Cost-effectiveness analysis of ribociclib versus palbociclib in the first-line treatment of HR+/HER2− advanced or metastatic breast cancer in Spain

Figures & data

Table 1 Duration and distribution of subsequent treatments considered

Subsequent treatments	Second line		Third line
	Distribution of treatments (%)	Duration of treatments (months)	Distribution of treatments (%)	Duration of treatments (months)
Endocrine therapy	31.35	4.9	11.31	4.9
Targeted therapy	16.15	4.9	5.57	4.9
Chemotherapy	47.50	3.7	50.63	3.1
No active treatment	5.00	–	32.50	–
Total	100	–	100	–

Figure 1 State diagram of the three health states considered.

Abbreviations: PD, progressed disease; PF, progression-free.

Table 2 Efficacy, safety, and quality of life parameters considered

Efficacy parameters
Progression-free survival				HR (vs LZE)		95% CI
Base case
Ribociclib+LZE (MAIC; MONALEESA-2; cutoff, January 2017^)29				0.524		0.407–0.676
Palbociclib+LZE (PALOMA-2; cutoff, May 2017)^Citation24				0.563		0.461–0.687
Sensitivity analysis
Ribociclib+LZE (unmatched HR; MONALEESA-2; cutoff, January 2017)^Citation23				0.568		0.457–0.704
Overall survival				HR (vs LZE)		95% CI
Base case
Ribociclib+LZE (MAIC; MONALEESA-2; cutoff, January 2017^)29				0.682		0.456–1.021
Palbociclib+LZE (PALOMA-1; cutoff, December 2016)^Citation25				0.897		0.623–1.294
Sensitivity analysis
Ribociclib+LZE (unmatched HR; MONALEESA-2; cutoff, January 2017)^Citation23				0.746		0.517–1.078
Response rates^Citation29				OR (vs LZE)		95% CI
Ribociclib+LZE				1.420		1.200–1.600
Palbociclib+LZE				1.230		1.030–1.440
Safety parametersa
First-line treatment	Diarrhea (%)	Infection (%)	Nausea (%)	Febrile neutropenia (%)	Pulmonary embolism (%)		Vomiting (%)
Ribociclib+LZE	1.20^Citation26	4.19^Citation26	2.40^Citation26	1.20^Citation26	0.90^Citation26		3.59^Citation26
Palbociclib+LZE	1.35^Citation27	5.16^Citation18	0.23^Citation27	1.80^Citation27	1.35^Citation27		0.45^Citation27
Quality of life
Health state				Mean		Standard error
Progression-free state (PR/CR)				0.8345		0.0068
Progression-free state (SD)				0.8296		0.0063
Progressed disease				0.5050		0.0505

Note:

a Only severe events (grade 3 or above) that met the following criteria were considered: AEs related to treatment and likely to result in hospitalization or expected to have a meaningful impact on patient’s well-being.

Abbreviations: AE, adverse event; CI, confidence interval; CR, complete response; HR, hazard ratio; LZE, letrozole; MAIC, matching-adjusted indirect comparison; OR, odds ratio; PR, partial response; SD, stable disease.

Table 3 Economic parameters considered

Drug costs
Pharmaceutical form	EFP per package (€; 2017)a		Posologyc							Monthly cost (€; 2017)b
Ribociclib 200 mg, 63 tablets	4,444.44		Recommended starting dose: 600 mg/day for 21 days+7 days without treatment (3/1 scheme)							4,831.34
Ribociclib 200 mg, 42 tablets	2,962.96		After first dose reduction: 400 mg/day for 21 days+7 days without treatment (3/1 scheme)							3,220.90
Ribociclib 200 mg, 21 tablets	1,481.48		After second dose reduction: 200 mg/day for 21 days+7 days without treatment (3/1 scheme)							1,610.45
Palbociclib 125 mg, 21 capsules	3,600.00		Recommended starting dose: 125 mg/day for 21 days+7 days without treatment (3/1 scheme)							3,913.39
Palbociclib 100 mg, 21 capsules	3,600.00		After first dose reduction: 100 mg/day for 21 days+7 days without treatment (3/1 scheme)							3,913.39
Palbociclib 75 mg, 21 capsules	3,600.00		After second dose reduction: 75 mg/day for 21 days+7 days without treatment (3/1 scheme)							3,913.39
Letrozole GE 2.5 mg, 30 tablets	59.00		2.5 mg/day							59.86
Administration costs
Type of administration	Unit cost (€; 2017)d		Frequencyc
Parenteral administration	211.67		Per day of active treatment with parenteral chemotherapy, endocrine therapy, or targeted therapy
Costs attributed to health state
Resource use	Unit cost (€; 2017)d		Patients (%)		Frequency (PF state)				Frequency (PD state)
General medicine visits	22.59		50.00		1 visit/2 months				1 visit/2 months
Outpatient visits (oncology)	84.32		100.00		1 visit/month				1 visit/month
Nursing visits	26.73		25.00		1 visit/2 months				1 visit/month
Computed tomography	175.51		20.00		1 visit/3 months				1 visit/3.5 months
Bone scintigraphy	173.73		8.00		1 visit/6 months				1 visit/6.5 months
Hospitalizations	544.77		12.50		–				8 days
Monitoring costs
Resource use	Unit cost (€; 2017)d		Frequencyc Ribociclib+letrozole				Frequencyc Palbociclib+letrozole
Liver function tests	22.67		Baseline Every 2 weeks, cycles 1 and 2 Once, cycles 3, 4, 5, and 6				–
Complete blood count	4.16		Baseline Every 2 weeks, cycles 1 and 2 Once, cycles 3, 4, 5, and 6				Baseline Every 2 weeks, cycles 1 and 2 Once, remaining cycles. For patients without grade >2 neutropenia during first six cycles, monitoring every 3 months
Electrocardiogram	38.83		Baseline Every 2 weeks, cycle 1 Once, cycle 2				–
Adverse event costs
Adverse event	Diarrhea	Infection		Nausea		Febrile neutropenia		Pulmonary embolism		Vomiting
Unit cost (€; 2017)	738.10e	4,791.79f		589.65e		2,624.35e		4,543.68d		589.65e
End-of-life care
	Unit cost (€; 2017)		Patients (%)		Frequency
Palliative care unit	332.30f		40.00		2–3 weeks until death (mean, 15.19 days)
Home care, doctor’s visits	65.38d		12.50		2–3 visits/week until death (mean, 8.74 visits)
Home care, nurse visits	45.26d		12.50		2–3 visits/week until death (mean, 8.74 visits)
Acute hospital unit	540.81g		35.00		1–2 weeks until death (mean, 9.01 days)

Notes:

a Reported EFP from the Spanish drug prices database.¹⁶

b Estimated from the described posology. A mean body surface area of 1.7 m² was considered.

c Technical specifications of the respective pharmaceutical forms.¹⁵

d Using average rates from the Spanish health costs database.³⁷

e Unit cost updated to 2017 Euros from the study by Alba et al.¹³

f Unit cost updated to 2017 Euros from the study by Isla et al.³⁶

g Unit cost updated to 2017 Euros and estimated from NHS minimum basic data set.³⁸

Abbreviations: EFP, ex-factory price; GE, generic equivalent; NHS, national health system; PD, progressed disease; PF, progression-free.

Table 4 Base case and univariate sensitivity analysis

Base case results
	Ribociclib + LZE	Palbociclib + LZE	Ribociclib + LZE vs palbociclib + LZE
Cost results
First-line line treatment (€)	90,923.49	91,895.72	−972.23
PF state (€)	4,155.48	3,902.99	252.49
PD state (€)	1,798.47	1,474.23	324.24
Subsequent treatments (€)	4,925.20	3,975.62	949.58
AEs (€)	317.24	369.93	−52.69
End-of-life (€)	3,458.24	3,519.78	−61.55
Total costs (€)	105,578.12	105,138.26	439.86
Health outcomes
LYG	4.474	4.037	0.437
QALY	3.313	3.028	0.285
Incremental ratios
ICER(€/LYG)	-	-	1,007.69
ICUR (€/QALY gained)	-	-	1,543.62

Univariate analysis results
Scenario	Δ Cost (€)	Δ LY	Δ QALY	ICER (€/LYG)	ICUR (€/QALY)
Alternative parametric distributions
PFS, Weibull distribution	988.86	0.470	0.289	2,106.07	3,421.83
PFS, gamma distribution	870.70	0.460	0.288	1,892.13	3,022.53
PFS, log-normal distribution	103.74	0.424	0.302	244.65	343.39
OS, Gompertz distribution	−468.08	0.260	0.196	Ribociclib is dominant	Ribociclib is dominant
OS, gamma distribution	1,945.13	0.738	0.437	2,634.84	4,447.75
OS, log-logistic distribution	2,532.82	0.873	0.505	2,901.96	5,012.69
Unadjusted HR (MONALEESA-2; cutoff, January 2017)
Ribociclib + LZE	65.36	0.258	0.142	252.84	460.18
PFS HR: 0.568 (0.457 - 0.704)
OS HR: 0.746 (0.517 - 1.078)
Patient characteristics
Patients’ age (+20%)	439.86	0.437	0.285	1,007.69	1,543.62
Patients’ age (−20%)	439.86	0.437	0.285	1,007.69	1,543.62
Quality of life questionnaires
Utility PF state (CR/PR) (+20%)	439.86	0.437	0.315	1,007.69	1,396.30
Utility PF state (CR/PR) (−20%)	439.86	0.437	0.255	1,007.69	1,725.69
Utility PF state (SD) (+20%)	439.86	0.437	0.288	1,007.69	1,529.45
Utility PF state (SD) (−20%)	439.86	0.437	0.282	1,007.69	1,558.06
Utility PD state (+20%)	439.86	0.437	0.309	1,007.69	1,422.39
Utility PD state (−20%)	439.86	0.437	0.261	1,007.69	1,687.44
Utility PF and PD states (MONALEESA-2)	439.86	0.437	0.352	1,007.69	1,249.29
Economic parameters
Disregarding palbociclib wastage	722.72	0.437	0.285	1,655.70	2,536.26
Price parity between CDK4/6 inhibitors	−16,321.32	0.437	0.285	Ribociclib is dominant	Ribociclib is dominant
Cost PF state (+20%)	553.16	0.437	0.285	1,267.25	1,941.21
Cost PF state (−20%)	326.57	0.437	0.285	748.14	1,146.03
Cost PD state (+20%)	631.83	0.437	0.285	1,447.48	2,217.30
Cost PD state (−20%)	247.89	0.437	0.285	567.91	869.94
Cost subsequent treatments (+20%)	629.78	0.437	0.285	1,442.78	2,210.10
Cost subsequent treatments (−20%)	249.95	0.437	0.285	572.61	877.14
Cost ribociclib monitoring (+20%)	517.59	0.437	0.285	1,185.77	1,816.40
Cost ribociclib monitoring (−20%)	362.13	0.437	0.285	829.62	1,270.84
Cost palbociclib monitoring (+20%)	421.64	0.437	0.285	965.95	1,479.68
Cost palbociclib monitoring (−20%)	458.08	0.437	0.285	1,049.44	1,607.56
Scenario	Δ Cost (€)	Δ LY	Δ QALY	ICER (€/LYG)	ICUR (€/QALY)
Cost AEs (+20%)	429.32	0.437	0.285	983.55	1,506.64
Cost AEs (−20%)	450.40	0.437	0.285	1,031.83	1,580.60
Structural parameters
Discount rate (0%)	467.44	0.502	0.329	931.00	1,421.02
Discount rate (5%)	432.00	0.400	0.260	1,080.89	1,658.60
Time horizon: 5 years	−208.42	0.235	0.151	Ribociclib is dominant	Ribociclib is dominant
Time horizon: 10 years	395.04	0.411	0.264	960.34	1,496.27
Time horizon: 20 years	459.07	0.444	0.291	1,034.70	1,577.98
Time horizon: 30 years	465.91	0.446	0.293	1,044.63	1,590.89

Abbreviations: AEs, adverse events; CDK4/6, cyclin-dependent kinase 4 and 6; CR, complete response; HR, hazard ratio; ICER, incremental cost-effectiveness ratio; ICUR, incremental cost-utility ratio; LY, life years; LYG, life-years gained; LZE, letrozole; OS, overall survival; PD, progressed disease; PF, progression-free; PFS, progression-free survival;PR, partial response; QALY, quality-adjusted life years; SD, stable disease; Δ, differential.

Figure 2 Ad hoc sensitivity analysis results.

Abbreviations: CDK4/6, cyclin-dependent kinase 4 and 6; EFP, ex-factory price.

Figure 3 Probabilistic sensitivity analysis results (without price parity between the two CDK4/6 inhibitors), represented through an incremental cost-utility plane (A) and a cost-effectiveness acceptability curve (B)

Abbreviations: CDK4/6, cyclin-dependent kinase 4 and 6; LZE, letrozole; QALY, quality-adjusted life year.

Figure 4 Probabilistic sensitivity analysis results (with price parity between the two CDK4/6 inhibitors), represented through an incremental cost-utility plane (A) and a cost-effectiveness acceptability curve (B)

Abbreviations: CDK4/6, cyclin-dependent kinase 4 and 6; LZE, letrozole; QALY, quality-adjusted life year.

Figure S1 Fit of the parametric distributions to the latest KM plots for PFS in MONALEESA-2 of letrozole monotherapy group (reference arm) with model extrapolation over a 20-year time horizon (240 months).

Abbreviations: KM, Kaplan–Meier; PFS, progression-free survival.

Figure S2 Fit of the parametric distributions to the latest KM plots for OS in MONALEESA-2 of letrozole monotherapy group (reference arm) with model extrapolation over a 20-year time horizon (240 months).

Abbreviations: KM, Kaplan–Meier; OS, overall survival.

Table S1 Details on goodness of fit with the KM curves and survival rates of letrozole monotherapy from MONALEESA-2 study (reference arm)

Parameterization of the PFS KM curves
Distribution	Goodness of fit		PFS rate (%)
	AIC	BIC	5 years	10 years
Exponential	1,693.30	1,697.11	6.79	0.46
Weibull	1,689.87	1,697.49	3.93	0.07
Gamma	1,689.11	1,696.73	4.53	0.15
Gompertz	1,692.06	1,699.68	1.97	0.00
Log-normal	1,688.60	1,696.22	12.16	4.07
Log-logistic	1,692.66	1,700.29	12.19	4.90
Parameterization of the OS KM curves
Distribution	Goodness of fit		OS rate (%)
	AIC	BIC	5 years	20 years
Exponential	763.63	767.44	60	13.0
Weibull	733.69	741.31	26	0.0
Gamma	735.99	743.61	37	0.1
Gompertz	729.74	737.36	4	0.0
Log-normal	741.89	749.51	49	7.8
Log-logistic	735.52	743.14	38	2.8

Abbreviations: AIC, Akaike information criteria; BIC, Bayesian information criteria; KM, Kaplan–Meier; OS, overall survival; PFS, progression-free survival.

Table S2 Detail of the economic parameters considered in the probabilistic sensitivity analysis\

Name	Base case value (€; 2017)	Lower CI (€; 2017)	Higher CI (€; 2017)	Standard error	Distribution
Health care costs
General medicine visits	22.59	10.45	43.35	32.24	Gamma
Outpatient visits (oncology)	84.32	25.25	149.31	121.58	Gamma
Nursing visits	26.73	12.37	49.27	36.16	Gamma
Hospitalizations	544.77	435.82	653.72	213.55	Gamma
Liver function tests	22.67	4.95	63.19	57.08	Gamma
Complete blood count	4.16	2.90	5.30	2.35	Gamma
Electrocardiogram	38.83	8.04	183.90	172.34	Gamma
Bone scintigraphy	173.73	138.98	208.48	68.10	Gamma
Computed tomography	175.51	36.67	743.49	692.68	Gamma
End-of-life cost	3,966.31	3,569.68	4,362.94	396.63	Log-normal
Subsequent treatment costs	6,746.43	6,071.79	7,421.08	674.64	Log-normal
Adverse events cost
Diarrhea	738.10	664.29	811.91	73.81	Gamma
Infection	4,791.79	4,312.61	5,270.97	479.18	Gamma
Nausea	589.65	530.68	648.61	58.96	Gamma
Febrile neutropenia	2,624.35	2,361.92	2,886.79	262.44	Gamma
Pulmonary embolism	4,543.68	4,089.31	4,998.05	454.37	Gamma
Vomiting	589.65	530.68	648.61	58.96	Gamma

Abbreviation: CI, confidence interval.

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