A cost-effectiveness analysis of first-line induction and maintenance treatment sequences in patients with advanced nonsquamous non-small-cell lung cancer in France

Figures & data

Table 1 Induction–maintenance regimens included in the model

Comparator
Induction →	Maintenance
Gemcitabine 1,000 mg/m^2 + cisplatin 75 mg/m^2 →	BSC
Docetaxel 75 mg/m^2 + cisplatin 75 mg/m^2 →	BSC
Vinorelbine 30 mg/m^2 + cisplatin 80 mg/m^2 →	BSC
Paclitaxel 225 mg/m^2 + carboplatin 400 mg/m^2 →	BSC
Pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2 →	BSC
Gemcitabine 1,250 mg/m^2 + cisplatin 80 mg/m^2 + bevacizumab 7.5 mg/kg →	Bevacizumab 7.5 mg/kg
Paclitaxel 200 mg/m^2 + carboplatin 400 mg/m^2 + bevacizumab 7.5 mg/kg →	Bevacizumab 7.5 mg/kg
Docetaxel 75 mg/m^2 + cisplatin 75 mg/m^2 →	Pemetrexed 500 mg/m^2
Vinorelbine 30 mg/m^2 + cisplatin 80 mg/m^2 →	Pemetrexed 500 mg/m^2
Paclitaxel 225 mg/m^2 + carboplatin 400 mg/m^2 →	Pemetrexed 500 mg/m^2
Gemcitabine 1,000 mg/m^2 + cisplatin 75 mg/m^2 →	Pemetrexed 500 mg/m^2
Pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2 →	Pemetrexed 500 mg/m^2

Abbreviation: BSC, best supportive care.

Table 2 Summary of key characteristics in the base-case model and sensitivity analyses conducted

Parameter
Country	France
CE model time horizon	10 years
Drug costs	French health-care payer
Cost-discount rate per annum	4%
Effect-discount rate per annum	4%
OS estimation for patients eligible for maintenance therapy	Within trial: Kaplan–Meier data (JMDB trial) Posttrial: parametric regression, Weibull distribution*
OS estimation for patients ineligible for maintenance therapy	Within trial: Kaplan–Meier data (JMDB trial) Posttrial: parametric regression, Weibull distribution*
PFS estimation for patients eligible for maintenance therapy	Within trial: Kaplan–Meier data (JMDB trial) Posttrial: parametric regression, Weibull distribution*
PFS estimation for patients ineligible for maintenance therapy	Within trial: Kaplan–Meier data (JMDB trial) Posttrial: parametric regression, Weibull distribution*
Adverse-event rate	Taken from trial data: trials differ for each comparator
Utility values	EQ-5D analysis of PARAMOUNT (using French tariffs)
Induction–maintenance treatment effect	Full time horizon
Proportion of induction-treatment effect for ineligible patients	0
Vial wastage	Included
Follow-up care cost	€158.10
Proportion of patients accruing terminal care cost	70.6%#
One-way sensitivity analyses conducted	• Changing baseline-risk parametric functions to Weibull for OS and log-logistic for PFS, and to log-logistic for OS and PFS
	• Allowing ineligible patients to receive 50% or 100% of induction-treatment effect
	• Using pooled hazard ratio for the treatment effect of pemetrexed maintenance therapy obtained from network meta-analyses
	• Using data from Nafees et al^Citation21 to estimate utilities
	• Changing the EQ-5D tariffs to UK weights
	• Using a 5-year time horizon
	• Excluding vial wastage
	• Turning treatment effect off at 32 months for induction (JMDB follow-up period) and 34 months for maintenance (PARAMOUNT 2012 data-lock follow-up period)
	• Setting discount rates for costs and outcomes at 3%
	• Varying proportion of patients assumed to incur terminal care costs by ±10%
	• Assuming adverse-event costs varied by ±20%

Note:

* Weibull distribution chosen, as visual assessment of survival curves showed that this provided both a reasonable extrapolation of event rates and a reasonable within-trial fit;

# data from Sesé et al.²² JMDB data taken from Scagliotti et al⁸; PARAMOUNT data taken from Paz-Ares et al.⁹

Abbreviations: CE, cost-effectiveness; EQ-5D, EuroQol five-dimension questionnaire; OS, overall survival; PFS, progression-free survival.

Table 3 PFS and OS HRs and 95% CIs for first-line induction and maintenance regimens included in the model (fixed-effect network meta-analysis*)

	PFS HR (95% CI)	OS HR (95% CI)
Pooled first-line induction regimens
Gemcitabine 1,000 mg/m^2 + cisplatin 75 mg/m^2	1 (referent)	1 (referent)
Docetaxel 75 mg/m^2 + cisplatin 75 mg/m^2	1.113 (0.88–1.397)	1.145 (0.931–1.413)
Vinorelbine 30 mg/m^2 + cisplatin 80 mg/m^2	1.142 (0.872–1.481)	1.068 (0.846–1.35)
Paclitaxel 225 mg/m^2 + carboplatin 400 mg/m^2	1.111 (0.939–1.306)	1.055 (0.9–1.237)
Gemcitabine 1,250 mg/m^2 + cisplatin 80 mg/m^2 + bevacizumab 7.5 mg/kg	0.799 (0.657–0.964)	0.978 (0.786–1.216)
Paclitaxel 200 mg/m^2 + carboplatin 400 mg/m^2 + bevacizumab 7.5 mg/kg	0.729 (0.657–0.964)	0.865 (0.699–1.069)
Pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2	0.899 (0.788–1.019)	0.811 (0.7–0.94)
Pooled first-line maintenance regimens
BSC	1 (referent)	1 (referent)
Pemetrexed 500 mg/m^2	0.55 (0.47–0.64)	0.74 (0.64–0.87)

Notes:

* Network meta-analyses conducted using WinBUGS. The primary analysis was not adjusted for covariates; however, covariate-adjusted analyses were also performed using the Cox proportional-hazard model (stratified by the nonplatinum component of induction chemotherapy). This was done to control for potential baseline characteristics that may have influenced the end point. The treatment effect was similar to and consistent with the primary analysis. Randomized controlled trials included in the network meta-analyses are available in Table S1.

Abbreviations: PFS, progression-free survival; OS, overall survival; HR, hazard ratios; CIs, credible intervals; BSC, best supportive care.

Table 4 Summary of costs included in the model

Drug acquisition and administration costs
Drug	Unit size (mg)	Price per unit	Administration cost‡
Pemetrexed*	500	€1,047.55#	€354.27
Docetaxel*	160	§	€394.27
Gemcitabine*	1,000	§	€788.54
Vinorelbine*	50	§	€788.54
Bevacizumab*	400	€932.94#	€354.27
Carboplatin	600	§	€394.27
Paclitaxel	300	§	€394.27

Hospitalization and other costs
Description	Cost	Source
Cost per hospitalization*	€2,288.08	04M091 DRG cost^Citation34
Terminal care#	€4,870	GHM 23Z02Z and 23Z02T (2013 cost inflated to 2015 using INSEE consumer price index)^Citation34
Follow-up care#,§	€158.10	Caisse Nationale d’Assurance Maladie (CNAM) and Caisse Nationale de l’Assurance Maladie des Travailleurs Salariés (CNAMTS) 2015^Citation35
Radiotherapy delivery‡	€135.88	GHM28Z23Z^Citation34
Radiotherapy preparation‡	€170	GHM28Z24Z^Citation34

Second-line therapy costs
Second-line therapy	Time on therapy	Dose	Doses per cycle	Administration costs per 21-day cycle§
Docetaxel	68.46 days*	75 mg/m^2#	1#	€394.27
Erlotinib	110.28 days*	150 mg/m^2#	21#	€0
Gemcitabine	63 days‡	1,200 mg/m^2#	3#	€788.54
Pemetrexed	63 days‡	500 mg/m^2#	1#	€354.27

Adverse-event costs
Adverse events (grade 3/4)	Cost	Source
Leukopenia	€22.09	Banz et al^Citation36
Thrombocytopenia	€71.75	Mickisch et al^Citation37
Neutropenia	€81.65	Banz et al^Citation36
Febrile neutropenia	€3,424.58	Durand-Zaleski et al^Citation38
Anemia	€5,050.89	Banz et al^Citation36
Infection	€3,058.58	Banz et al^Citation36
Fatigue/asthenia	€514.89	Banz et al^Citation36
Nausea/vomiting	€1,824.68	Banz et al^Citation36
Acne-like rash	€203.65	Banz et al^Citation36

Notes:

* Drugs for which drug wastage was included;

# data from the French Health Insurance document on drug base and pricing information;³⁴

‡ data from Diagnosis-Related Group (DRG) code GHS-NRO 9606;34

§ included in the DRG.

Notes:

* Based on a single respiratory neoplasm-related stay;

# base case;

‡ sensitivity analysis;

§ including cost of one consultation, one full-body computed tomography scan, and one standard biological test once every two cycles.

Notes:

* Derived from PARAMOUNT data⁹;

# PARAMOUNT protocol regimen;

‡ assumption based on expert clinical opinion (CC);

§ data from DRG code GHS-NRO 9606.³⁴

Table 5 Clinical effectiveness and cost-effectiveness of first-line induction–maintenance regimens included in the model

Comparator	Median PFS (months)*	Mean PFS (months)*	Median OS (months)*	Mean OS (months)*	Total LYs	Total QALYs	Total costs	Incremental QALYs gained (compared to referent)	Incremental costs (compared to referent)	Fully incremental ICER/QALY gained#,‡
Paclitaxel 225 mg/m^2 + carboplatin 400 mg/m^2 → BSC	4.37	5.64	9.66	12.39	1	0.65	€12,762	Referent	Referent	Referent
Vinorelbine 30 mg/m^2 + cisplatin 80 mg/m^2 → BSC	4.37	5.52	9.66	12.27	0.99	0.64	€13,200	−0.01	€438	Dominated
Gemcitabine 1,000 mg/m^2 + cisplatin 75 mg/m^2 → BSC	4.83	6.15	10.12	12.92	1.04	0.68	€13,285	0.03	€523	€16,593
Docetaxel 75 mg/m^2 + cisplatin 75 mg/m^2 → BSC	4.37	5.64	9.2	11.64	0.94	0.61	€13,573	−0.04	€811	Dominated
Pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2 → BSC	5.29	6.74	11.5	15.16	1.22	0.8	€23,134	0.15	€10,372	€80,656
Vinorelbine 30 mg/m^2 + cisplatin 80 mg/m^2 → pemetrexed 500 mg/m^2	5.52	8.61	10.81	14.56	1.17	0.78	€26,557	0.13	€13,795	Dominated
Paclitaxel 225 mg/m^2 + carboplatin 400 mg/m^2 → pemetrexed 500 mg/m^2	5.75	8.85	10.81	14.72	1.18	0.79	€26,845	0.14	€14,083	Dominated
Docetaxel 75 mg/m^2 + cisplatin 75 mg/m^2 → pemetrexed 500 mg/m^2	5.75	8.85	10.35	13.81	1.11	0.74	€27,571	0.09	€14,809	Dominated
Gemcitabine 1,000 mg/m^2 + cisplatin 75 mg/m^2 → pemetrexed 500 mg/m^2	5.98	9.86	11.5	15.44	1.23	0.84	€28,580	0.19	€15,818	Extendedly dominated
Gemcitabine 1,250 mg/m^2 + cisplatin 80 mg/m^2 + bevacizumab 7.5 mg/kg → bevacizumab 7.5 mg/kg	5.52	7.45	10.12	13.16	1.06	0.7	€30,638	0.05	€17,876	Dominated
Paclitaxel 200 mg/m^2 + carboplatin 400 mg/m^2 + bevacizumab 7.5 mg/kg → bevacizumab 7.5 mg/kg	5.75	8.07	11.04	14.45	1.16	0.77	€32,411	0.12	€19,649	Dominated
Pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2 → pemetrexed 500 mg/m^2	5.98	9.29	12.88	17.21	1.37	0.93	€35,617	0.28	€22,855	€102,179

Notes:

* Rounded to the nearest week (0.23 months), due to a cycle length of 1 week;

# fully incremental analysis conducted by comparing regimens to the next most cost-effective option;

‡ due to the rounding of these values, it may not be possible to precisely recreate these results.

Abbreviations: BSC, best supportive care; ICER, incremental cost-effectiveness ratio; LYs, life-years; OS, overall survival; PFS, progression-free survival; QALY, quality-adjusted LYs.

Table 6 Costs of treatment

Comparator	Acquisition induction	Administration induction	Acquisition maintenance	Administration maintenance	Long-term follow-up*	Adverse events†	Second-line therapy	Total
Paclitaxel 225 mg/m^2 + carboplatin 400 mg/m^2 → BSC	–	€1,571	–	–	€4,759	€2,063	€4,369	€12,762
Vinorelbine 30 mg/m^2 + cisplatin 80 mg/m^2 → BSC	–	€1,571	–	–	€4,746	€2,395	€4,488	€13,200
Gemcitabine 1,000 mg/m^2 + cisplatin 75 mg/m^2 → BSC	–	€1,961	–	–	€4,817	€2,028	€4,479	€13,285
Docetaxel 75 mg/m^2 + cisplatin 75 mg/m^2 → BSC	–	€1,961	–	–	€4,687	€2,193	€4,732	€13,573
Pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2 → BSC	€9,978	€1,762	–	–	€5,041	€2,228	€4,125	€23,134
Vinorelbine 30 mg/m^2 + cisplatin 80 mg/m^2 → pemetrexed 500 mg/m^2	–	€1,378	€11,575	€2,044	€5,007	€2,703	€3,851	€26,557
Paclitaxel 225 mg/m^2 + carboplatin 400 mg/m^2 → pemetrexed 500 mg/m^2	–	€1,383	€11,957	€2,112	€5,026	€2,374	€3,994	€26,845
Docetaxel 75 mg/m^2 + cisplatin 75 mg/m^2 → pemetrexed 500 mg/m^2	–	€1,382	€11,951	€2,111	€4,939	€2,481	€4,707	€27,571
Gemcitabine 1,000 mg/m^2 + cisplatin 75 mg/m^2 → pemetrexed 500 mg/m^2	–	€1,400	€13,500	€2,384	€5,108	€2,357	€3,832	€28,580
Gemcitabine 1,250 mg/m^2 + cisplatin 80 mg/m^2 + bevacizumab 7.5 mg/kg → bevacizumab 7.5 mg/kg	€7,772	€1,557	€7,700	€1,543	€4,859	€2,981	€4,225	€30,638
Paclitaxel 200 mg/m^2 + carboplatin 400 mg/m^2 + bevacizumab 7.5 mg/kg → bevacizumab 7.5 mg/kg	€9,143	€1,832	€7,746	€1,552	€4,992	€2,815	€4,331	€32,411
Pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2 → pemetrexed 500 mg/m^2	€7,202	€1,272	€12,709	€2,244	€5,268	€2,556	€4,366	€35,617

Notes:

* Includes best supportive care (BSC), computed tomography scan, consultant, terminal care, follow-up care, and concomitant radiotherapy costs preprogression;

† includes adverse events and hospitalizations. ‘–’ indicates not applicable.

Table 7 Sensitivity analyses with the greatest impact on results

Comparators	Weibull OS, log-logistic PFS	Log-logistic OS, log-logistic PFS	Ineligible patients allowed to receive 50% of induction-treatment effect	Pooled HR for pemetrexed maintenance	No vial wastage	Nafees et al^Citation21 utility data	Treatment effect turned off
Paclitaxel 225 mg/m^2 + carboplatin 400 mg/m^2 → BSC	Referent	Referent	Referent	Referent	Referent	Referent	Referent
Vinorelbine 30 mg/m^2 + cisplatin 80 mg/m^2 → BSC	Dominated	Dominated	Dominated	Dominated	Dominated	Dominated	Dominated
Gemcitabine 1,000 mg/m^2 + cisplatin 75 mg/m^2 → BSC	€15,619	€11,029	€12,730	€16,593	€16,602	€19,194	€16,931
Docetaxel 75 mg/m^2 + cisplatin 75 mg/m^2 → BSC	Dominated	Dominated	Dominated	Dominated	Dominated	Dominated	Dominated
Pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2 → BSC	€79,095	Extendedly dominated	€56,609	€80,656	€76,484	Extendedly dominated	€85,662
Vinorelbine 30 mg/m^2 + cisplatin 80 mg/m^2 → pemetrexed 500 mg/m^2	Dominated	Dominated	Dominated	Dominated	Dominated	Dominated	Dominated
Paclitaxel 225 mg/m^2 + carboplatin 400 mg/m^2 → pemetrexed 500 mg/m^2	Dominated	Extendedly dominated	Dominated	Dominated	Dominated	Extendedly dominated	Dominated
Docetaxel 75 mg/m^2 + cisplatin 75 mg/m^2 → pemetrexed 500 mg/m^2	Dominated	Dominated	Dominated	Dominated	Dominated	Dominated	Dominated
Gemcitabine 1,000 mg/m^2 + cisplatin 75 mg/m^2 → pemetrexed 500 mg/m^2	Extendedly dominated	Extendedly dominated	Dominated	Extendedly dominated	Extendedly dominated	€105,956	Extendedly dominated
Gemcitabine 1,250 mg/m^2 + cisplatin 80 mg/m^2 + bevacizumab 7.5 mg/kg → bevacizumab 7.5 mg/kg	Dominated	Dominated	Dominated	Dominated	Dominated	Dominated	Dominated
Paclitaxel 200 mg/m^2 + carboplatin 400 mg/m^2 + bevacizumab 7.5 mg/kg → bevacizumab 7.5 mg/kg	Dominated	Dominated	Extendedly dominated	Dominated	Dominated	Dominated	Dominated
Pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2 → pemetrexed 500 mg/m^2	€108,845	€52,129	€80,155	€89,983	€96,442	€122,005	€118,930

Note: Results showing values in Euros reflect incremental cost per quality-adjusted life-year gained.

Abbreviations: BSC, best supportive care; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.

Figure 1 Cost-effectiveness acceptability frontier (CEAF).

Notes: The CEAF was created by running probabilistic sensitivity analyses, and shows the probability that the treatment selected on the basis of the expected values is cost-effective. For details of the regimens, refer to Table 1.
Abbreviations: BSC, best supportive care; Carb, carboplatin; Cis, cisplatin; Gem, gemcitabine; Pac, paclitaxel; Pem, pemetrexed.

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