Evaluating the cost-effectiveness of afatinib after platinum-based therapy for the treatment of squamous non-small-cell lung cancer in France

Figures & data

Figure 1 Overview of model structure depicting transition from pre-progression to post-progression and death health states.

Abbreviations: PFS, progression-free survival; OS, overall survival; S(t), survival function (probability of survival beyond time t); t, time.

Table 1 Proportion of patients who experienced grade 3 and 4 AE for each treatment arm

Grade 3/4 AE	Proportion of patients who experienced afatinib AE (95% CI)	Proportion of patients who experienced erlotinib AE (95% CI)
Diarrhea grade 3	9.9% (7.1; 13.0)	2.3% (1.1; 4.0)
Diarrhea grade 4	0.5% (0.1; 1.4)	0.3% (0.0; 1.0)
Rash/acne	5.9% (3.8; 8.4)	10.4% (7.6; 13.6)
Stomatitis grade 3	4.1% (2.4; 6.3)	0.0%
Fatigue grade 3	1.5% (0.5; 2.9)	1.8% (0.7; 3.3)
Nausea grade 3	1.0% (0.3; 2.2)	0.8% (0.2; 1.9)

Notes: The data were taken directly from the Clinical Study Report of the LUX-Lung 8 trial, which was made available by the study sponsor to HEVA-HEOR (unpublished data, 2015). These data were reported for additional outcomes but in less detail by Soria et al.¹⁶

Abbreviations: AE, adverse event; CI, confidence interval.

Table 2 Clinical and cost-effectiveness outcomes

Health outcome	Afatinib	Erlotinib	Difference
Progression-free survival time (months)	5.05	3.85	1.2
Post-progression survival time (months)	6.84	6.12	0.72
Life expectancy (years)	0.94	0.78	0.16
Quality-adjusted life expectancy (QALY)	0.567	0.473	0.094
Total costs (EUR)	12,364	9,510	2,854
ICER based on life expectancy	EUR18,568 per LY gained
ICER based on quality-adjusted life expectancy	EUR30,277 per QALY gained

Abbreviations: ICER, incremental cost-effectiveness ratio; LY, life year; QALY, quality-adjusted life year.

Table 3 Breakdown of costs

Health outcome	Afatinib		Erlotinib
	Cost (EUR)	Proportion of total costs (%)	Cost (EUR)	Proportion of total costs (%)
Drug acquisition cost in pre-progression	9,158	74	7,007	74
Monitoring cost in pre-progression (including transportation costs)	1,143	9	846	9
Monitoring cost in post-progression (including transportation costs)	1,715	14	1,535	16
Adverse events costs	348	3	122	1
Total costs	12,364	100	9,510	100

Note: Total costs for drug acquisition and administration and monitoring are shown in bold.

Figure 2 Tornado diagram of DSA results.

Abbreviations: DSA, deterministic sensitivity analysis; QALY, quality-adjusted life year.

Figure 3 PSA outcomes, cost-effectiveness plane.

Note: Willingness-to-pay (cost per QALY) for afatinib.
Abbreviations: PSA, probabilistic sensitivity analysis; QALY, quality-adjusted life year.

Figure 4 PSA outcomes, cost-effectiveness acceptability curve.

Note: Willingness-to-pay (cost per QALY) for afatinib versus erlotinib.
Abbreviations: PSA, probabilistic sensitivity analysis; QALY, quality-adjusted life year.

Table S1 Drug acquisition costs

Product	Dosage	Price per package (including all taxes) (EUR)	Dispensing fee (EUR)	Monthly treatment cost (EUR)
Compared treatments
Afatinib (GIOTRIF^®; Boehringer Ingelheim, Ingelheim, Germany) 40 mg; 28 tablets CIP: 3400927565878	40 mg/day orally	1,870.48	1.02/pack	2,033.04
Erlotinib (TARCEVA^®; Roche, Basel, Switzerland) 150 mg; 30 tablets CIP: 3400936923522	150 mg/day orally	2,071.92	1.02/pack	2.072.94
Post-progression treatments for additional sensitivity analyses
Nivolumab (OPDIVO^®; Bristo-Myers Squibb, New York, NY, USA) 10 mg/mL; vial of 10 mL*	3 mg/kg every 2 weeks intravenously until death	1,344.33	N/A	8,757.66
Docetaxel	75 mg/m^2 every 3 weeks intravenously	Cost included in DRG cost	Cost included in DRG cost	Cost included in DRG cost
Paclitaxel	200 mg/m^2 every 3 weeks intravenously	Cost included in DRG cost	Cost included in DRG cost	Cost included in DRG cost
Best supportive care	N/A	N/A	N/A	N/A

Note:

* UK cost estimated in euros using an exchange rate of 1.19474 (July 2016).

Abbreviations: CIP, Club Inter Pharmaceutique (ID code for pharmaceuticals in France); DRG, diagnosis-related group; N/A, not applicable.

Table S2 Unit costs of resources

Resource	Data source	Unit cost (EUR, 2016)
Medical follow-up (with excess fees)		45.88
Specialist visit (oncologist or lung specialist)	French medical insurance and physician fees (updated to 2016 using a CPI).^Citation1,Citation2	45.88
Blood tests		52.11
Sedimentation rate	TNB 1124^Citation5	1.89
C-reactive protein	TNB 1804^Citation5	2.70
Blood count (with platelets)	TNB 1104^Citation5	7.83
Creatinine with GFR estimation	TNB 0592^Citation5	1.89
Serum electrolytes	TNB 1610^Citation5	7.29
Liver function tests		9.45
Transaminases (ALT, AST)	TNB 0522^Citation5	2.97
Alkaline phosphatase	TNB 0514^Citation5	1.89
GammaGT	TNB 0519^Citation5	1.89
Total bilirubin	TNB 1610^Citation5	2.70
Hemostasis screening tests		21.06
Quick’s time	TNB 0125^Citation5	5.40
Activated cephalin time	TNB 1127^Citation5	5.40
Fibrinogen concentrate	TNB 0174^Citation5	4.86
Bleeding time	TNB 0171^Citation5	5.40
Sampling act by direct venipuncture	NGAP-Titre XVI, chapter 1^Citation7	4.73
Security package for management of a blood sample	TNB 9105^Citation5	1.35
Package of pre-analytical management of a blood sample	TNB 9005^Citation5	4.05
Imaging tests		70.49
Chest radiography	CCAM LJQK002^Citation6	45.22
CT scan with injection	CCAM ZBQH001^Citation6	25.27

Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase; CCAM, Classification Commune des Actes Médicaux [general classification of medical procedures]; CPI, consumer price index; CT, computed tomography; GFR, glomerular filtration rate; NGAP, nomenclature générale des actes professionnels [general nomenclature for professional procedures]; TNB, Table Nationale de codage de biologie [national table for diagnostic codes].

Table S3 Parameters included in the DSA

Parameters	Base case value	Low value	High value	Justification of tested values
Discounting (%)	4	0	6	HAS recommendations
Safety (reported probability of event)
Afatinib – diarrhea grade 3	0.099	0.071	0.130	95% CI
Afatinib – diarrhea grade 4	0.005	0.001	0.014	95% CI
Afatinib – rash/acne	0.059	0.038	0.084	95% CI
Afatinib – stomatitis grade 3	0.041	0.024	0.063	95% CI
Afatinib – fatigue grade 3	0.015	0.005	0.029	95% CI
Afatinib – nausea grade 3	0.010	0.003	0.022	95% CI
Erlotinib – diarrhea grade 3	0.023	0.011	0.040	95% CI
Erlotinib – diarrhea grade 4	0.003	0.0001	0.010	95% CI
Erlotinib – rash/acne	0.104	0.076	0.136	95% CI
Erlotinib – fatigue grade 3	0.018	0.007	0.033	95% CI
Erlotinib – nausea grade 3	0.008	0.002	0.019	95% CI
Utilities and disutilities
Progression-free survival utility	0.65	0.63	0.75	Low value: low value of 95% CI of two data sources (LUX-Lung 8 trial^Citation3 and Nafees et al^Citation4) High value: high value of 95% CI of LUX-Lung 8 trial^Citation3 data source
Post-progression survival utility	0.58	0.47	0.61	Low value: Nafees et al^Citation4 High value: high value of 95% CI of LUX-Lung 8 trial^Citation3 data source
Diarrhea grade 3 disutility	0.050	0.019	0.096	95% CI
Diarrhea grade 4 disutility	0.050	0.019	0.096	95% CI
Rash/acne disutility	0.030	0.004	0.080	95% CI
Stomatitis grade 3 disutility	0.131	0.112	0.151	95% CI
Fatigue grade 3 disutility	0.070	0.036	0.114	95% CI
Nausea grade 3 disutility	0.050	0.019	0.096	95% CI
Costs (EUR)
Mean transportation cost per round-trip	77.06	64.76	89.41	Low value: estimated VSL cost High value: estimated taxi cost
Unit cost for diarrhea grade 3	2,801.76	1,813.15	4,002.05	95% CI
Unit cost for diarrhea grade 4	2,801.76	1,813.15	4,002.05	95% CI
Unit cost for rash/acne	225.67	146.04	322.35	95% CI
Unit cost for stomatitis grade 3	569.44	303.80	670.56	95% CI
Unit cost for fatigue grade 3	570.57	369.24	815.01	95% CI
Unit cost for nausea grade 3	1,997.00	1,292.35	2,852.52	95% CI
Monthly monitoring costs in pre-progression and post-progression for all arms	253.63	202.90	304.36	±20%

Abbreviations: CI, confidence interval; DSA, deterministic sensitivity analysis; HAS, Haute Autorité de Santé [French National Authority for Health]; VSL, véhicule sanitaire léger [ambulance transport].

Table S4 Summarized results from the additional sensitivity analyses in comparison to the base case

Parameters	Base case	Additional sensitivity analyses	Results (EUR per QALY gained)
Time horizon	10 years	1 year	55,064
		2 years	33,947
		5 years	30,123
Post-progression treatments included	No	Yes	37,338
Progression-free survival function	Afatinib independent review – loglogistic Erlotinib independent review – loglogistic	Afatinib independent review – Weibull Erlotinib independent review – Weibull	24,842
		Afatinib independent review – lognormal Erlotinib independent review – lognormal	29,876
		Afatinib investigator choice – Weibull Erlotinib investigator choice – Weibull	25,687
		Afatinib investigator choice – loglogistic Erlotinib investigator choice – loglogistic	31,025
		Afatinib investigator choice – lognormal Erlotinib investigator choice – lognormal	29,291
Overall survival function	Afatinib: Weibull Erlotinib: Weibull	Afatinib: lognormal Erlotinib: lognormal (extreme scenario)	20,919
		Afatinib: Weibull Erlotinib: lognormal (extreme scenario)	62,546
Health state utility data source	LUX-Lung 8^Citation3	NICE Nivolumab guidance	27,315
		Nafees et al^Citation27	31,609
AE consideration method	Considering a distribution of the probability of each AE over the time spent in pre- progression	Considering that the probability of each AE is applied one time at the first cycle of the model for all patients	29,040

Abbreviations: AE, adverse event; NICE, National Institute for Health and Care Excellence; QALY, quality-adjusted life year.

Table S5 ICER for low and high values for parameters included in the DSA

Main parameters (base case: EUR30,277 per QALY gained)	Low value	High value	Low cost per QALY gained (EUR per QALY gained)	High cost per QALY gained (EUR per QALY gained)
Progression-free survival utility	0.63	0.75	30,973	27,463
Post-progression survival utility	0.47	0.61	32,440	29,759
Afatinib diarrhea grade 3 frequency	0.071	0.130	29,378	31,310
Monthly follow-up costs	EUR202.90	EUR304.36	29,266	31,288
Erlotinib diarrhea grade 3 frequency	0.011	0.040	30,675	29,733
Diarrhea grade 3 cost	EUR1,813.15	EUR4,002.05	29,832	30,722
Afatinib stomatitis grade 3 frequency	0.024	0.063	30,041	30,577
Afatinib diarrhea grade 4 frequency	0.001	0.014	30,133	30,572
Afatinib nausea grade 3 frequency	0.003	0.022	30,100	30,568
Discounting	0%	6%	30,000	30,432

Abbreviations: DSA, deterministic sensitivity analysis; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year.

SoriaJ-CFelipECoboMAfatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trialLancet Oncol201516889790726156651

 PubMed Web of Science ®Google Scholar

National Healthcare Insurance Online (AMELI)Activity of physicians by specialty and region2014 [cited Feburary 9, 2016]. Available from: https://www.ameli.fr/fileadmin/user_upload/documents/Activ-ite_des_medecins_par_departement_en_2014.xlsAccessed October 6, 2017 French

 Google Scholar

National Healthcare Insurance Online (AMELI)Salaries of health-care professionals, by specialty and region2014 [cited February 9, 2016]. Available from: https://www.ameli.fr/fileadmin/user_upload/documents/Honoraires_des_professionnels_de_sante_APE_par_region_en_2014.xlsAccessed October 6, 2017 French

 Google Scholar

National Healthcare Insurance for Employees (CNAMTS)National table for diagnostic codes2016 [cited October 5, 2016]. Available from: http://www.codage.ext.cnamts.fr/codif/nabm/index.php?p_site=AMELIAccessed October 6, 2017 French

 Google Scholar

National Healthcare Insurance Online (AMELI)General nomenclature for professional procedures (NGAP) Version dated March 11, 2015 [cited October 5, 2016]. Available from: http://www.ameli.fr/professionnels-de-sante/directeurs-d-etablissements-de-sante/codage/ngap.phpAccessed October 6, 2017 French

 Google Scholar

National Healthcare InsuranceClassification of medical procedures Version 432016 [cited January 10, 2017]. Available from: http://www.ameli.fr/accueil-de-la-ccam/telechargement/version-actuelle/index.phpAccessed October 6, 2017 French

 Google Scholar

SoriaJCFelipECoboMAfatinib versus erlotinib as secondline treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trialLancet Oncol201516889790726156651

 PubMed Web of Science ®Google Scholar

NafeesBStaffordMGavrielSBhallaSWatkinsJHealth state utilities for non small cell lung cancerHealth Qual Life Outcomes200868418939982

 PubMed Web of Science ®Google Scholar

NafeesBStaffordMGavrielSBhallaSWatkinsJHealth state utilities for non small cell lung cancerHealth Qual Life Outcomes200868418939982

 PubMed Web of Science ®Google Scholar