Cost-effectiveness of dabrafenib and trametinib in combination as adjuvant treatment of BRAF V600E/K mutation-positive melanoma from a US healthcare payer perspective

Figures & data

Figure 1. Simplified model schematic.

Figure 2. Parametric and Kaplan-Meier survival distributions for (A) RFS, (B) 1LPFS, and (C) 2LOS.

Table 1. Probabilities and utility values.

Parameter	Point estimate	Standard error	Distribution	Source
Mean age / % female	50 / 45%	0.01	N/A / Beta	–
Parametric distributions fit to patient-level data from COMBI-AD, by health state
RFS	Log-logistic unrestricted cure	N/A	Bootstrap	–
1LPFS	Generalized F	N/A	Bootstrap	–
2LOS	Lognormal	N/A	Bootstrap	–
HR recurrence, LR vs RFS state, months 1–12 / 13–58 / 59+	4.47 / 1.69 / 1.00	–	–	^16
Incidence of Grade 3+ AEs, Dabrafenib + Trametinib/Observation
Hypertension	6% / 2%	–	–	^8
Pyrexia	5% / 0%	–	–	^8
Probability of discontinuation
D + T: Q1 / Q2 / Q3 / Q4	0.11 / 0.06 / 0.03 / 1.00	–	–	–
2L DR: Q1 / Q2 / Q3 / Q4+	0.40 / 0.53 / 0.55 / 0.52 / 0.42	–	–	^38
RDI: Dabrafenib / Trametinib	0.838 / 0.905	0.009 / 0.007	Normal	–
Utility values
RFS On- / Off-Treatment	0.8845 / 0.8966	Multiple	Multivariate Normal	–
LR	0.8720	Multiple	Multivariate Normal	–
1L DR	0.732	0.0075	Lognormal	^18
2L DR	0.658	0.0075	Lognormal	^19
General population utility, Females / Males
30–39 years	0.901 / 0.901	0.002 / 0.002	Lognormal	^20
40–49 years	0.871 / 0.871	0.002 / 0.002	Lognormal	^20
50–59 years	0.842 / 0.842	0.002 / 0.002	Lognormal	^20
60–69 years	0.823 / 0.823	0.003 / 0.003	Lognormal	^20
70–79 years	0.790 / 0.790	0.004 / 0.004	Lognormal	^20
80+ years	0.736 / 0.736	0.006 / 0.006	Lognormal	^20
Probability of receiving 1L DR therapies, Dabrafenib + Trametinib / Observation
Dabrafenib + Trametinib	0.120 / 0.160	0.120/0.160	Dirichlet	–
Ipilimumab	0.230 / 0.110	0.230/0.110	Dirichlet	–
Nivolumab	0.060 / 0.010	0.060/0.010	Dirichlet	–
Pembrolizumab	0.130 / 0.010	0.130/0.010	Dirichlet	–
Vemurafenib	0.010 / 0.170	0.010/0.170	Dirichlet	–
Nivolumab + Ipilimumab	0.080 / 0.060	0.080/0.060	Dirichlet	–
Vemurafenib + Cobimetinib	0.030 / 0.050	0.030/0.050	Dirichlet	–
Dabrafenib	0.040 / 0.180	0.040/0.180	Dirichlet	–
Best Supportive Care	0.300 / 0.000	0.300/–	Dirichlet	–
Probability distribution of RFS events, dabrafenib + trametinib / observation
Deaths	0.019 / 0.004	N/A	Bootstrap	–
LR	0.338 / 0.444	N/A	Bootstrap	–
DR	0.644 / 0.552	N/A	Bootstrap	–
Probability distribution of LR events
Deaths / DR	0.004 / 0.996	N/A	Bootstrap	–
Probability distribution of 1LPFS events
Deaths / progress to second-line	0.0369 / 0.631	N/A	Bootstrap	–

Table 2. Costs inputs.

Item	Unit cost ($)	Source
BRAF testing, cost per positive patient	480	^35
Unit costs of medications
Dabrafenib, (per mg)	1.07	^36
Trametinib, (per mg)	174.64	^36
Ipilimumab, (per mg ml)	139.26	^36
Dacarbazine (BSC), (per mg)	0.08	^36
Vemurafenib, (per mg)	0.19	^36
Pembrolizumab, (per mg ml)	45.13	^36
Nivolumab, (per mg ml)	25.45	^36
Cobimetinib, (per mg)	5.20	^36
Dispensing	11.77	^43
Cost of locoregional recurrence	5,306	^39
Monthly costs of follow-up and monitoring, years 1–2 / 3–4 / 5+
Adjuvant setting	1,076 / 538 / 268	^39
Metastatic setting	9,542 / 4,771 / 2,385	^39
Costs of treating grade 3+ adverse events
Pyrexia	9,658	^41
Hypertension	11,281	^41
Terminal care	16,783	^42

Figure 3. Model projections of RFS and OS for dabrafenib plus trametinib and observation.

Table 3. Base-case results.

Outcome	Dabrafenib +  Trametinib	Observation	Incremental
Life Years, Discounted
RFS	10.91	7.82	3.09
LR	0.14	0.24	−0.10
1L DR	1.16	1.56	−0.40
2L DR	0.75	1.01	−0.26
Total	12.97	10.63	2.34
QALYs, Discounted
RFS	9.53	6.83	2.70
LR	0.12	0.21	−0.09
1L DR	0.84	1.13	−0.29
2L DR	0.49	0.66	−0.17
Total	10.98	8.83	2.15
Costs, $, Discounted
RFS
Medications	165,580	0	165,580
BRAF testing	481	0	481
Adverse events	1,159	254	905
Follow-up and monitoring	59,517	42,303	17,214
Total costs in RFS	226,736	42,557	184,179
LR
Acute treatment	842	1,463	−622
Adverse events	40	70	−30
Follow-up and monitoring	1,505	2,620	−1,115
Total costs in LR	2,387	4,153	−1,766
1L DR
Medications	100,720	149,583	−48,863
BRAF testing	0	119	−119
Follow-up and monitoring	73,789	101,948	−28,160
Total costs in 1L DR	174,509	251,650	−77,141
2L DR
Medications	20,125	28,637	−8,511
Follow-up and monitoring	59,369	79,540	−20,171
Total costs in 2L DR	79,494	108,176	−28,682
Terminal care	6,552	8,624	−2,072
Total healthcare costs	489,678	415,160	74,518
Cost per QALY gained, $			34,689

Abbreviations. LY, life-years; QALY, quality-adjusted life-years; RFS, relapse-free survival; LR, locoregional recurrence; 1 L DR, first-line distant recurrence; 2 L DR, second-line distant recurrence.

Figure 4. Tornado chart for incremental cost-effectiveness ratio.

Table 4. Results of scenario analyses.

No.	Scenario description	ΔCost ($)	ΔLY	ΔQALY	ICER ($/QALY)	NMB ($)
—	Base-case	74,518	2.34	2.15	34,689	140,297
1	RFS for both comparators uses hazard rate from EORTC 18071 after 50 months	88,482	1.92	1.77	49,941	88,691
2	RFS for D + T based on estimated RFS for OBS after 50 months	68,825	2.50	2.30	29,971	160,811
3	RFS based on Gamma unrestricted cure model (more favorable)	37,387	3.27	3.00	12,458	262,705
4	RFS based on log-logistic restricted cure models (less favorable)	125,159	0.99	0.92	136,308	−33,338
5	1LPFS for D + T and OBS based on pooled log-logistic cure model	49,084	2.18	2.04	24,055	154,969
6	1LPFS for D + T and OBS based on treatment-group specific log-logistic restricted cure model	75,610	2.51	2.27	33,374	150,941
7	2LOS for D + T and OBS based on lognormal restricted model	85,663	2.53	2.27	37,690	141,619
8	D + T and OBS both utilize 1LPFS Log-Logistic restricted Cure model and 2LOS Lognormal restricted model fit to respective trial arms	85,671	2.68	2.38	36,018	152,184
9	Commercially insured patients only (adults aged less than 65 years)	64,832	2.51	2.25	28,815	160,160
10	Medicare eligible patients (adults aged at least 65 years)	96,842	1.34	1.24	78,321	26,805
11	Timeframe 10 years	81,081	0.93	0.93	86,964	12,154
12	Timeframe 20 years	75,515	1.64	1.57	48,025	81,726

Abbreviations. NMB, net monetary benefit; ICER, incremental cost-effectiveness ratio; LY, life-years; QALY, quality-adjusted life-years; RFS, relapse-free survival; OBS, observation; 1LPFS, first-line progression-free survival; 2LOS, second-line overall survival; D + T, dabrafenib + trametinib.

Figure 5. Cost-effectiveness acceptability curve and scatter plot of PSA simulations.

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