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Jennifer Baird, Jane,a Geronian, Brent Milovac, & Vivian Nguyen
Pi# Street Health Plan Pharmacy & Therapeu5cs Individual Drug Review
BRISTOL-‐MYERS SQUIBB
Yervoy® (ipilimumab)
ObjecBves 1. Product Overview 2. Disease Background
3. Clinical Assessment
4. Economic Analysis
5. P&T RecommendaBons
Ipilimumab Overview • Therapeu5c Class
– Recombinant, human monoclonal anBbody that binds to cytotoxic T-‐lymphocyte-‐associated anBgen 4 (CTLA-‐4)
• Indica5on – Treatment of unresectable or metastaBc melanoma
• Mechanism of Ac5on – Blocks interacBon of CTLA-‐4 with ligands, thereby upregulaBng immune acBvity
• Dosing/Administra5on – 3 mg/kg, administered intravenously over 90 minutes every 3 weeks for a total of 4 doses
Disease Background • Melanoma
– One of the 10 most prevalent cancers in the United States – Commonly found on the head, neck, legs, shoulders, hips
• Risk Factors – Environmental – GeneBc
• Diagnosis – Physical examinaBon – Skin biopsy – MRI, PET, CT scan
Burden of Disease • Prevalence
– In 2011, the prevalence of melanoma in the United States was esBmated to be 960,231
– Incidence in 2014 is esBmated to exceed 76,000 – Per 100,000 individuals, the approximated annual number of new cases was 27, with nearly 15 of these individuals expected to be 75 or older
• Humanis5c and Economic Burden – PaBents with metastaBc melanoma have a median survival Bme of 9 months and 3-‐year survival rates below 15%
– Average healthcare costs in the year following diagnosis esBmated to be $48,921
Grade A Study
Ref. and Evidence
Grade Drug Regimens Design Results
Hodi 2010 (A) n = 676 NNT = 13
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)
Phase III, RCT, DB, AC 125 centers in 13 countries
• 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) • Rates of Survival (%) for Ipi + Gp, Ipi alone, and Gp alone, respectively: 43.6, 45.6, 25.3 at 12 months 30.0, 33.2, and 16.3 at 18 months 21.6, 23.5, and 13.7 at 24 months • Response (%) for Ipi + Gp, Ipi alone, and Gp alone, respectively: CR: 0.2, 1.5, 0 PR: 5.5, 9.5, 1.5 SD: 14.4, 17.5, 9.6 PD: 59.3, 51.1, 65.4 (P=0.04 for Ipi + Gp vs. Gp alone, P=0.001 for Ipi alone vs. Gp alone)
Grade B Studies Ref. and Evidence
Grade Drug Regimens Design Results
Robert 2011 (B) n = 502 NNT = 12
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, eligible patients could receive a dose every 12 weeks (maintenance)
Phase III, RCT, DB, PC
• Median Overall Survival (primary end point): (P<0.001) Ipilimumab + dacarbazine: 11.2 mos, Placebo + dacarbazine: 9.1 mos • Progression Free Survival (%) for Ipilimumab + dacarbazine, Placebo
+ dacarbazine, respectively: (P=0.006) 1 yr: 47.3, 36.3 2 yr: 28.5, 17.9 3 yr: 20.8, 12.2 • Best Overall Response (%) (P=0.09) Ipilimumab + dacarbazine: 15.2 Placebo + dacarbazine: 10.3
Wolchok 2010 (B) N = 217 NNT = 9
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)
Phase II, DB, PG 66 centers in 12 countries
• Best Overall Response Rate (primary end point) (P=0.0015) 0.3 mg/kg: 0% 3 mg/kg: 4.2% 10 mg/kg: 11.1% • Response (%) for Ipilimumab 0.3 mg/kg, 3 mg/kg, and 10 mg/kg CR: 0, 0, 2 PR: 0, 3, 6 SD: 10, 16, 13 PD: 43, 41, 36 • Survival (%) for Ipilimumab 0.3 mg/kg, 3 mg/kg, and 10 mg/kg 1 year: 39.6, 39.3, 48.6 18 months: 23.0, 30.2, 34.5 24 months: 18.4, 24.2, 29.8
Grade B Studies cont.
Ref. and Evidence
Grade Drug Regimens Design Results
Thompson 2012 (B) n = 115 NNT = 2
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)
Retrospective analysis of a Phase II trial
• Median Overall Survival for treatment-naïve patients (n=62) taking ipilimumab: 30.5 months
• Survival rates for treatment-naïve patients taking ipilimumab: 12 months: 69.4% 18 months: 62.9% 24 months: 56.9% • Median Overall Survival for previously-treated patients (n=53) taking
ipilimumab: 13.6 months • Survival rates for previously-treated patients taking ipilimumab: 12 months: 50.0% 18 months: 37.7% 24 months: 28.5% • No meaningful differences in the number of objective responses or
rate of grade ≥ 2 diarrhea between groups
Grade B/U Studies Ref. and Evidence
Grade Drug Regimens Design Results
O’Day 2010 (B/U) n = 155 NNT = 17
Ipilimumab 10 mg/kg every 3 weeks for 4 doses (induction) Beginning week 24, maintenance dose every 12 weeks
Phase II, nonrandomized, open-label, single-arm 50 sites in Europe and North America
• Overall Response Rate: 5.8% • Mean Overall Survival: 10.2 months • 1 year Overall Survival: 47.2%
Hersh 2011 (B/U) N = 72 NNT = 11
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)
Phase II, RCT, open-label
• Best Overall Response Rate (primary end point) Ipilimumab: 5.4% Ipilimumab + DTIC: 14.3% • Response (%) for Ipilimumab and Ipilimumab + DTIC, respectively: CR: 0, 5.7 PR: 5.4, 8.6 SD: 16.2, 22.9 PD: 75.7, 57.1 • Survival (%) for Ipilimumab and Ipilimumab + DTIC, respectively: 12 months: 45, 62 24 months: 21, 24 36 months: 9, 20
Grade B/U Studies cont.
Ref. and Evidence
Grade Drug Regimens Design Results
Hamid 2011 (B/U) n = 82 NNT = 42
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)
Phase II, PCS, DB 14 sites in 7 European, North American, and South American countries
• Response (%) for Ipilimumab 3 mg/kg and 10 mg/kg, respectively: CR : 0, 2.4 PR: 7.5, 9.5 SD: 25.0, 7.1 PD: 47.5, 57.1 • Overall Response Rate (%) 3 mg/kg: 7.5 10 mg/kg: 11.9 • Overall Survival (months) 3 mg/kg: 12.9 10 mg/kg: 11.8
Clinical Assessment
Clinical Assessment
Safety Profile -‐ General Table 3. General adverse events from Hodi et al. Dose: ipilimumab 3 mg/kg, n = 131. Numbers listed as percentages of total. Diarrhea ColiBs PruriBs Rash FaBgue
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 ColiBs PruriBs Rash FaBgue Nausea VomiBng
Any grade 18 4 15 17 12 13 5
Grade > 3 1 1 1 1 1 0 1
Safety Profile -‐ Immune Events
• Boxed warning for severe, potenBally fatal immune-‐related adverse reacBons due to T-‐cell acBvaBon and proliferaBon
Table 5. Immune-‐related adverse events in Hodi et al (%) and Wolchok et al (n). EnterocoliBs Hepatotoxicity DermaBBs Endocrinopathy Neuropathy
Hodi et al (%) 7 1 2 4 1
Wolchok et al (n) 23 0 32 4 Not reported
Real World ComparaBve EffecBveness • Evidence from RCT’s for increased survival is convincing
– LimitaBons • Large sample sizes difficult to construct • Inclusion/exclusion criteria somewhat inconsistent • Prior therapies differ vastly in those previously treated
• Few studies directly compare ipilimumab to other agents as monotherapy – Available data trend toward superior efficacy with more extensive adverse event profile for ipilimumab
• Ongoing trials: high-‐dose interferon alfa-‐2b monotherapy in high-‐risk paBents; sargramosBm combinaBon therapy
Health Plan and UBlizaBon • Pi, Street Health Plan
– 3.4 million members – $630 million in retail drugs annually
– 51.4% Female; 48.6% Male – Age distribuBon
• <18 years of age: 28.5% • 18-‐65 years of age: 61% • >65 years of age: 10.5%
• Treatment UBlizaBon – Incidence of metastaBc
melanoma qualifying for treatment is 27 per 100,000
– Pi, Street Health Plan can expect 85 members to qualify for treatment per year
– Predicted market share of ipilimumab is 35.1% as per BMS impact model
– The plan can expect 30 members to be treated with ipilimumab annually
Economic Review • 30 paBents treated annually x $120,000 = $3,600,000 therapy regime • 90 x $504 = $45,360 for administraBon costs • 30 x $936 = $28,080 cost to treat toxiciBes 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
• Limita5ons: – Elevated cost: fails to consider comparator pricing – Rebates not taken into consideraBon – Assumes that all member will complete a full course of treatment
Cost-‐EffecBveness Analysis
• Ipilimumab • Cost: $168,602 • LY: 2.88 • QALY: 1.76 • ICER: $78,218/LY • ICUR: $128,656/QALY
Barzey V, Atkins MB, Garrison LP, et al. Ipilimumab in 2nd line treatment of pa?ents with advanced melanoma: a cost-‐effec?veness analysis. J Med Econ. 2013: 16(2):202-‐212.
• gp100 • Cost: $21,886 • LY: 1.0 • QALY: 0.62
Current Formulary Design
Current Preferred Formulary
Current Non-‐preferred/ Non-‐Formulary
Aldesleukin (Proleukin®) Ipilimumab (Yervoy®) Peginterferon alfa-‐2b (Sylaton®)
Interferon alfa-‐2b (Intron-‐A®) Temozolomide (Temodar®) Pembrolizumab (Keytruda®)
Vemurafenib (Zelboraf®) ImaBnib (Gleevec®) Dabrafenib/Trame5nib Combo
Dabrafenib (Tafinlar®) TrameBnib (Mekinist®) Dacarbazine (DBc-‐Dome®)
Dark gray shading indicates NCCN category 1 preferred agents Nivolumab (Opdivo®) is also a preferred agent Light gray shading indicates NCCN therapeuBc alternaBve agents.
Cost Comparison of Preferred Agents Medica5on
Dose and Dura5on
Dose Assump5ons
AWP per day
Drug cost for 12 weeks
Drug cost for 48 weeks
Ipilimumab (Yervoy®)
3mg/kg Q3W x 4 doses
150mg 23,269 93,077 93,077
Pembrolizumab (Keytruda®)
2mg/kg Q3W 100mg 5,179 20,717 82,867
Dabrafenib/ Trame5nib Combo
D:150mg BID T: 2mg QD
See below 755 63,401 253,603
Nivolumab (Opdivo®)
3mg/kg Q2W
160mg (10mg of waste)
4,604 27,625 110,500
Drug Dose and Dura5on
Dose Assump5ons
AWP per day
Drug cost for 12 weeks
Drug cost for 48 weeks
Aldesleukin (Proleukin®)
720,000 units/kg TID x 4-‐5 days; repeat once
1,080,000 units 693
5,544-‐ 6,930
5,544-‐ 6,930
Vemurafenib (Zelboraf®)
960mg BID
8 x 240mg tabs
434 36,459 145,834
Dabrafenib (Tafinlar®)
150mg BID
4 x 75mg tabs 352 29,561 118,245
Temozolomide (Temodar®)-‐ Off Label
200 mg/m2/day for 5 days every 28 days x 12 cycles
3 x 100mg tabs
960 2,881 34,569
ImaBnib (Gleevec®)
400 mg BID
2 x 400mg tabs
737 61,895 247,580
TrameBnib (Mekinist®) 2mg QD 1 x 2mg 403 33,839 135,358
Dacarbazine (DBc-‐Dome®)
250 mg/m2 x5 days Q3 W
400mg (25 mg of waste)
25 508 2,034
Dose and duraBon are based on FDA approval and NCCN recommendaBons Dose assumpBons: 50kg, 160cm, 1.5m2
12 weeks was chosen based on the ipilimumab treatment regimen
48 weeks corresponds with the drug’s overall survival period
AWP informaBon was obtained from UpToDate. This table does not include costs associated with administraBon or treaBng adverse events.
Formulary Revisions Proposed Tier 1 Proposed Tier 2 Proposed Non-‐Formulary
Ipilimumab (Yervoy®) Nivolumab (Opdivo®) Peginterferon alfa-‐2b (Sylaton®)
Pembrolizumab (Keytruda®) Interferon alfa-‐2b (Intron-‐A®)
Vemurafenib (Zelboraf®) ImaBnib (Gleevec®)
Aldesleukin (Proleukin®) Dabrafenib/Trame5nib Combo
Dacarbazine (DBc-‐Dome®) Dabrafenib (Tafinlar®)
TrameBnib (Mekinist®)
Temozolomide (Temodar®)
We recommend moving all of these agents to the specialty Ber due to their difficult dosing regimens, intensive monitoring parameters, high cost, and osen injectable route of administraBon.
Summary • Effec5veness considera5on
– Increased median overall survival (months) – Increased 12-‐month survival (%)
• Safety considera5on – Acceptable safety profile – Risks monitored through REMS program
• Economic considera5on – High costs are jusBfiable due to survival benefit and low disease incidence
P&T RecommendaBons • Preferred/Formulary; Specialty MedicaBon Tier • Prior AuthorizaBon:
1. The prescribing physician is an oncologist and 2. The individual is an adult (at least 18 years of age) with the
diagnosis of unresectable or metastaBc melanoma and 3. The individual has an Eastern CooperaBve Oncology Group
(ECOG) performance status of 0 or 1 and 4. The individual has saBsfied all REMS requirements and 5. The individual has documented tesBng for BRAFV600
mutaBons
• 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
P&T RecommendaBons cont. • PaBents may be eligible for maintenance therapy if they meet all
previous prior authorizaBon criteria and the following: • A Response EvaluaBon Criteria In Solid Tumors (RECIST) score of complete response, parBal response, or stable disease upon evaluaBon occurring aser the final dose of inducBon 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