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1.
Cost-Effectiveness of Ribociclib plus Letrozole for Treatment-Naïve
Post-Menopausal Women with HR+/HER2- Advanced or
Metastatic Breast Cancer from a US Third-Party Payer Perspective
Suri G,1
Mistry R,1
Young KC,2
Hettle R,1
May JR,1
Brixner D,3
Oderda G,3
Biskupiak J,3
Tang D,4
Bhattacharyya D,5
* Bhattacharyya S,5
Mishra D,5
Dalal A4
1
PAREXEL, London, UK; 2
PAREXEL, Horsham, PA, USA; 3
University of Utah, Salt Lake City, UT, USA; 4
Novartis, East Hanover, NJ, USA; 5
Novartis, Hyderabad, Telangana, India
*Corresponding author (devarshi.bhattacharyya@novartis.com)
Background
• Treatment options for hormone receptor-positive (HR+), human epidermal
growth factor receptor 2-negative (HER2-) advanced or meta-static breast
cancer in post-menopausal patients include aromatase inhibitors (e.g., letrozole),
selective estrogen receptor modulators (e.g., tamoxifen), estrogen receptor
antagonists (e.g., fulvestrant), and, most recently, oral, highly-selective,
cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors1,2
• Clinicalstudieshaveshownthatthecombinationofribocicliborpalbociclibwith
letrozoleisatolerable,safe,andefficaciousalternativetoletrozolemonotherapyfor
first-linepostmenopausalHR+/HER2-advancedbreastcancer3-5
Objective
• To evaluate the cost-effectiveness of ribociclib plus letrozole versus palbociclib
plus letrozole or versus letrozole monotherapy in the first-line treatment of post-
menopausal women with HR+/HER2- advanced or metastatic breast cancer
from a United States (US) private third-party payer perspective
Methods
Model Overview
• A partitioned survival model was developed in Microsoft Excel® 2010 with a
three-state structure comprising progression free (PF; either with objective
response or with stable disease), progressed disease (PD), and death (Figure 1)
Figure 1. Health State Structure of the Economic Model
Progression free
(response/stable
disease)
Progressed
disease
Death
• The analysis was performed using two primary sources for modelling
progression-free survival (PFS; MONALEESA-25
) and overall survival (OS;
PALOMA-13
)
• Costs and benefits were calculated over a 40-year lifetime horizon with a 1-month
cycle length and half-cycle correction
• The model incorporated subsequent (second- and third-line) therapies for
patients who progressed while on treatment; the subsequent use of a CDK4/6
inhibitor was considered clinically inappropriate
Clinical Inputs
• State occupancies over time were estimated from PFS and OS curves
–– For letrozole monotherapy, using a Weibull parametric model, PFS was
estimated from the control arm of MONALEESA-2 (PFS and objective
response)5
and OS from the control arm of PALOMA-1 (OS)3
–– For ribociclib plus letrozole, using the same model, PFS was estimated from
the active arm of MONALEESA-2 (PFS and objective response)5
and OS
from the active arm of PALOMA-1 (OS)3
–– For palbociclib plus letrozole, survival was modelled using objective
response, PFS, and OS for letrozole adjusted for the relative efficacy of
palbociclib plus letrozole versus letrozole from a meta-analysis of PALOMA-1
and PALOMA-26
• Objectiveresponsetotherapywasassumedtoaccruelinearlyoverthefirst12months
(inlinewithMONALEESA-2),5
afterwhichitwasassumedtodeclinewithPFS
• Treatment duration for letrozole was modelled on the time spent in the PF health
state. Treatment duration with a CDK4/6 inhibitor was modelled independently
of PFS, using data from MONALEESA-25
. Discontinuation for palbociclib was
modelled from the ribociclib data adjusted for any differences in PFS between
CDK 4/6 inhibitors (hazard ratio [HR]=1.010; 95% CI: 0.730-1.390)
• The comparative efficacy of CDK 4/6 inhibitors was obtained from a Bayesian
network meta-analysis7
Cost and Utility Data
Cost Data
• All costs were in 2016 US dollars inflated using the Consumer Price Index (CPI)8
• Only costs relating to direct reimbursable medical care were considered; these
included drug acquisition, administration, and monitoring, disease management
(health state costs), subsequent treatments, and adverse events
• DrugacquisitioncostsweresourcedfromMedi-SpanPriceRx®9
usingthelowest
wholesaleacquisitioncost(WAC)ofeachmedicationandallowedforpatientco-
payments(ribociclibplusletrozoleorpalbociclibplusletrozole,$567;letrozole,$11);
thetreatmentacquisitioncostofribociclibwasprovidedbyNovartis(Table1)
• Monthly treatment administration costs were taken from the 2016 Physician’s Fee
Schedule using Medicare facility prices.10
No administration costs were applied to
oral formulations
• Drug-specific monitoring costs were applied to ribociclib and palbociclib at
treatment initiation and at fixed intervals up to a maximum of 6 or 12 months,
respectively, as directed by the product labels (Table 1)11,12
• Costs of subsequent (second- or third-line) treatment were applied as a one-off
cost at the start of the model evaluation. Market share and treatment data were
sourced from Novartis (data on file), and the lowest WAC formulation on the
market was used9
. Eribulin was used as a proxy representing all chemotherapies
because it was the highest cost first-line chemotherapy
• The model included serious adverse events (AEs) (Common Terminology
Criteria for Adverse Events Grade ≥3) reported more frequently with ribociclib5
or palbociclib3
versus placebo (anemia, diarrhea, fatigue, infection, nausea,
febrile neutropenia, pulmonary embolism, and vomiting) and that (from previous
HTA submissions and consultations with modelling experts) were deemed
relevant and related to treatment, were likely to result in hospitalization, or had a
meaningful impact on patient well-being
• The probability of patients experiencing a Grade ≥3 AE was obtained from clinical
studies (Table 1).3-5
The cost of each AE was assumed to reflect an average
hospitalization related to that event8,13,14
and was applied as a one-off cost at the
beginning of the model
Utility Data
• Life-years (LYs) were calculated from survival projections whereas quality-
adjusted life-years (QALYs) were calculated from time spent in each state
combined with health state utility (HSU) values
• Utility values were obtained from the literature and relevant clinical trials (Novartis,
data on file)15-17
Table 1. Model Inputs
Rib + Let
Let
monotherapy
Pal + Let
Drugs and disease management
Drug acquisition costs
($)
600 mg: 10,950
400 mg: 8,760
200 mg: 4,380
0a
10,963
Drugmonitoringcosts($)
Initial: 138
Follow-up: 22
0
Initial: 42
Follow-up: 11
Disease management
costs ($)
PF: 687
PD: 6,200
PF: 687
PD: 6,200
PF: 687
PD: 6,200
Adverse event (≥Grade 3)
Incidence (%) Unit cost ($)
Diarrhea 1.2 0.9 1.7 7,377
Fatigue 2.4 0.9 2.3 6,908
Infection 4.2 2.4 4.4 10,128
Nausea 2.4 0.6 0.6 6,182
Febrile neutropenia 1.2 0.0 0.4 21,156
Pulmonary embolism 0 0.3 5.0 10,036
Vomiting 3.6 0.9 0.4 5,246
Anemia 1.2 1.2 5.5 6,777
Utility inputsb
Complete/partial response 0.837 (0.007)
Stable disease 0.830 (0.006)
Progressed disease 0.443 (0.044)
a
WAC price of $8; however, with a co-payment of $11, the acquisition costs is reduced to $0.
b
Mean (standard error); Rib, Ribociclib; Let, Letrozole; Pal, Palbociclib
Analyses
• The outputs of the analysis included total and incremental costs and QALYs
gained with ribociclib plus letrozole versus palbociclib plus letrozole and versus
letrozole monotherapy)
• Costs and outcomes were discounted at 3.0% per annum18
• A one-way deterministic sensitivity analysis (DSA) was performed by varying
key parameters: discount rate (0%–6% variation), treatment acquisition costs
(±10%) for ribociclib plus letrozole and the selected comparator, health state
(PF, PD) costs (±10%), AE incidence rates (±10%), and utilities for PF and PD
health states (±10%)
• Probabilistic uncertainty was assessed through a Monte Carlo probabilistic
sensitivity analysis (PSA; n=1000 iterations) of clinical data (survival distributions
for PFS and OS and time to treatment distribution), cost data (drug acquisition
and monitoring costs, disease management costs, and AE costs), and utility data
(utility weights assigned to PF and PD states, and disutility of AEs)
Results
Base Case
Deterministic Base Case Results
• Treatment with ribociclib plus letrozole cost of $432,095 versus $475,132 for
palbociclib plus letrozole and $287,180 for letrozole monotherapy (Table 2)
• The total QALYs for ribociclib plus letrozole were 3.07 (PFS=2.17; PD=0.90)
versus 2.99 (PF=1.99; PD=1.00) for palbociclib plus letrozole and 2.38 (PF=1.26;
PD=1.12) for letrozole monotherapy (Table 2)
Table 2. Total and Incremental Costs and QALYs
Treatment Incremental
Rib + Let Let Pal + Let
Rib + Let
vs. Let
Rib + Let
vs. Pal +
Let
Drug costs ($)
CDK-4/6 inhibitor 228,605 0 256,393 228,605 -27,788
Letrozole 0 0 0 0 0
Monitoring 196 0 116 196 80
Health-state costs ($)
PF 21,790 12,834 19,931 8,956 1,859
Responder 9,672 3,830 7,104 5,842 2,567
Stable disease 12,118 9,003 12,826 3,115 -708
PD 150,772 187,606 167,575 -36,834 16,803
Second-line+ 27,285 84,027 27,285 -56,742 0
AEs 1,349 573 1,735 776 -386
End of life 2,098 2,140 2,098 -42 0
Total ($) 203,294 287,180 218,623 -83,886 -15,330
Total cost ($) 432,095 287,180 475,132 144,915 -43,037
Total QALY 3.07 2.38 2.99 0.689 0.086
PF 2.17 1.26 1.99
PD 0.90 1.12 1.00
ICER 210,369 Dominated
byRib+Let
AE, Adverse event; CDK 4/6, Cyclin-dependent kinase 4 and 6; ICER, Incremental cost-effectiveness
ratio; Let, Letrozole; Pal, Palbociclib; PD, Progressed disease; PF, Progression free; Rib, Ribociclib;
QALY, Quality-adjusted life year
• Ribociclib plus letrozole provided a cost reduction of $43,037 and a gain of 0.086
QALYs compared with palbociclib plus letrozole and was therefore dominant
versus palbociclib plus letrozole
• Compared with letrozole monotherapy, ribociclib plus letrozole was associated
with an incremental cost of $144,915 and an incremental QALY gain of 0.689,
giving an ICER of $210,369 per QALY
Sensitivity Analyses
• From the DSA, the key model drivers were the PFS HR for palbociclib plus
letrozole versus letrozole, the OS HRs for ribociclib plus letrozole, PD health state
costs, the utility of objective response, and the cost discount rate (Figure 2)
Figure 2. Key Model Drivers from Deterministic Sensitivity Analysis
190,000 195,000 200,000 205,000 210,000 215,000 220,000 225,000 230,000
Inc. rate forneutropenia
Inc. rate for infection
Utility (PD)
Health state costs (PF)
Health state costs (PD)
Utility (stable disease)
HR OS (vs. letrozole)
Discountrate -costs
Utility (response)
Discountrate -benefits
ICER ($)
21,698 31,698 41,698 51,698 61,698 71,698
Inc. rate for infection
Health state costs (PF)
Utility (stable disease)
Discount rate - benefits
Discount rate - costs
Utility (response)
Health state costs (PD)
HR PFS of palbociclib
(vs. letrozole)
HR OS (vs. letrozole)
HR OS of palbociclib
(vs. letrozole)
Netmonetarybenefit($)
HR, Hazard ratio; Inc., Including; OS: Overall survival; PD, Progressed disease; PF, Progression free;
PFS: Progression-free survival; vs., Versus
• From the PSA, ribociclib plus letrozole remained dominant versus palbociclib plus
letrozole, with a mean incremental cost reduction of $45,511 and a mean increase
of 0.040 QALYs (Figure 3)
Figure 3. Cost-effectiveness Acceptability Curve for Ribociclib Plus
Letrozole Versus Palbociclib Plus Letrozole
0
10
20
30
40
50
60
70
80
90
100
0 50000 100000 150000 200000
Percentage
Threshold($'s)
Ribociclib + Letrozole Palbociclib + Letrozole
• In comparison with letrozole, ribociclib plus letrozole resulted in a mean
incremental cost of $143,834 and a mean incremental QALY of 0.757 equating
to an ICER of $190,001 per QALY gained. The probability that ribociclib plus
letrozole was cost-effective versus letrozole at thresholds of $50,000, $100,000
and $200,000 per QALY gained was 1.60, 6.30 and 50.50%, respectively
Conclusions
• The results from this analysis suggest that, in the US, ribociclib plus letrozole
is a cost-effective alternative to palbociclib plus letrozole for the first-line
treatment of post-menopausal women with HR+/HER2- advanced or
metastatic breast cancer
• Furthermore, at willingness-to-pay thresholds above $198,000 per QALY,
treatment with ribociclib plus letrozole is also cost-effective versus letrozole
monotherapy
• The conclusions of this analysis are broadly consistent with other published
analyses of the cost-effectiveness of CDK4/6 inhibitors in HR+/HER2- breast
cancer19,20
References
1. Cardoso, F. Ann Oncol. 2017; 28:16-33.
2. Gradishar, W.J. J Natl Compr Canc Netw. 2016;
14:324-54.
3. Finn, R.S. Lancet Oncol. 2015; 16:25-35.
4. Finn, R.S. J Clin Oncol. 2016; 34:507.
5. Hortobagyi, G.N. N Engl J Med. 2016; 375:1738-48.
6. Analysis Group. NMA of Treatments in HR+ HER2-
Advanced Breast Bancer in Postmenopausal
Women. 2016.
7. Analysis Group. Systematic Literature Review
and Network Meta-Analysis of Clinical Trials in the
First-line Setting for Advanced HR+ HER2- Breast
Cancer. 2017.
8. U.S. Bureau of Labor Statistics. 2016.
9. Medispan Price Rx. [cited 2017; Available from:
https://pricerx.medispan.com/IngredientName.
aspx.
10. Medicare. Medicare Facility Prices 2016.
11. Novartis. KISQALI Prescribing Information. 2017.
12. Pfizer Inc. IBRANCE Prescribing Information. 2017.
13. Healthcare Cost and Utilization Project (National
Inpatient Sample. 2013.
14. Michels, S.L. Pharmacoeconomics. 2012; 30:809-
23.
15. Devlin, N.J. Health Econ, 2017; doi 10.1002/hec.3584.
16. Lloyd, A. Br J Cancer. 2006; 95:683-90.
17. Hudgens, S. Value Health. 2014; 17:A557.
18. Gold, M.R. Cost-Effectiveness in Health and
Medicine. 1996.
19. Bhattacharya, K. Value Health. 2016; 19:A150.
20. Matter-Walstra, K. Breast Cancer Res Treat. 2017;
163:635.
Presented at the ISPOR 20th Annual European Congress, 4-8 November,
Glasgow, UK.
This study was funded by Novartis.
PCN133
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