Milovac P&T Competition Presentation

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


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


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


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


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

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


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



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

Milovac P&T Competition Presentation

Documents

Transcript of Milovac P&T Competition Presentation