Economic analysis of bevacizumab, cetuximab, and panitumumab with fluoropyrimidine-based chemotherapy in the first-line treatment of KRAS wild-type metastatic colorectal cancer (mCRC)

Figures & data

Figure 1. Markov model structure.

Table 1. Key clinical trials.

	Hurwitz et al.13 (2009)	CRYSTAL clinical trial; Van Cutsem et al.10 (2011)	PRIME clinical trial; Douillard et al.11 (2010)
Trial design	Phase III multinational RCT of 813 untreated mCRC patients	Phase III multinational RCT of 1198 untreated patients with unresectable metastases	Phase III multinational RCT of 1183 mCRC patients with no prior chemotherapy
Comparators	Bevacizumab + IFL vs IFL + placebo	Cetuximab + FOLFIRI vs FOLFIRI	Panitumumab + FOLFOX vs FOLFOX
# of KRAS-WT patients	152	666	656
PFS results (median months)	13.5 bevacizumab + IFL 7.4 IFL + placebo p < 0.001	9.9 cetuximab + FOLFIRI 8.4 FOLFIRI p = 0.0012	9.6 panitumumab + FOLFOX 8.0 FOLFOX p = 0.02
OS results (median months)	27.7 bevacizumab + IFL 17.6 IFL + placebo p = 0.04	23.5 cetuximab + FOLFIRI 20.0 FOLFIRI p = 0.0093	23.9 panitumumab + FOLFOX 19.7 FOLFOX p = 0.072 (not significant)

Table 2. Base case model parameters.

Variable	Value	Source (reference)
Drug costs per cycle (q 2 weeks)
Bevacizumab
Dosing: 5 mg/kg	$1,712	Hurwitz et al.9, IMS Brogan
Cetuximab
Dosing (loading cycle): 400 mg/m^2	$2,499	Van Cutsem et al.10, IMS Brogan
Dosing (maintenance): 250 mg/m^2	$1,562
Panitumumab		Douillard et al.11, IMS Brogan
Dosing: 6 mg/kg	$2,520
FOLFOX		Douillard et al.11, Dranitsaris et al.23
Dosing: oxaliplatin 85 mg/m^2, folinic acid   200 mg/m^2, fluorouracil 400 mg/m^2   bolus then 600 mg/m^2 CIV*	$1,530
FOLFIRI, IFL (assumed)		Van Cutsem et al.10, Dranitsaris et al.23
Dosing: irinotecan 180 mg/m^2,   leucovorin 400 mg/m^2, fluorouracil   400 mg/m^2 bolus then   2400–3000 mg/m^2 CIV**	$179
Adverse events (%)
Bevacizumab		Hurwitz et al.13
Hypertension	9.4%
Arterial Thromboembolic Event	1.2%
GI Perforation	1.2%
Diarrhea	24.7%
Cetuximab		Van Cutsem et al.10
Diarrhea	16.4%
Skin Reactions	21.1%
Infusion Related Reactions	1.6%
Panitumumab		Douillard et al.11
Diarrhea	18.3%
Skin Reactions	39.4%
Infusion Related Reactions	0.6%
Hypomagnesimia	6.2%
Adverse events costs (by adverse event)
Arterial thromboembolic event	$12,852	Advisor Input, Canadian cost sources26–30
Diarrhea	$271
GI perforation	$30,510
Hypertension	$110
Hypomagnesemia	$432
Infusion-related reactions	$5
Skin conditions	$370
Adverse events costs (one time, by chemotherapy)
FBC	$0	Assumption
Bevacizumab	$588	Advisor Input, Canadian cost sources26–30
Cetuximab	$135
Panitumumab	$227
Supportive care costs (q 2 weeks)
Progression-Free	$1,501 port-line	LRHSC Ontario Case Costing Initiative28
FBC	$514	Dranitsaris et al.23
Bevacizumab	$514
Cetuximab	$941
Panitumumab	$601
Progression until Death	$1,233/month
Subsequent chemotherapy costs (one time)
FBC	$6,426.00	Advisor Input, Canadian cost sources26–30
Bevacizumab	$6,426.00
Cetuximab	$6,426.00
Panitumumab	$751.80
Utility		Petrou and Campbell32
Pre-Progression	0.95
Progression	0.575
Discounting		CADTH Guidelines15
Costs	5%
Outcomes	5%
Time horizion	Lifetime	Assumption
Calibrated transition probabilities		Model calibrated values from extracted PFS and OS curves
FBC
Progression Free to Progression	4.198%
Progression Free to Death	0.461%
Progression to Death	3.187%
Bevacizumab + FBC
Progression Free to Progression	2.806%
Progression Free to Death	0.256%
Progression to Death	2.617%
Cetuximab +FBC
Progression Free to Progression	2.123%
Progression Free to Death	0.694%
Progression to Death	2.394%
Panitumumab +FBC
Progression Free to Progression	2.831%
Progression Free to Death	0.769%
Progression to Death	1.867%

*Fluorouracil bolus given days 1, 2; continuous intravenous (CIV) over 22 h days 1, 2.

**Fluorouracil bolus given day 1; CIV over 46 h day 1.

Figure 2. Model calibration results—survival curves. (a) IFL13; (b) Bevacizumab + IFL13; (c) Cetuximab + FOLFIRI10; (d) Panitumumab + FOLFOX11.

Table 3. Base case results (per patient)*.

Comparator	Total cost	Total QALYs	Δ Cost	Δ QALYs	ICER
FBC	$38,307	1.35	–	–	–
Bevacizumab + FBC	$103,290	1.85	$64,983	0.49	$131,613
Panitumumab + FBC	$151,596	1.81	$48,306	−0.04	Dominated
Cetuximab + FBC	$169,774	1.86	$66,484	0.02	$3,844,571

*Costs and QALYs discounted at 5% per year.

Figure 3. Cost-effectiveness frontier.

Table 4. Patient survival sensitivity analysis results: ICERs*.

	Panitumumab + FBC	Cetuximab + FBC
vs Bevacizumab + FBC
Best case scenario	Dominated	Dominated
Base case scenario	Dominated	$3,844,571
Worst case scenario	$535,182	$386,906

Best Case Scenario: bevacizumab + FBC lowest calibrated mortality vs comparator highest calibrated mortality; Base Case Scenario: bevacizumab + FBC base case calibrated mortality vs comparator base case calibrated mortality; Worst Case Scenario: bevacizumab + FBC highest calibrated mortality vs comparator lowest calibrated mortality.

*Discounted at 5% per year.

Figure 4. Cost-effectiveness acceptability curves.

Table 5. Sensitivity analyses results: transition probabilities.

Scenario	Transition probabilities				Cost per QALY
	FBC	Bevacizumab + FBC	Cetuximab + FBC	Panitumumab	Bevacizumab + FBC vs FBC	Panitumumab + FBC vs Bevacizumab + FBC	Cetuximab + FBC vs Bevacizumab + FBC
Base	Base	Base	Base	Base	$131,613	Dominated	$3,844,571
#1	Base	LCL	Base	Base	$145,597	$1,014,688	$650,399
#2	Base	UCL	Base	Base	$107,017	Dominated	Dominated
#3	Base	Base	LCL	Base	$131,613	Dominated	Dominated
#4	Base	Base	UCL	Base	$131,613	Dominated	$629,215
#5	Base	Base	Base	LCL	$131,613	Dominated	$3,844,571
#6	Base	Base	Base	UCL	$131,613	$2,478,159	$3,844,571
#7	Base	LCL	LCL	Base	$145,597	$1,014,688	$7,332,614
#8	Base	UCL	LCL	Base	$107,017	Dominated	Dominated
#9	Base	LCL	UCL	Base	$145,597	$1,014,688	$386,906
#10	Base	UCL	UCL	Base	$107,017	Dominated	Dominated
#11	Base	LCL	Base	LCL	$145,597	Dominated	$650,399
#12	Base	UCL	Base	LCL	$107,017	Dominated	Dominated
#13	Base	Base	LCL	LCL	$131,613	Dominated	Dominated
#14	Base	Base	UCL	LCL	$131,613	Dominated	$629,215
#15	Base	LCL	Base	UCL	$145,597	$535,182	$650,399
#16	Base	UCL	Base	UCL	$107,017	Dominated	Dominated
#17	Base	Base	LCL	UCL	$131,613	$2,478,159	Dominated
#18	Base	Base	UCL	UCL	$131,613	$2,478,159	$629,215
#19	Base	LCL	LCL	LCL	$145,597	Dominated	$7,332,614
#20	Base	UCL	LCL	LCL	$107,017	Dominated	Dominated
#21	Base	LCL	UCL	LCL	$145,597	Dominated	$386,906
#22	Base	UCL	UCL	LCL	$107,017	Dominated	Dominated
#23	Base	LCL	LCL	UCL	$145,597	$535,182	$7,332,614
#24	Base	UCL	LCL	UCL	$107,017	Dominated	Dominated
#25	Base	LCL	UCL	UCL	$145,597	$535,182	$386,906
#26	Base	UCL	UCL	UCL	$107,017	Dominated	Dominated

Base, Base Case Transition Probabilities; LCL, Lower confidence limit corresponding to higher mortality rates than in the base case (i.e., ‘worst case’); UCL, Upper confidence limit corresponding to lower mortality rates than in the base case (i.e., ‘best case’).

Table 6. One-way sensitivity analyses results.

Description	ICER (Cost per QALY)
	Bevacizumab + FBC vs FBC	Panitumumab + FBC vs Bevacizumab + FBC	Cetuximab + FBC vs Bevacizumab + FBC
Base Case	$131,613	Dominated	$3,844,571
Adverse event costs: 20% increase	$131,851	Dominated	$3,839,331
Adverse event costs: 20% decrease	$131,374	Dominated	$3,849,812
Supportive care costs: 20% increase	$135,086	Dominated	$4,003,301
Supportive care costs: 20% decrease	$128,139	Dominated	$3,685,842
Subsequent chemotherapy costs: 20% increase	$131,609	Dominated	$3,832,580
Subsequent chemotherapy costs: 20% decrease	$131,616	Dominated	$3,856,563
Utility: 20% increase (to a maximum value of 1.0)	$121,108	Dominated	$10,345,419
Utility: 20% decrease	$164,516	Dominated	$4,805,714
Adverse events were assumed to reduce utility by 10% from its baseline level (Bevacizumab + FBC).	$210,313	Weakly dominated	$329,037
Adverse events were assumed to reduce utility by 10% from its baseline level (Panitumumab + FBC)	$131,616	Dominated	$3,844,571
Adverse events were assumed to reduce utility by 10% from its baseline level (Cetuximab + FBC)	$131,616	Dominated	Dominated
Discounting rate for costs/outcomes: 3%	$128,505	Dominated	$3,335,770
Discounting rate for costs/outcomes: 0%	$123,765	Dominated	$2,724,086

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