Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Breast cancer


Published on

Breast cancer

Published in: Health & Medicine
  • Be the first to comment

  • Be the first to like this

Breast cancer

  1. 1. Full Terms & Conditions of access and use can be found at Current Medical Research and Opinion ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: Budget impact of including ribociclib in combination with letrozole on US payer formulary: first-line treatment of post-menopausal women with HR+/HER2− advanced or metastatic breast cancer Rohit Mistry, Gaurav Suri, Kate Young, Robert Hettle, Jessica R. May, Diana Brixner, Gary Oderda, Joseph Biskupiak, Derek Tang, Devarshi Bhattacharyya, Subrata Bhattacharyya, Dinesh Mishra & Anand A. Dalal To cite this article: Rohit Mistry, Gaurav Suri, Kate Young, Robert Hettle, Jessica R. May, Diana Brixner, Gary Oderda, Joseph Biskupiak, Derek Tang, Devarshi Bhattacharyya, Subrata Bhattacharyya, Dinesh Mishra & Anand A. Dalal (2018): Budget impact of including ribociclib in combination with letrozole on US payer formulary: first-line treatment of post-menopausal women with HR+/HER2− advanced or metastatic breast cancer, Current Medical Research and Opinion, DOI: 10.1080/03007995.2018.1503484 To link to this article: Accepted author version posted online: 23 Jul 2018. Published online: 17 Aug 2018. Submit your article to this journal Article views: 74 View Crossmark data
  2. 2. ORIGINAL ARTICLE Budget impact of including ribociclib in combination with letrozole on US payer formulary: first-line treatment of post-menopausal women with HRþ/HER2À advanced or metastatic breast cancer Rohit Mistrya , Gaurav Suria , Kate Youngb , Robert Hettlea , Jessica R. Maya , Diana Brixnerc , Gary Oderdac , Joseph Biskupiakc , Derek Tangd , Devarshi Bhattacharyyae , Subrata Bhattacharyyae , Dinesh Mishrae and Anand A. Dalald a PAREXEL, London, UK; b PAREXEL, Horsham, PA, USA; c Department of Pharmacotherapy, University of Utah, Salt Lake City, UT, USA; d Novartis, East Hanover, NJ, USA; e Novartis, Hyderabad, India ABSTRACT Objectives: The combination of a cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitor with the aroma- tase inhibitor letrozole is a safe and effective alternative to letrozole monotherapy for first-line hor- mone receptor-positive (HRþ)/human epidermal growth factor receptor 2-negative (HER2À) breast cancer. This study evaluates the budget impact of using the CDK 4/6 inhibitor ribociclib plus letrozole as a first-line treatment option for postmenopausal women with HRþ/HER2À advanced breast cancer, from a United States (US) payer perspective. Methods: A cohort-based budget impact model was used to calculate the incremental cost of intro- ducing ribociclib plus letrozole over three years for the target population. The analysis compared two scenarios: treatment options excluding or including ribociclib plus letrozole. Market shares were derived from market research and the assumption was the introduction of ribociclib plus letrozole would only displace existing CDK-based therapies. Treatment duration was based on the median time to treatment discontinuation or median progression-free survival for first-line treatment, and on clinical trial data for second- and third-line treatment. Acquisition costs were based on wholesale acquisition costs and considered co-payment. Costs for drug administration and monitoring, subsequent therapy, and relevant adverse events were included. Results: Of 1 million insured members, 263 were eligible for CDK 4/6 inhibitor treatment. Cumulative total savings with ribociclib plus letrozole were $3.01M over three years, corresponding to a cumula- tive incremental cost saving of $318.11 per member treated per month. Conclusions: In the US, ribociclib plus letrozole represents a cost-saving first-line treatment option for postmenopausal women with HRþ/HER2À advanced breast cancer. ARTICLE HISTORY Received 2 January 2018 Revised 27 June 2018 Accepted 29 June 2018 KEYWORDS Ribociclib; budget impact; postmenopausal women; hormone receptor-positive; human epidermal growth factor receptor 2-negative; advanced breast cancer; metastatic breast cancer Introduction Significant recent additions to the breast cancer treatment armamentarium are the orally bioavailable cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors ribociclib (KISQALIVR , Novartis), palbociclib (IBRANCEVR , Pfizer Inc.), and abemaciclib (VERSENIOVR , Eli Lilly)1 . The antitumor activity of these agents results from the inhibition of the retinoblastoma protein, which regulates cell proliferation2 . The MONALEESA-2 clinical trial has demonstrated that the combination of ribociclib with letrozole is a safe alternative to letrozole monotherapy as a first-line treatment for postmenopausal women with HRþ/HER2À advanced breast cancer, achieving substantially longer progression-free survival (PFS)3 . Specifically, in the MONALEESA-2 study, the combination of ribociclib and letro- zole increased PFS by 7.1 months compared with letrozole monotherapy, corresponding to a 44% reduction in the rate of disease progression or death (hazard ratio [HR] ¼ 0.56; 95% confidence interval [CI], 0.43–0.72, p < .0001)3 . Whereas the clinical efficacy and safety of the CDK 4/6 inhibitors have been demonstrated, their cost-effectiveness and budget impact to payers remain to be established. Previous studies have demonstrated that palbociclib with letrozole is not cost-effective or cost-saving compared with letrozole monotherapy in this patient population4–6 . No stud- ies have specifically assessed the budget impact of the CDK 4/6 inhibitors. To fill this gap, we conducted a budget impact analysis of introducing ribociclib plus letrozole as a first-line treatment option for postmenopausal women with HRþ/ HER2À advanced or metastatic breast cancer from a US payer perspective. Methods Model structure A cohort-based budget impact model was developed using Microsoft ExcelVR 2010 to calculate the incremental cost of CONTACT Rohit Mistry PAREXEL, Evergreen Building North, 160 Euston Road, London NW1 2DX, UK ß 2018 Informa UK Limited, trading as Taylor & Francis Group CURRENT MEDICAL RESEARCH AND OPINION Article RT-0186.R1/1503484 All rights reserved: reproduction in whole or part not permitted
  3. 3. introducing ribociclib plus letrozole over 5 years for the first- line treatment of postmenopausal women with HRþ/HER2À advanced or metastatic breast cancer. Prior to model devel- opment, a systematic literature review was performed to identify randomized controlled trials (RCTs) of existing treat- ments for postmenopausal women with HRþ/HER2À advanced or metastatic breast cancer in the first-line setting from which clinical and health utilization modelled inputs could be obtained. The MONALEESA-2 study was identified as the only relevant RCT3 ; model inputs not derived from this study were obtained by targeted literature searches. The model comprised a hypothetical cohort of 1,000,000 health plan members with the following demographic and clinical characteristics: female, 50.8%7 ; postmenopausal (age !50 years), 33.9%7 ; postmenopausal with breast cancer, 3%8 ; proportion of patients with advanced or metastatic breast cancer, 6.9%9 ; and HRþ/HER2À subtype, 74%9 . From this, the annual incidence of newly diagnosed post-menopausal HRþ/HER2À advanced or metastatic breast cancer was calcu- lated as 0.0263. Patients entered the model at the beginning of Years 1, 2, and 3 and received treatment for three years from the point of entry. At each entry point, the number of eligible patients entering was calculated by applying the annual incidence rate to the number of undiagnosed patients remaining from the 1,000,000 cohort. The model compared two scenarios: treatment options for the patient population excluding ribo- ciclib plus letrozole and a scenario where ribociclib plus letrozole was included. Direct medical costs related to treat- ment acquisition, treatment administration, treatment moni- toring, adverse events (AEs), and subsequent therapy were considered in the model. Treatment costs were calculated on a monthly basis and reported for the first, second, and third year of treatment after treatment initiation. Treatments It was assumed that each patient eligible for treatment received treatment for up to three years without stopping treatment or dying. Three lines of therapy were included, as this was the expected average number of lines of therapy that the patient population would receive in normal clinical practice. Treatments included in the model were based on treatment guidance from the NCCN10 and market research (Novartis, data on file), which informed the treatments to be included in the model and their market shares. Within these data sources, chemotherapy was bundled as a single entry. Given that many of the chemotherapies used in this indica- tion are generic and their price per dose is small, the deci- sion was taken to use the most expensive chemotherapy on the market at the time as a representative price. All chemo- therapies in the analysis were represented by eribulin, because this was the highest-cost first-line chemotherapy and represented a conservative analysis. For first-line treatment, a treatment was assigned to each patient according to anticipated market share. Market shares in the scenario with ribociclib were provided by Novartis based on anticipated uptake of ribociclib; market shares were adjusted in the without-ribociclib scenario on the assumption that ribociclib displaces other CDK inhibitor- based therapies (Table 1). The market share of chemotherapy only changes with the introduction of CDK 4/6 treatment class and not following the introduction of ribociclib specific- ally; therefore, for this analysis, chemotherapy pricing has a net zero impact on the incremental results. Treatment dur- ation was based on the median time to treatment discon- tinuation or median PFS3,11,12 ; the use of median rather than mean values reflected the fact that the data were highly right-skewed due to outliers and the use of median values mitigated against the effect of outliers. Clinical data used for the chemotherapy class were sourced from a literature review. For endocrine therapies, the median TTD was assumed to be equal to the median PFS. In the second-line setting, treatment was assigned accord- ing to the prevailing market shares with the assumption, based on market research, that 83% of patients would receive hormonal therapy and 17% of patients would receive chemotherapy. In alignment with the ASCO guideline on hor- monal therapy13 , patients who received a CDK 4/6 inhibitor in the first-line setting were assumed not to receive a subse- quent CDK inhibitor. The duration of treatment for hormonal therapies and chemotherapy was sourced from RCTs of the target population (Novartis, data on file)11,12,14 . All chemo- therapies in the analysis were represented by eribulin and were assigned a 4.9-month treatment duration9 . In the third-line setting, treatment was assigned according to the prevailing market shares with the assumption that 39% of patients received hormonal therapies and 30% of patients received chemotherapy, while 31% of patients received no treatment (Novartis, data on file). The duration of treatment for hormonal therapies and chemotherapy was sourced from RCTs for the target population11,15–17 . All che- motherapies were assigned a 4.7-month treatment duration12 due to the absence of treatment duration data in the third- line setting. Cost inputs All costs were calculated in 2016 US dollars inflated using the Consumer Price Index (CPI)18 . Acquisition and administration costs were provided for all treatments by differentiating Table 1. Treatment market shares. Market share (%) Scenario without ribociclib Scenario with ribociclib Drug Year 1 Year 2 Year 3 Year 1 Year 2 Year 3 Ribociclib þ letrozole 0.0 0.0 0.0 3.3 11.9 19.3 Palbociclib þ letrozole 39.2 47.7 51.0 35.9 35.8 32.4 Letrozole monotherapy 7.2 5.6 4.6 7.2 5.6 4.6 Fulvestrant þ anastrozole 5.7 4.8 4.1 5.7 4.8 4.1 Fulvestrant monotherapy 5.7 4.8 4.1 5.7 4.8 4.1 Exemestane 7.2 5.6 4.6 7.2 5.6 4.6 Tamoxifen 7.2 5.6 4.6 7.2 5.6 4.6 Anastrozole monotherapy 7.2 5.6 4.6 7.2 5.6 4.6 Palbociclib þ fulvestrant 8.5 10.5 13.6 8.5 10.5 12.9 Fulvestrant þ letrozole 5.7 4.8 4.1 5.7 4.8 4.1 Chemotherapy (eribulin) 6.4 5.2 4.7 6.4 5.2 4.7 2 R. MISTRY ET AL.
  4. 4. between first and subsequent doses as required (Table 2). The model accounted for dose reduction and drug wastage with ribociclib and palbociclib. In terms of dose reduction, a dosing analysis of MONALEESA-2 was used to identify the proportion of patients utilizing 600 mg, 400 mg, and 200 mg doses of ribociclib, calculated as 52%, 31%, and 17%, respectively (Novartis, data on file). The proportion of patients per dose for palbociclib was obtained from a retro- spective observational claims analysis19 . This study estimated that during the 12 months post-treatment index date among patients initiated on palbociclib, dose reduction rates were approximately 32% and dose reduction or interruption rates were approximately 70%. With regard to drug wastage, the model assumed no wastage for ribociclib as it is formulated as a 200 mg tablet and each dose regimen may be achieved by taking one or more tablets. In the case of palbociclib, available as 125 mg, 100 mg, and 75 mg capsules, there is some degree of drug wastage when its dose is reduced mid- cycle. In the same study, the authors demonstrated that among patients who changed dose, 31.1% of patients had overlap between consecutive fills with different doses. The mean potential drug wastage cost among patients with fill overlap was $5471 per patient19 . The net drug acquisition cost represented the lowest wholesale acquisition cost (WAC) of each medication within Medi-Span Price RxVR minus the patient co-payment ($567 for ribociclib and palbociclib, $373 for fulvestrant, $840 for eri- bulin, and $11 for others) effective from 12 October 201620,21 . For some treatments that required a higher dose at first administration compared with subsequent administra- tions, the monthly acquisition cost for Month 1 was higher than for Month 2 þ (Month 2 and subsequent months). The drug acquisition costs for the various presentations of ribociclib were provided by Novartis, and pricing was based on a semi-linear pricing strategy (Novartis, data on file). Comparison of the data show that the listed WAC of palboci- cib has a flat price for all presentations, i.e. palbociclib 125 mg, 100 mg and 75 mg are all priced at $10,963.05, effective from 1 January 201720 . Monthly treatment administration costs were derived from the 2016 Medicare Physician Fee Schedule using Medicare facility prices ($179 for fulvestrant and $771 for chemotherapy; $0 for all other treatments)21 . Health state management, or disease management, costs included outpatient visits, bone metastases management, hospitalization, laboratory testing, and either imaging (for treatment duration) or palliative care costs (for subsequent treatment only) (total cost per month: $686 for the treatment duration and $6,199 for subsequent treatment)18,22 . Monthly disease monitoring, such as routine laboratory testing, was included under health-state costs. Additional drug-specific monitoring costs were driven by respective product labels. Blood monitoring was required for ribociclib from the time of treatment initiation to 6 months23 and for palbociclib from the time of treatment initiation onwards24 . Cardiac and liver monitoring were considered for ribociclib only23 . These monitoring costs were modelled as monthly add-on costs at treatment initiation (hepatic enzymes, complete blood count, and ECG) for ribociclib and palbociclib upon treatment initiation ($138.48 vs. $42.36) and regularly thereafter ($21.72 vs. $10.59)19,22,23 . Adverse events The model included serious AEs (CTCAE [Common termin- ology criteria for AEs] Grade !3) reported more frequently Table 2. Drug acquisition and administration costs. Drug Dose (mg) WAC cost/month ($) Total acq. cost per month ($) Net acq. cost per month ($)a Admin. cost ($) Ribociclib þ letrozoleb 600 10,950 5358 8560.92c – 400 8760 2540 200 4380 663 Palbociclib þ letrozoleb 125/100/75 10,963 10,396 10,396 – Letrozole monotherapy 2.5 7 0 0 – Fulvestrant þ anastrozoled First dose 500 3727 3354 3354 358 Subs. dose 500 1863 1490 1490 179 Fulvestrant monotherapy First dose 500.0 3727 3354 3354 358 Subs. dose 500 1863 1490 1490 179 Exemestane 25 304 293 293 – Tamoxifen 20 21 10 10 – Anastrozole monotherapy 1.0 4 0 0 – Palbociclib þ fulvestrante First dose 125/100/75 10,963 10,396 13,750 358d Subs. dose 179e Fulvestrant þ letrozolea First dose 500d 3727 3354 3354d 358d Subs. dose 500e 1863 1490 1490e 179e Chemotherapy (eribulin) 1.23 4200 3360 3360 771 Source: References (20,21 ). Abbreviations. acq., Acquisition; admin., Administration; WAC, Wholesale acquisition cost; Subs., Subsequent. a Equivalent to WAC cost/month minus the monthly patient co-payment ($567 for ribociclib and palbociclib, $373 for fulvestrant, $840 for eribulin, and $11 for all other therapies). b Letrozole 2.5 mg included in total overall acquisition cost (equal to letrozole monotherapy). c 600 mg, 400 mg, and 200 mg doses of ribociclib used by 52%, 31%, and 17% of patients, respectively (Novartis, data on file). d Anastrozole 1.0 mg included in total overall acquisition cost (equal to anastrozole monotherapy). e Fulvestrant 500 mg initial and subsequent doses included in total overall acquisition cost (equal to fulvestrant monotherapy). 3
  5. 5. with ribociclib3 or palbociclib25 versus placebo. These AEs included anemia, diarrhea, fatigue, infection, nausea, febrile neutropenia, pulmonary embolism, and vomiting. Besides the need to be serious and more frequent, the AEs needed to be relevant and related to treatment (based on previous HTA submissions and consultations with modelling experts) and likely to either result in hospitalization or have a meaningful impact on patient well-being. The frequency of each AE for each treatment was obtained from the literature (Table 3)3,11,16,25–29 . The unit cost of each AE was assumed to reflect an average hospitalization related to that event (Table 3)30,31 . Deterministic sensitivity analysis A one-way deterministic sensitivity analysis (DSA) was per- formed to assess the influence of key model input parameters (acquisition cost, monitoring cost, first-line treatment duration, progression-free health state costs, and post-progression health state costs; ±10% variation) on budget impact. Results The model considered a hypothetical US health plan com- prising 1,000,000 members within which, over a period of five years, a proportion of members, postmenopausal women diagnosed with HRþ/HER2À advanced or metastatic breast cancer, entered a treatment pathway lasting three years. At the start of Year 1, totally 263 members were considered eli- gible for treatment. In subsequent years, the proportion of the total cohort receiving treatment increased as previously diagnosed patients continued treatment and newly diag- nosed patients initiated treatment. At the same time, the proportion of treated patients newly receiving ribociclib plus letrozole or palbociclib plus letrozole increased as these treatment options gained market share. The introduction of ribociclib resulted in $3.01M cumula- tive total savings over three years, attributing to reduced costs (drug acquisition, $2.72M; subsequent therapy, $96K; AEs, $82K) (Table 4). Within both scenarios, with or without ribociclib plus letrozole, drug acquisition cost was the major component of total cost (Table 4). Savings per year increased over the time horizon with increased market share of riboci- clib: $125K, $1.04M, and $1.85M in Years 1–3, respectively (Table 5). Considering the patients treated, the introduction of ribociclib resulted in a cost saving per treated patient per month of $39.57 in Year 1, $327.73 in Year 2, and $525.28 in Year 3, yielding a cumulative incremental cost saving of $318.11 per member treated per month. Considering the whole cohort of one million members, the introduction of ribociclib resulted in a cost saving of $0.01, $0.09, and $0.15 per patient per month in Years 1, 2, and 3, respectively) (Table 5). Key drivers of the budget impact determined from the DSA included the acquisition cost of ribociclib from Month 2 onwards, which resulted in changes of þ38% and À38% fol- lowing a reduction and increase, respectively, in the base case parameter, the acquisition cost of palbociclib plus letro- zole from Month 2 onwards (À45%, þ45%), and the treat- ment durations of both ribociclib plus letrozole (þ39%, À41%) and palbociclib plus letrozole (À47%, þ39%) (Figure 1). Discussion Despite progress in medical treatment, breast cancer remains a deadly disease imposing a substantial clinical and eco- nomic burden on healthcare systems32–34 . As payers priori- tize scarce resources to manage their budgets, newer agents are viewed skeptically when balancing the value provided by these agents with the costs they impose on payer budgets. The expectation of payers is that newer agents will result in an increase to the pharmacy budget with some medical cost offsets that may mitigate the increase in pharmacy spend. In this budget impact analysis, the introduction of riboci- clib plus letrozole as a first-line treatment option for postme- nopausal women with HRþ/HER2À advanced or metastatic breast cancer in the US resulted in $3.01M cumulative total savings over three years, with reduced drug acquisition, AE, and subsequent treatment costs for payers. While modest budget reductions following the introduc- tion of ribociclib were achieved in the areas of AEs and sub- sequent therapy, the greatest gain was observed in relation Table 3. Adverse event frequencies and costs. Treatment Frequency (%) Total cost ($) Ref. Diarrhea Fatigue Infection Nausea Febrile neutropenia Pulmonary embolism Vomiting Anemia Cost ($) 7377.28 6907.56 10,113.53 6181.93 21,156.00 10,035.78 5245.73 6776.90 30,31 Ribociclib þ letrozole 1.2 2.4 4.2 2.4 1.2 0.0 3.6 1.2 1348.79 3,39 Palbociclib þ letrozole 1.7 2.3 4.4 0.6 0.4 5.0 0.4 5.5 1734.76 25,26 Letrozole 0.9 0.9 2.4 0.6 0.0 0.3 0.9 1.2 572.75 Fulvestrant þ anastrozole 0.4 0.4 2.5 1.2 0.8 0.8 0.8 2.1 831.00 11 Fulvestrant 0.6 1.2 1.7 0.6 0.6 0.0 0.6 1.7 607.25 40 Exemestane 0.4 0.4 2.5 0.4 0.8 0.4 0.4 0.8 639.90 16 Tamoxifen 1.5 1.5 2.9 0.7 0.7 0.7 1.5 1.5 959.14 29 Anastrozolea 0.9 0.9 2.4 0.6 0.0 0.3 0.9 1.2 572.75 Palbociclib þ fulvestrant 1.7 2.0 2.0 0.6 0.6 0.9 0.3 2.6 911.40 40 Fulvestrant þ letrozoleb 0.4 0.4 2.5 1.2 0.8 0.4 0.8 2.1 789.36 Chemotherapy (eribulin) 0.0 8.7 0.2 1.2 0.2 1.0 1.0 2.0 1026.78 28 Source: See table content. a All rates assumed to be equivalent to those for letrozole. b All rates assumed to be equivalent to those for fulvestrant plus anastrozole. 4 R. MISTRY ET AL.
  6. 6. to drug acquisition cost. Two factors appeared to contribute to the net budget impact afforded by the introduction of ribociclib: dose reduction and drug wastage. As the highest recommended doses of ribociclib and palbociclib are simi- larly priced, ribociclib is provided in a single dosage form, 200 mg tablets, with differential pricing by pack size, whereas palbociclib is provided as multiple capsules that cannot be manipulated to accommodate dose and does not afford a price reduction with dose reduction. Thus, longer-term treat- ment with ribociclib offers budget savings in terms of both dose reduction and drug wastage, which represents a signifi- cant cost savings to payers, as demonstrated by this BIM. The output of this BIM estimates a cost saving of $585.23 per treated member per month by Year 3, which is a Table 5. Incremental cost results for the scenario with ribociclib versus the scenario without ribociclib. Cost center Incremental cost, $ (%) Cumulative Year 1 Year 2 Year 3 Drug acquisition À197K (À1.1) À943K (À3.5) À1575K (À5.4) À2716K (À3.7) Drug administration 0 0 À1K (À1.0) À1K (À0.3) Drug monitoring 2K (þ16.4) 10K (þ36.3) 16K (þ45.4) 28K (þ37.3) Disease monitoring/non-drug medical 0 À60K (À0.9) À85K (À1.2) À145K (À0.9) Adverse events À3K (À1.1) À24K (À3.9) À54K (À5.7) À82K (À4.4) Subsequent therapy 73K (þ3.6) À19K (À0.2) À151K (À1.9) À96K (À0.5) Second line 0 (0) 0 (0) 0 (0) 0 (0) Third line 73K (þ23.4) À19K (À1.1) À151K (À8.7) À96K (À2.5) Total À125K À1036K À1850K À3012K Total PMPM À0.01 À0.09 À0.15 Total PMTM À39.57 À327.73 À585.28 Abbreviations. 1K, 1000; PMPM, Per member per month; PMTM, Per member treated per month. Table 4. Cumulative and disaggregated costs. Cost ($) Without ribociclib With ribociclib Year 1 Year 2 Year 3 Cumulative Year 1 Year 2 Year 3 Cumulative Drug acquisition Ribociclib + letrozole 0K 0K 0K 0K 896K 4M 7M 12M Palbociclib + letrozole 13M 21M 22M 56M 12M 16M 14M 42M Other comparators 4.65M 6.88M 8.22M 19.74M 4.65M 6.88M 7.87M 19.39M Total 18M 28M 31M 76M 17M 27M 29M 73M Drug admin. 107K 116K 110K 334K 107K 116K 109K 332K Drug-specific monitoring 10K 17K 19K 47K 12K 27K 36K 75K Health state management 3M 7M 7M 17M 3M 7M 7M 17M Adverse events 303K 651K 1M 2M 299K 627K 953K 2M Subsequent therapies Second line 2M 6M 6M 14M 2M 6M 6M 14M Third line 240K 2M 2M 4M 313K 2M 2M 4M Total 2M 8M 8M 18M 2M 8M 8M 18M Total 23M 44M 47M 23M 43M 45M Cumulative total 23M 66M 113M 23M 65M 110M Total PMPM 1.90 3.64 3.90 1.89 3.55 3.74 Abbreviations. 1K, 1000; 1M, 1 million; admin., Adminstration; PMPM, Per member per month. Figure 1. Deterministic sensitivity analysis. ‘Acquisition, 1st month’ and ‘acquisition, 2þ months’ refer to the monthly drug acquisition cost for Month 1 and Month 2 and subsequent months, respectively. 5
  7. 7. relevant financial impact in the management of patients eli- gible for CDK therapy. It is noteworthy that abemaciclib was not considered as a treatment option in this model because it had not received FDA approval at the point of model development. The sub- sequent approval included the same patient population but with different use: in combination with fulvestrant for disease progression following endocrine therapy or as monotherapy for disease progression following endocrine therapy and prior chemotherapy in the metastatic setting35 . Abemaciclib too has a dose regimen and dose sizes that allow for dose reduction (from 150 mg [combination therapy] or 200 mg [monotherapy] twice daily, with drug supplied as 50 mg, 100 mg, 150 mg, and 200 mg tablets in 14-tablet blister packs)35 . No study has been published regarding the budget impact of this agent. However, if a flat pricing structure simi- lar to that for palbociclib were to be adopted for abemaci- clib, and assuming similar rates of dose adjustment, then dose reduction and drug wastage might increase the budget impact of abemaciclib in the same way as they do for palbociclib. This is the first study to assess the budget impact of ribo- ciclib in the treatment of patients with advanced breast can- cer. In recent years it has been unusual for a new breast cancer treatment to be cost-saving upon introduction. In pre- vious cost-effectiveness studies, palbociclib plus letrozole appeared highly unlikely to be cost-effective and increased the healthcare budget versus letrozole alone4–6 . By contrast, a recent study found ribociclib plus letrozole to be cost- effective and cost-saving versus palbociclib plus letrozole (paper under review). It is encouraging that ribociclib is cost- saving not only compared with an approved agent in the same therapeutic class, but also the prevailing basket of available treatments. Our findings are subject to a number of limitations. The patient population may not be an accurate real-world repre- sentation since it was based on inputs from prior publica- tions and not a population from a healthcare setting. In addition, as indicated by the DSA, the model outcome is sensitive to the chosen values of cost inputs, such as acquisition cost, treatment duration, and disease monitoring. Furthermore, the market shares for the treatments consid- ered within the model may not take into account patient entry or dropout that occurred during the year since they were based on estimates at a particular time point. Nonetheless, the rate of displacement of palbociclib by ribo- ciclib was set as conservative and still achieved a net budget reduction. Still, the model utilized drug acquisition costs from 2016 and did not factor in any price adjustment for ribociclib or palbociclib as their market shares changed with use or other US market conditions. The model utilized interim data from the MONALEESA-2 study published in 20163 . Since the time of model and manuscript development, updated efficacy and safety data from MONALEESA-2 have been published36 along with other studies involving ribociclib, in particular the MONALEESA-3 study37 , which assessed ribociclib vs. placebo in combination with fulvestrant in post-menopausal patients who were either treatment-naïve or had received up to one line of endocrine therapy, and the MONALEESA-7 study38 , which assessed ribociclib plus endocrine therapy vs. endocrine ther- apy alone in pre-menopausal women. The MONALEESA-2 second interim analysis comprised data with a median duration of follow-up of 26.4 months (com- pared with 15.3 months for the first interim analysis). The HR for PFS was similar for the two analyses (0.568 vs. 0.56, respectively). In MONALEESA-3, median PFS was significantly improved with ribociclib plus fulvestrant vs. placebo plus ful- vestrant (HR: all patients 0.594 [95% CI 0.480-0.732]; treat- ment-naïve, 0.577 [0.415-0.802]; up to one line of prior endocrine therapy, 0.565 [0.428-0.744]). In MONALEESA-7, ribociclib plus endocrine therapy improved progression-free survival compared with placebo plus endocrine therapy (HR 0.55 [0.44-0.69]) and had a manageable safety profile. Use of these data to inform the model inputs may provide add- itional insight into the cost implications of introducing riboci- clib as a first-line treatment option for postmenopausal women with HRþ/HER2À advanced or metastatic breast can- cer in the US, as well as the value of extending the treated population to include pre-menopausal women. Conclusions Clinical trial data support the use of ribociclib plus letrozole for improving breast cancer patient sensitivity to hormonal therapy, as indicated in the MONALEESA-2 study by signifi- cantly longer PFS compared with letrozole monotherapy. Our study adds to this knowledge, by demonstrating that the introduction of ribociclib plus letrozole as a first-line treat- ment option for postmenopausal women with HRþ/HER2À advanced or metastatic breast cancer in the US is also a cost-saving choice for payers. Given the importance of dose- reduction strategies and pricing structures for the drug acquisition costs of the CDK 4/6 inhibitors, future studies to define dose-reduction profiles and agreed pricing agree- ments in the real-world setting are warranted. Transparency Declaration of funding Funding for this study was provided by Novartis, which manufactures ribociclib and which supplied input into the study design and data col- lection, analysis, and interpretation. Declaration of financial/other relationships RM, JRM, GS and KY are employees of PAREXEL; DT, DM, DB and AAD are employees of Novartis. RH was an employee of PAREXEL during the study period; SB was an employee of Novartis during the study period. DT and AAD hold stock in Novartis. Author contributions All authors were involved in the study design, data analysis and inter- pretation, and development of the paper, including approval of the final version to be published. All authors agree to be accountable for all 6 R. MISTRY ET AL.
  8. 8. aspects of the work. Peer reviewers on this manuscript have received an honorarium from CMRO for their review work, but have no other rele- vant financial relationships to disclose. Acknowledgments Editorial support was provided by Lorena Tonarelli and by Nick Rusbridge (PAREXEL) and funded by Novartis. References 1. Kwapisz D. Cyclin-dependent kinase 4/6 inhibitors in breast can- cer: palbociclib, ribociclib, and abemaciclib. Breast Cancer Res Treat 2017;166:41-54 2. Tripathy D, Bardia A, Sellers WR. Ribociclib (LEE011): mechanism of action and clinical impact of this selective cyclin-dependent kinase 4/6 inhibitor in various solid tumors. Clin Cancer Res 2017;23(13):3251-3262 3. Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first- line therapy for HR-positive, advanced breast cancer. N Engl J Med 2016;375:1738-48 4. Mamiya H, Tahara RK, Tolaney SM, et al. Cost-effectiveness of pal- bociclib in hormone receptor-positive advanced breast cancer. Ann Oncol 2017;28:1825-31 5. Matter-Walstra K, Ruhstaller T, et al. Palbociclib as a first-line treat- ment in oestrogen receptor-positive, HER2-negative, advanced breast cancer not cost-effective with current pricing: a health eco- nomic analysis of the Swiss Group for Clinical Cancer Research (SAKK). Breast Cancer Res Treat 2016;158:51-7 6. Matter-Walstra K, Schwenkglenks M, Dedes KJ. Cost-effectiveness of palbociclib plus letrozole versus letrozole alone as a first-line treatment in women with oestrogen receptor-positive, HER2-nega- tive, advanced breast cancer. Revised results for the Swiss health care setting. Breast Cancer Res Treat 2017;163:635 7. Howden LM, Meyer, JA. Census briefs: age and sex composition. Washington, D.C.: U.S. Department of Commerce Economics and Statistics Administration U.S. CENSUS BUREAU; 2010. 8. Howlader N, Noone AM, Krapcho M, et al. (eds). SEER cancer stat- istical review, 1975–2013. Bethesda, MD: National Cancer Institute; 2016. Available at: 9. Xie J, Diener M, De G, et al. Budget impact analysis of everolimus for the treatment of hormone receptor positive, human epidermal growth factor receptor-2 negative (HER2-) advanced breast cancer in the United States. J Med Econ 2013;16:278-88 10. Gradishar WJ, Anderson BO, Balassanian R, et al. Invasive Breast Cancer Version 1.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2016;14:324-54 11. Johnston SR, Kilburn LS, Ellis P, et al. Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non- steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial. Lancet Oncol 2013;14:989-98 12. Bachelot T, Bourgier C, Cropet C, et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth fac- tor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol 2012;30:2718-24 13. Rugo HS, Rumble RB, Burstein HJ. Endocrine therapy for hormone receptor positive metastatic breast cancer: American Society of Clinical Oncology guideline summary. J Oncol Pract 2016;12:583-7 14. Finn RS, Crown JP, Ettl J, et al. Efficacy and safety of palbociclib in combination with letrozole as first-line treatment of ER-positive, HER2-negative, advanced breast cancer: expanded analyses of subgroups from the randomized pivotal trial PALOMA-1/TRIO-18. Breast Cancer Res 2016;18:67 15. Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med 2016;375:1925-36 16. Baselga J, Campone M, Piccart M, et al. Everolimus in postmeno- pausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012;366:520-9 17. Ellis MJ, Llombart-Cussac A, Feltl D, et al. Fulvestrant 500 mg ver- sus Anastrozole 1 mg for the first-line treatment of advanced breast cancer: overall survival analysis from the phase II first study. J Clin Oncol 2015;33:3781-7 18. U.S. Bureau of Labor Statistics. Consumer Price Index for all urban consumers; medical care. Washington, D.C.: U.S. Bureau of Labor Statistics; 2016. 19. Li N, Du EX, Chu L, Peeples M, et al. Real-world palbociclib dosing patterns and implications for drug costs in the treatment of HRþ/ HER2- metastatic breast cancer. Expert Opin Pharmacother 2017;18:1167-78 20. Medispan Price Rx. [cited 2017 October 12, 2016, and January 2, 2017]. Available to: aspx. 21. Medicare. Medicare facility prices 2016. 2016. 22. Xie J, Hao Y, Zhou ZY, et al. Economic evaluations of everolimus versus other hormonal therapies in the treatment of HRþ/HER2À advanced breast cancer from a US payer perspective. Clin Breast Cancer 2015;15:e263-76 23. Novartis Pharmaceuticals Corporation. KISQALI prescribing infor- mation 2017 [cited 2017]. Available to: https://www.accessdata. 24. Pfizer Inc. IBRANCE prescribing information 2017. Available from: 207103s004lbl.pdf. 25. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2- negative, advanced breast cancer (PALOMA-1/TRIO-18): a rando- mised phase 2 study. Lancet Oncol 2015;16:25-35 26. Finn RS, Martin M, Rugo HS, et al. PALOMA-2: primary results from a phase III trial of palbociclib (P) with letrozole (L) compared with letro- zole alone in postmenopausal women with ERþ/HER2– advanced breast cancer (ABC). J Clin Oncol. 2016;34(15_Suppl):507-507 27. Turner NC, Huang Bartlett C, Cristofanilli M. Palbociclib in hor- mone-receptor-positive advanced breast cancer. N Engl J Med 2015;373:1672-3 28. Cortes J, O’Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet 2011;377:914-23 29. Paridaens RJ, Dirix LY, Beex LV, et al. Phase III study comparing exemestane with tamoxifen as first-line hormonal treatment of metastatic breast cancer in postmenopausal women: the European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group. J Clin Oncol 2008;26:4883-90 30. HCUP Databases. Healthcare Cost and Utilization Project (HCUP). Rockville, MD: Agency for Healthcare Research and Quality; 2013. Available at: 31. Michels SL, Barron RL, Reynolds MW, et al. Costs associated with febrile neutropenia in the US. Pharmacoeconomics 2012;30:809-23 32. Xie J, Hao Y, Li N, et al. Clinical outcomes among HRþ/HER2- metastatic breast cancer patients with multiple metastatic sites: a chart review study in the US. Exp Hematol Oncol 2015;4:31 33. Foster TS, Miller JD, Boye ME, et al. The economic burden of metastatic breast cancer: a systematic review of literature from developed countries. Cancer Treat Rev 2011;37:405-15 34. Montero AJ, Eapen S, Gorin B, et al. The economic burden of metastatic breast cancer: a U.S. managed care perspective. Breast Cancer Res Treat 2012;134:815-22 35. Eli Lilly & Co. Versenio prescribing information. 2017. 36. Hortobagyi GN, Stemmer SM, Burris HA, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor- 7
  9. 9. positive, HER2-negative advanced breast cancer. Ann Oncol 2018;29(7):1541-1547 37. Slamon DJ, Neven P, Chia S, et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol 2018;36:JCO2018789909. doi: 10.1200/JCO.2018.78.9909 38. Tripathy D, Im SA, Colleoni M, et al. Ribociclib plus endocrine ther- apy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol 2018;19(7):904-915 39. Novartis. Clinical study report: A randomized double-blind, placebo- controlled study of LEE011 in combination with letrozole for the treatment of postmenopausal women with hormone receptor posi- tive, HER2-negative, advanced breast cancer who received no prior therapy for advanced disease. East Hanover, NJ: Novartis;2016. 40. Turner NC, Ro J, Andre F, et al. Palbociclib in Hormone-Receptor- Positive Advanced Breast Cancer. N Engl J Med 2015;373:209-19 8 R. MISTRY ET AL.