long run, BRAF inhibitors produce a large cost burden to the plan as they require ongoing therapy. Ipilimumab, on the other hand, is comprised of a 12-week course that does not require re-treatment to provide long-term survival. Thus, cost savings are seen in the patient population that demonstrates long-term survival.

One of the clinical benefits of this drug is its ability to be efficacious in patients with or without BRAFV600 mutations. While Hodi et al addressed the HLA genotype when determining inclusion criteria, the specific allele is not necessary for ipilimumab efficacy. When it comes to age stratification, the budget impact model assumes that out of the 25 new cases of unresectable or metastatic melanoma per 1 million, 16.3 will be ages 18-64, 4.2 will be ages 65-74, and 4.3 will be ages 75 and above. However, the model did not provide specific PMPM costs based on age category.

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Table 1. Clinical evidence summaryRef. andEvidence

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

Hodi 2010

(A)

Treatment (3:1:1)

Ipilimumab 3 mg/kg IV over 90 minutes plus gp100 peptide vaccine (n=403)

Ipilimumab 3 mg/kg IV over 90 minutes plus gp 100 placebo (n=137)

Gp100 peptide vaccine plus ipilimumab placebo (n=136)

676 2 years Mean age: 56.2 years

Male: 59.3%Female: 40.7%

ECOG 0: 55.3%ECOG 1: 43.0%

Phase III, RCT, DB, AC

125 centers in 13 countries

1. Median Overall Survival (primary end point):Ipi + Gp: 10 mos, Ipi alone: 10.1 mos, Gp alone: 6.4 mos( P<0.001 for Ipi + Gp vs. Gp alone, P=0.003 for Ipi alone vs. Gp alone)

2. Rates of Survival (%) for Ipi + Gp, Ipi alone, and Gp alone, respectively:43.6, 45.6, 25.3 at 12 months30.0, 33.2, and 16.3 at 18 months21.6, 23.5, and 13.7 at 24 months

3. Response (%) for Ipi + Gp, Ipi alone, and Gp alone, respectively:CR: 0.2, 1.5, 0PR: 5.5, 9.5, 1.5SD: 14.4, 17.5, 9.6PD: 59.3, 51.1, 65.4(P=0.04 for Ipi + Gp vs. Gp alone, P=0.001 for Ipi alone vs. Gp alone)

13

For every 13 patients treated with Ipi + Gp, 1 additional patient will survive 2 yrs

Robert 2011

(B)

Treatment (1:1)

Ipilimumab 10 mg/kg IV plus dacarbazine 850 mg/m2 IV 10 (n=250) or dacarbazine plus placebo (n=252) weeks 1, 4, 7, and 10 followed by dacarbazine alone every 3 weeks through week 22 (induction phase)

At week 24, if objective response or stable disease and no dose-limiting toxicity, eligible to enter maintenance phase of placebo or ipilimumab every 12 weeks until progression, toxic effects, or end of study

502 3 years Mean ageIpilimumab: 57.5 yearsPlacebo: 56.4 years

Gender (male)Ipilimumab: 60.8%Placebo: 59.1%

ECOG 0Ipilimumab: 70.8%Placebo: 71.0%

ECOG 1Ipilimumab: 29.2%Placebo: 29.0%

Phase III, RCT, DB, PC

1. Median Overall Survival (primary end point):Ipilimumab + dacarbazine: 11.2 mos, Placebo + dacarbazine: 9.1 mos(P<0.001)

2. Progression Free Survival (%) for Ipilimumab + dacarbazine, Placebo + dacarbazine, respectively:1 yr: 47.3, 36.32 yr: 28.5, 17.93 yr: 20.8, 12.2(P=0.006)

3. Best Overall Response (%)Ipilimumab + dacarbazine: 15.2Placebo + dacarbazine: 10.3(P=0.09)

12

For every 12 patients treated with Ipi + dacarbazine, 1 additional patient will survive 3 yrs

O’Day 2010

(B/U)

Ipilimumab 10 mg/kg every 3 weeks for 4 doses (induction)

Beginning week 24, maintenance dose every 12 weeks

155 1 year Median age: 59.0 years

Male: 52%Female: 48%

ECOG 0: 61%ECOG 1: 39%

Phase II, nonrandomized, open-label, single-arm

50 sites in Europe and North America

1. Overall Response Rate: 5.8%2. Mean Overall Survival: 10.2 months3. 1 year Overall Survival: 47.2%

17

For every 17 patients treated with Ipi, 1 additional patient will respond to treatment

13


Ref. andEvidence


Hersh 2011

(B/U)

Treatment (1:1)

Ipilimumab 3 mg/kg every 4 weeks for 4 doses alone (n=37)

Ipilimumab 3 mg/kg every 4 weeks for 4 doses in combination with 5-day courses of dacarbazine (DTIC) at 250 mg/m2 every 3 weeks for 6 cycles (n=35)

Patients that progressed with monotherapy could cross over and receive combination therapy (n=13)

72 3 years Median ageIpi: 66.0 yearsIpi + DTIC: 60.0 years

Gender (male)Ipi: 56.8%Ipi + DTIC: 74.3%

Phase II, RCT, open-label

1. Best Overall Response Rate (primary end point)Ipilimumab: 5.4%Ipilimumab + DTIC: 14.3%

2. Response (%) for Ipilimumab and Ipilimumab + DTIC, respectively:CR: 0, 5.7PR: 5.4, 8.6SD: 16.2, 22.9PD: 75.7, 57.1

3. Survival (%) for Ipilimumab and Ipilimumab + DTIC, respectively:12 months: 45, 6224 months: 21, 2436 months: 9, 20

11

For every 11 patients treated with Ipi + DTIC, 1 additional patient will respond to treatment

Wolchok 2010

(B)

Treatment (1:1:1)

Ipilimumab 0.3 mg/kg (n=73) at weeks 1, 4, 7, and 10 (induction)

Ipilimumab 3 mg/kg (n=72) at weeks 1, 4, 7, and 10 (induction)

Ipilimumab 10 mg/kg (n=72) at weeks 1, 4, 7, and 10 (induction)

217 2 years Mean age0.3 mg/kg: 59 years3 mg/kg: 59 years10 mg/kg: 56 years

Gender (male)0.3 mg/kg: 71%3 mg/kg: 67%10 mg/kg: 61%

ECOG 00.3 mg/kg: 63%3 mg/kg: 61%10 mg/kg: 57%

ECOG 10.3 mg/kg: 36%3 mg/kg: 39%10 mg/kg: 43%

Phase II, DB, PG

66 centers in 12 countries

1. Best Overall Response Rate (primary end point)0.3 mg/kg: 0%3 mg/kg: 4.2%10 mg/kg: 11.1%(P=0.0015)

2. Response (%) for Ipilimumab 0.3 mg/kg, 3 mg/kg, and 10 mg/kgCR: 0, 0, 2PR: 0, 3, 6SD: 10, 16, 13PD: 43, 41, 36

3. Survival (%) for Ipilimumab 0.3 mg/kg, 3 mg/kg, and 10 mg/kg1 year: 39.6, 39.3, 48.618 months: 23.0, 30.2, 34.524 months: 18.4, 24.2, 29.8

9

For every 9 patients treated with Ipi 10 mg/kg, 1 additional patient will respond to treatment

14


Ref. andEvidence


Hamid 2011

(B/U)

Treatment (1:1)

3 mg/kg (n=40) ipilimumab every 3 weeks for 4 doses (induction)

10 mg/kg (n=42) ipilimumab every 3 weeks for 4 doses (induction)

At week 24, eligible patients could receive a dose every 12 weeks (maintenance)

82 1 year Mean age3 mg/kg: 53.9 years10 mg/kg: 56.2 years

Gender (male)3 mg/kg: 70.0%10 mg/kg: 57.1%

ECOG 03 mg/kg: 62.5%10 mg/kg: 64.3%

ECOG 13 mg/kg: 37.5%10 mg/kg: 35.7%

Phase II, PCS, DB

14 sites in 7 European, North American, and South American countries

1. Response (%) for Ipilimumab 3 mg/kg and 10 mg/kg, respectively:CR : 0, 2.4PR: 7.5, 9.5SD: 25.0, 7.1PD: 47.5, 57.1

2. Overall Response Rate (%)0.3 mg/kg: 7.510 mg/kg: 11.9

3. Overall Survival (months)3 mg/kg: 12.910 mg/kg: 11.8

42

For every 42 patients treated with Ipi 10 mg/kg, 1 additional patient will completely respond to treatment

Thompson 2012

(B)

Treatment (1:1)

Oral budesonide 9 mg once daily and ipilimumab 10 mg/kg every 3 weeks for 4 doses (induction)

Placebo and ipilimumab 10 mg/kg every 3 weeks for 4 doses (induction)

At week 24, eligible patient could continue ipilimumab at 10 mg/kg every 12 weeks (maintenance)

115 2 years Median ageIpi + Budesonide: 58 yearsIpi + Placebo: 61 years

Gender (male)Ipi + Budesonide: 74%Ipi + Placebo: 67%

ECOG 0Ipi + Budesonide: 69%Ipi + Placebo: 74%

ECOG 1Ipi + Budesonide: 29%Ipi + Placebo: 26%

Retrospective analysis of a Phase II trial

1. Median Overall Survival for treatment-naïve patients (n=62) taking ipilimumab: 30.5 months

2. Survival rates for treatment-naïve patients taking ipilimumab:12 months: 69.4%18 months: 62.9%24 months: 56.9%

3. Median Overall Survival for previously-treated patients (n=53) taking ipilimumab: 13.6 months

4. Survival rates for previously-treated patients taking ipilimumab:12 months: 50.0%18 months: 37.7%24 months: 28.5%

5. No meaningful differences in the number of objective responses or rate of grade ≥ 2 diarrhea between groups

*No efficacy endpoint was affected by budesonide therapy, so efficacy data was pooled for budesonide and placebo groups.

2

For every 2 treatment- naïve patients treated with Ipi, 1 additional patient will survive 2 yrs

15


Ref. andEvidence


Wolchok 2013

(B)

Study 1: 10 mg/kg every 3 weeks × 4 doses; maintenance every 12 weeks from week 24 for eligible patients

Study 2: 0.3, 3, or 10 mg/kg every 3 weeks × 4 doses; maintenance every 12 weeks from week 24 for eligible patients

Study 3: 10 mg/kg every 3 weeks × 4 doses, plus oral budesonide or placebo

Patients with PD at week 12 in original studies could enroll for follow-up and survival data alone

Study 1: 155

2: 217

3: 115

4 years Study 1: Pre-treated patients with PD

Study 2: Patients who were intolerant to or progress on prior therapy

Study 3: Both previously treated and treatment-naïve patients

PCS 1. Overall survival rate, year 3 and year 4, %Study 1: 23.3, 19.7Study 2:

Ipi 10 mg/kg: 24.8, 21.5Ipi 3 mg/kg: 19.7, 18.2Ipi 0.3 mg/kg: 13.8, 13.8

Study 3:Ipi alone: 34.4, 32.0Ipi + budes: 38.7, 36.2

2. BOR in patients with OS >4 yrs (8, 22, 7)Study 1: CR: 2, PR: 8, SD: 13, PD: 3Study 2: CR: 0, PR: 9, SD: 9, PD: 15Study 3: CR: 5, PR: 11, SD: 7, PD: 4

Study 1: 5

Study 2: 13

Study 3: 24

For every 5, 13, 24 patients treated with Ipi 10 mg/kg, 1 additional patient will survive 4 yrs (respectively)

Margolin 2012

(B/U)

2 parallel cohorts

Cohort A (n=51): neurologically asymptomatic & no corticosteroid treatment

Cohort B (n=21): symptomatic & on stable dose of corticosteroids

All patients receive 10 mg/kg ipilimumab every 3 weeks for a total of 4 doses (induction)

Patients clinically stable at 24 weeks were eligible to continue ipilimumab treatment every 12 weeks (maintenance)

72 2 years Mean ageCohort A: 59 yearsCohort B: 57 years

Gender (male)Cohort A: 65%Cohort B: 52%

ECOG 0Cohort A: 49%Cohort B: 67%

ECOG 1Cohort A: 51%Cohort B: 22%

Phase II, parallel cohort

1. Median Overall SurvivalCohort A: 7.0 monthsCohort B: 3.7 months

2. Overall Survival (%) in Cohort A and B6 months: 55, 3812 months: 31, 1918 months: 26, 1924 months: 26, 10

Cohort A: 4

Cohort B: 10

A: For every 4 patients receiving Ipi 10 mg/kg, 1 additional patient will survive 2 yrs

B: For every 10 patient receiving Ipi 10 mg/kg, 1 additional patient will survive 2 yrs

16


Ref. andEvidence


*Abbreviations used in this table: AC =active control, CCS = case-control study, CR = complete response, DB = double blind, PC = placebo control, PCS = prospective cohort study, PD = progressive disease, PG = parallel group, PR = partial response, MA = meta-analysis MC = multicenter, RCS = retrospective cohort study, RCT = randomized controlled trial, SD = stable disease, XO = crossover

Table 2. Cost-effectiveness evidence summary

Ref. andSponsor

Study Design and Treatments Compared

Time Horizon and Demographics

Model Inputs and Data Sources

Results:Base Case, Sensitivity Analysis and Limitations

Barzey, et al. IMS Health Economics and Outcomes Researchl; 2013

CEA of ipilimumab based on US payer perspective

Three-state Markov Model measuring clinical outcomes, quality of life, and healthcare resources use with ipilimumab and BSC

Lifetime horizon

Evaluated clinical outcomes from patients participating in the MDX010-20 study

Disease management costs: retrospective medical chart studyUtility Data: study of health state preferences of the general population

MDX010-20

Gain in life years: 1.88 years (95% CI= 1.62-1.34)QALYs 1.14 years (95% CI=1.01-1.34)ICER per life year gained: $78,218ICER per QALY gained: $128,656

SA: one-way and probabilistic, conclusions unchanged when adjusting the time horizon and the method of quality adjustment

Limitations: BSC as a comparator, underestimation of quality of life

Curl P, et al.University of California San Francisco

Cost-utility analysis to compare ICER and QALY values for patients treated with vemurafenib, dacarbazine, and ipilimumab.

Remaining life expectancy

BRAF positive patients with metastatic melanoma included in Phase 3 clinical trials

Clinical probabilities from Hodi, et al. and Chapman, et al.

Health utility inputs from directly measured utilities specific to metastatic melanoma

Drug costs from Redbook

Vemurafenib was found to increase both quality and duration of life when compared with dacarbazine, but at a treatment cost higher than any desirable cost-effectiveness threshold. The addition of ipilimumab to vemurafenib was found to be more cost-effective, but still above most desirable thresholds.

SA: one-way varying disease control, drug and other health care associated costs, health state utilities, and side effects. Varying treatment costs of vemurafenib resulted in the largest change of ICER and QALY values.

Limitations: lack of long-term follow-up in the clinical trials and prognosis data after 1 year of survival, assumption of additive benefits of using ipilimumab after vemurafenib failure

Abbreviations used in this table: LYS = life-years saved, QALY = quality-adjusted life-year, QOL = quality of life, CEA= cost effectiveness analysis, BSC= basic supportive care, ICER= incremental cost effectiveness ratio, SA=sensitivities analysis

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BACKGROUND INFORMATION

DISEASE BACKGROUND

Melanoma is a tumor of melanin-forming cells, with more advanced disease commonly marked by metastatic growths and some degree of drug resistance. Patients with metastatic melanoma often require prompt, aggressive treatment, as median survival time is approximately 9 months, and estimated 3-year survival rates are below 15%. Recent therapeutic developments have been aimed at a number of specific molecular targets in disease progression, allowing clinicians to individualize the course of therapy for each patient.

DISEASE BURDEN

In 2011, the prevalence of melanoma in the United States was estimated to be 960,231. Total incidence in 2014 is estimated to exceed 76,000. Per 100,000 individuals, the approximated annual number of new cases was found to be 27, with nearly 15 of these individuals expected to be aged 75 or older. Those aged 65-74 were expected to account for another 10 cases. Incidence thus appears to be heavily reliant upon age. While melanoma can occur on any area of the skin, it is most often found on the skin on the head, on the neck, or between the shoulders and the hips for men. For women, it is often found on the skin on the lower legs or between the shoulders and the hips. Melanoma rarely occurs in individuals with dark skin. If melanoma does develop in individuals with dark skin, it is most often found under the fingernails, under the toenails, on the palms of the hands, or on the soles of the feet. Melanoma is more likely than any other skin cancer to spread throughout the body.

PATHOPHYSIOLOGY

Melanoma can be caused by environmental factors as well as genetic susceptibilities. In its earliest stages, melanoma can be described as an uncontrolled production of epidermal melanocytes, which is often mediated by over-secretion of melanocortins due to UV light exposure. The radial growth phase involves horizontal cell proliferation and can be caused by growth factor secretion. Mutations in tumor suppressor genes and activation of oncogenes—such as CDKN2A and BRAF, respectively—may also aid in tumor proliferation. As the disease progresses, numbers of protective transmembrane proteins like e-cadherin decrease, and vertical growth may occur, during which melanocytes have the potential to cross the basement membrane and enter the dermis. From here, malignant melanocytes have access to the bloodstream and tend to metastasize to the lymph nodes, where they may further invade soft tissues and organs, including the skin, lungs, and brain.

Treatment Alternatives

According to the NCCN’s Melanoma Treatment Guidelines, resection may be an option for limited metastatic disease, with systemic therapy following if residual disease exists. Resection, in addition to radiation therapy, may also be considered for patients with brain metastases, regardless of severity. For all other cases of disseminated disease, systemic therapy or enrollment in a clinical trial is indicated.

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Preferred Existing Therapy

Preferred regimens, as recommended by the NCCN, include ipilimumab, dabrafenib (BRAF inhibitor) + trametinib (MEK inhibitor) combination therapy, pembrolizumab (anti-programmed-death-receptor-1), nivolumab (anti-programmed-death-receptor-1), or a clinical trial. NCCN officials recommend clinical trials as optimal management in any cancer patient.

Other Therapeutic Alternatives

Therapeutic alternatives include vemurafenib (BRAF inhibitor), dabrafenib or trametinib monotherapy, high-dose aldesleukin (IL-2, immunoregulatory), temozolomide (DNA alkylation), dacarbazine (unknown mechanism), and imatinib for C-kit mutated tumors.

PRODUCT BACKGROUND

PHARMACOLOGY

Ipilimumab, also known as MDX-010 or MDX-101, is a recombinant, human monoclonal antibody (IgG1K) that binds to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), blocking the interaction of this protein with ligands CD80/CD86. CTLA-4 normally acts as a negative regulator of T-cell activation. By blocking CTLA-4, ipilimumab acts indirectly to enhance T-cell mediated anti-tumor immune responses.

PHARMACOKINETICS

Peak concentration (Cmax), trough concentration (Cmin), and area under the plasma concentration versus time curve (AUC) of ipilimumab have been shown to increase proportionally with dose administered. Ipilimumab clearance increases with increasing body weight, but no dose adjustment is required if dosed on a mg/kg basis. Renal impairment does not appear to have a clinically important effect on ipilimumab clearance. Mild hepatic impairment has not been shown to affect ipilimumab clearance, though moderate and severe hepatic impairment have not been studied.

19

Route of Administration: Intravenous injectionClearance: 16.8 mL/hVolume of distribution: 7.21 litersHalf-life: Terminal T1/2 = 15.4 daysCmin: 19.4 mcg/mL

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ADVERSE EFFECT PROFILE

Table 3. General adverse events from Hodi et al. Dose: ipilimumab 3 mg/kg, n = 131. Numbers listed as percentages of total.

Diarrhea Colitis Pruritis Rash Fatigue

Any grade 32 8 31 29 41

Grade > 3 5 5 0 2 7

Table 4. General adverse events from Wolchok et al. Dose: ipilimumab 3 mg/kg, n = 71.

Diarrhea Colitis Pruritis Rash Fatigue Nausea Vomiting

Any grade

18 4 15 17 12 13 5

Grade > 3

1 1 1 1 1 0 1

Table 5. Immune-related adverse events in Hodi et al (%) and Wolchok et al (n).

Enterocolitis

Hepatotoxicity Dermatitis Endocrinopathy Neuropathy

Hodi et al (%) 7 1 2 4 1

Wolchok et al (n)

23 0 32 4 Not reported

DRUG INTERACTIONS

No formal pharmacokinetic drug interaction studies have been conducted.

CONTRACTING AND SITE OF CARE

ASP: $128.955 per mg CMS payer limit WAP: $6,463 per 50mg/ml_$129.26 per mg Recommended dose: $32,078.00 Administration fee per infusion: $504.00Recommended site of infusion: Inpatient *pricing as per Medicare service pricing and service reimbursement at CMS.gov

METHODOLOGY OF THIS REVIEW

DATABASES SEARCHED: PubMed, Ovid, New England Journal of Medicine

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SECONDARY SOURCES: NCCN GuidelinesSEARCH STRATEGY:

PubMed: Using the key words: “ipilimumab,” “metastatic,” and “melanoma”

Ovid MEDLINE (R) 1946 to November Week 3 2014:ipilimumab.mp. search as Keyword 738melanoma (include all subheadings) 69,0461 and 2 519Limit 1 and 2 to (English language and full text and humans) 91

INCLUSION CRITERIA: English language, full text, humans

Search Results:

Study Type NRandomized controlled trials (RCT) 5Meta-analysesIndirect Comparison studiesProspective observational studies 3Retrospective observational studies 1Economic or QALY modeling studies 1Case SeriesRCT abstracts, not peer-reviewedOther abstracts, posters, etc., not peer-reviewed

Articles Excluded from Evidence Synthesis:

Reason for Exclusion NPrimary end point is not testing ipilimumab’s efficacy (Weber 2009) 1Study focuses on safety/efficacy of retreatment with ipilimumab (Robert 2013) 1Study includes patients with metastatic uveal melanoma (Danielli 2012) 1Study tests the effectiveness of ipilimumab in lung cancer (Lynch 2012) 1

REFERENCES

1. NCCN Clinical Practice Guidelines in Oncology. 2014 National Comprehensive Cancer Network, Inc. Melanoma. V2.2015. Revised February 10, 2014.

2. National Cancer Center. What you need to know about melanoma and other skin cancers. Available at: http://www.cancer.gov/cancerinfo/wyntk/melanoma. Accessed on December 22, 2014.

3. Cutaneous Melnoma. Thompson JF1, Scolyer RA, Kefford RF. Lancet. 2005 Feb 19-25;365(9460):687-701.

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4. Eggermont AM. Advances in systemic treatment of melanoma. Ann Oncol. 2010;21(Suppl. 7):viii339–viii344.

5. Yervoy [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Co. December 2013.

6. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-23.

7. Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11(2):155-164.

8. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517-26.

9. O'Day SJ, Maio M, Chiarion-Sileni V, et al. Efficacy and safety of ipilimumab monotherapy in patients with previously treated, advanced melanoma: a multicenter, single-arm phase II study, dose-ranging study. Ann Oncol. 2010;21(8):1712-7.

10. Hersh EM, O'Day SJ, Powderly J, et al. A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naïve patients with advanced melanoma. Invest New Drugs. 2011;29(3):489-498.

11. Margolin K, Ernstoff MS, Hamid O. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012;13(5):459-465.

12. Thompson JA, Hamid O, Minor D, et al. Ipilimumab in treatment-naive and previously treated patients with metastatic melanoma: retrospective analysis of efficacy and safety data from a phase II trial. J Immunother. 2012;35(1):73-77.

13. Hamid O, Schmidt H, Nissan A, et al. A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med. 2011;9:204.

14. Healthcare. Updated periodically. Accessed 2013 Oct 25. (n.d.).

15. RED BOOK Online [internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Accessed 2013 Oct 25. (n.d.).

16. Curl P, Vujic I, van ‘t Veer LJ, Ortiz-Urda S, Kahn JG (2014) Cost-Effectiveness of Treatment Strategies for BRAF-Mutated Metastatic Melanoma. PLoSONE 9(9): e107255.

17. Gogas HJ, Kirkwood JM, Sondak VK. Chemotherapy for metastatic melanoma: time for a change? Cancer. Feb 1 2007;109(3):455-464.

18. BRAF Gene Mutation Testing To Select Melanoma Patients for BRAF Inhibitor Targeted Therapy. Blue Cross of Idaho. Oct 2011. Accessed Jan 16 2015. <https://www.bcidaho.com/providers/medical_policies/Med/mp_20477.asp>.

19. 2013 ASP Drug Pricing Files. CMS.gov. Accessed 1/18/2015. <http://www.cms.gov/Medicare/Medicare-Fee-for-Service-Part-B-Drugs/McrPartBDrugAvgSalesPrice/2013ASPFiles.html>.

20. Barzey V, Atkins MB, Garrison LP. Ipilimumab in 2nd line treatment of patients with advanced melanoma: a cost-effectiveness analysis. J of Med Econ. 2013;16(2):202-12.

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