Cost-effectiveness of pembrolizumab for the first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma in the United States

Figures & data

Figure 1. Long-term survival and time-on-treatment extrapolations for pembrolizumab regimens and comparators in patients with CPS ≥1 (left column) and in overall R/M HNSCC population (right column). Abbreviations. CPS, combined positive score; EXTREME regimen, Cetuximab + platinum + 5-Fluorouacil; KM, Kaplan-Meier; OS, overall survival; PF, progression-free; PFS, progression-free survival; TPEx regimen, Cisplatin + docetaxel + cetuximab; 5-FU, 5-fluorouracil.

Table 1. Drug regimens and the calculated average cost per week.

Regimen	Drugs	Vial size, mg	WAC per vial, $^45	Dosing schedule	Average weekly cost, $
Pembrolizumab monotherapy	Pembrolizumab	100	4862.00	200 mg IV, Q3W, up to 35 cycles^31	3,241.36
Pembrolizumab combination therapy	Pembrolizumab	100	4862.00	200 mg IV, Q3W, up to 35 cycles^31	3,241.36
	Cisplatin	100	30.00	100 mg/m^2, Q3W, up to 6 cycles^47	18.40
	Carboplatin	600	51.71	500 mg, Q3W, up to 6 cycles^48
	5-FU	2500	11.90	4000 mg/m^2, Q3W, up to 6 cycles^51	11.60
		5000	22.90
Cetuximab + platinum + 5-FU (EXTREME)	Cetuximab	100	656.63	400 mg/m^2, first week^46	5,253.04
		200	1313.26	250 mg/m^2, Q1W thereafter^42	3,283.15
	Cisplatin	100	30.00	100 mg/m^2, Q3W, up to 6 cycles^47	18.40
	Carboplatin	600	51.71	500 mg, Q3W, up to 6 cycles^48
	5-FU	2500	11.90	4000 mg/m^2, Q3W, up to 6 cycles^51	11.60
		5000	22.90
Platinum + 5-FU	Cisplatin	100	30.00	100 mg/m^2, Q3W, up to 6 cycles^47	18.40
	Carboplatin	600	51.71	500 mg, Q3W, up to 6 cycles^48
	5-FU	2500	11.90	4000 mg/m^2, Q3W, up to 6 cycles^51	11.60
		5000	22.90
Cisplatin + docetaxel + cetuximab (TPEx)	Cisplatin	50	18.05	75 mg/m², Q3W, up to 6 cycles^47	16.02
		100	30.00
	Docetaxel	160	170.00	75 mg/m², Q3W, up to 6 cycles^49	56.67
	Cetuximab	100	656.63	400 mg/m^2, first week^46	5,253.04
		200	1313.26	250 mg/m^2, Q1W thereafter^46	3,283.15
Cisplatin + Paclitaxel	Cisplatin	50	18.05	75 mg/m², Q3W, up to 6 cycles^47	16.02
		100	30.00
	Paclitaxel	300	55.00	135 mg/m^2, Q3W, up to 6 cycles^50	18.33

Abbreviations. BSA, body surface area; Q1W, every week; Q2W, every 2 weeks; Q3W, every 3 weeks; WAC, weighted average costs.

The calculated costs shown reflect the drug cost applicable while patients are on treatment, expressed as average cost per week (cost per dose ÷ dosing frequency [in weeks]), and are based on public weighted average prices from Medi-Span, 2021. The dosing for weight-based therapies was approximated based on an average patient with a BSA of 1.87/m² and using the less expensive combination of vial sizes required, without allowing for vial sharing. The cost for a regimen including cisplatin or carboplatin is calculated based on 42.13% of patients treated with cisplatin and 57.87% with carboplatin.

Table 2. Model inputs for direct medical costs and health utility.

Input	Value	Source
Direct medical care costs, $
Disease management
Pre-progression, per weekly cycle^a	138.18	Supplemental Material, Table S3
Post-progression, per weekly cycle^a	68.92	Supplemental Material, Table S3
Disease progression one-time cost^b	342.16	^55
Terminal care cost	17,481.14	^56
PD-L1 test one-time cost^c	149.53	^19^,^52
Drug administration
Administration of first agent
First hour, or less	142.55	^52
Additional hours	30.68	^52
Administration of additional agents, per hour	69.29	^52
Adverse event, per week on treatment^d		Supplemental Material, Tables S1 and S2
Pembrolizumab monotherapy	32.44
Pembrolizumab combination therapy	463.12
EXTREME regimen	547.78
Platinum + 5-FU	676.23
Cisplatin + paclitaxel	1031.28
TPEx regimen	509.70
Subsequent treatments^e		Supplemental Material, Tables S4 and S5
Patients with CPS ≥1, one-time cost
Pembrolizumab monotherapy	28,127.71
Comparators	37,396.29
Overall population, one-time cost
Pembrolizumab combination therapy	15,592.90
Comparators	40,368.08
Health utility^f		Supplemental Material, Table S6
PF state	0.82065
PD state	0.77848
Disutilities for TRAE grade 3–5	−0.01892
Disutilities prior to death
90–180 days	−0.03438
30–90 days	−0.11050
0–30 days	−0.22590

Abbreviations. CPS, combined positive score; CPT, current procedural terminology; ECOG, Eastern Cooperative Oncology Group; EQ-5D-3L, EuroQol five-dimension three-level; EXTREME regimen, Cetuximab + platinum+5-Fluorouacil; TPEx regimen, Cisplatin + docetaxel + cetuximab; PFS, progression-free survival; TRAE, treatment-related adverse events; 5-FU, 5-fluorouracil; ToT, time on treatment.

^aThe weekly costs were obtained by multiplying CPT code-based unit cost for each resource by their weekly utilization in each respective health state.

^bThe one-off disease progression cost included an oncologist visit (CPT 99215, $148.33) and a CT scan (weighted average of computed tomography CPT codes, $193.83).

^cAs each test cost $127.40, and 85.2% of patients have a CPS <1, a one-time cost for PD-L1 testing of $149.53 per patient was applied to patients of the pembrolizumab monotherapy group.

^dTRAEs grade 3–5 occurring in at least 5% of patients in any KEYNOTE-048 trial study arm or for any alternative comparators were included. The cost of managing TRAEs was obtained by multiplying the estimated number of TRAEs by their respective costs. The number of TRAE occurring during a cycle was obtained by applying the weekly incidence of events to the number of patients still on treatment.

^eThe average cost of subsequent treatment was determined based on the expected proportions of patients receiving subsequent therapies. The most utilized treatments following primary treatment were considered. The duration of subsequent treatments was assumed independent of the primary treatment, and the mean across each intervention arm was used. Subsequent treatment costs included average costs of treatment (estimated using recommended dosing schedule and mean ToT), average treatment costs of drug administration, as well as the costs of managing TRAEs.

^fHealth utility values and disutility due to the presence of TRAEs and proximity to death in the last months of life were modeled using a multivariate linear mixed regression with the same weights applied to each treatment arm and based on health utilities derived from patient-level EQ-5D-3L responses collected every three weeks before treatment discontinuation in the KEYNOTE-048, trial and mapped to an index score using the US social tariff. Based on the statistical significance of covariates and clinical interpretations, the final model retained the ECOG score status (1 or >1) as an additional variable amongst several others also considered for inclusion, such as age, gender, smoking status, disease presentation (R/M or neither recurrent nor metastatic), human papillomavirus (positive or negative), baseline PD-L1 expression level, and tumor location (oral cavity or not).

Table 3. Base-case cost-effectiveness analysis results for first-line pembrolizumab vs. comparators in R/M HNSCC over a 20-year time horizon.

	Pembrolizumab regimen	EXTREME regimen	TPEx regimen	Platinum+5-FU	Cisplatin + paclitaxel
Pembrolizumab monotherapy vs. comparators (CPS ≥1)
Costs, $	151,464	159,573	229,089	58,827	65,438
Treatment-related	123,245	135,400	203,002	35,538	42,187
Drug acquisition	101,349	89,906	152,780	419	476
PD-L1 test	150	0	0	0	0
Drug administration	1486	3952	7248	788	4241
Subsequent treatment	19,307	27,213	19,988	25,724	24,421
Adverse event	953	14,329	22,986	8607	13,049
Disease management	28,219	24,173	26,088	23,289	23,251
LYs, years	2.447	1.344	1.543	1.099	1.113
QALYs, years	1.932	1.064	1.229	0.865	0.876
Progression-free	0.675	0.526	0.712	0.356	0.355
Progressive Disease	1.264	0.547	0.526	0.517	0.530
Adverse Events Disutilities	−0.00005	−0.00061	−0.00102	−0.00038	−0.00055
Time to death Disutilities	−0.00787	−0.00870	−0.00847	−0.00844	−0.00831
Incremental costs per LY, $		Dominant	Dominant	68,707	64,488
Incremental costs per QALY, $		Dominant	Dominant	86,827	81,473
Pembrolizumab combination therapy vs. comparators (overall population)
Costs, $	167,189	165,343	213,674	62,154	68,544
Treatment-related	138,520	141,061	188,452	39,396	45,271
Drug acquisition	110,815	92,884	137,920	433	493
PD-L1 test cost	0	0	0	0	0
Drug administration	2307	4081	6618	814	4387
Subsequent treatment	10,446	29,274	23,248	29,188	26,802
Adverse event	14,952	14,822	20,666	8961	13,589
Disease management	28,669	24,283	25,223	22,758	23,273
Total LYs	2.683	1.354	1.423	1.060	1.290
Total QALYs	2.114	1.071	1.131	0.833	1.012
Progression-free	0.666	0.507	0.640	0.323	0.322
Progressive Disease	1.457	0.573	0.501	0.519	0.699
Adverse Events Disutilities	−0.00066	−0.00063	−0.00092		−0.00057
Time to death Disutilities	−0.00786	−0.00866	−0.00850		−0.00815
Incremental costs per LY, $		1389	Dominant		70,827
Incremental costs per QALY, $		1769	Dominant		89,505

Abbreviations. CPS, combined positive score; EXTREME regimen, Cetuximab + platinum + 5-Fluorouacil; LY, life-years; PD-L1, programmed death-ligand 1; QALY, quality-adjusted life years; R/M HNSCC, recurrent or metastatic head and neck squamous cell carcinoma; TPEx regimen, Cisplatin + docetaxel + cetuximab; 5-FU, 5 fluorouracil.

Figure 2. The main variation in ICER of pembrolizumab regimens vs. the EXTREME regimen trial comparator upon one-way deterministic changes in model parameters. Abbreviations. CPS, combined positive score; EXTREME regimen, Cetuximab + platinum+5-Fluorouacil; PD, progressive disease; PF, progression-free; PFS, progression-free survival; QALY, quality-adjusted life years; R/M HNSCC, recurrent or metastatic head and neck squamous cell carcinoma; 5-FU, 5-fluorouracil.

Figure 3. Cost-effectiveness acceptability curves for pembrolizumab monotherapy and comparators in R/M HNSCC patients with CPS ≥1 and pembrolizumab combination and comparators in the overall R/M HNSCC population. Abbreviations. CPS, combined positive score; EXTREME regimen, Cetuximab + platinum+5-Fluorouacil; QALY, quality-adjusted life years; R/M HNSCC, recurrent or metastatic head and neck squamous cell carcinoma; TPEx regimen, Cisplatin + docetaxel + cetuximab; 5-FU, 5-fluorouracil.

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