Supplementary Information to ‘Cost-effectiveness of an
individualized first-line treatment strategy offering erlotinib based on
EGFR mutation testing in advanced lung adenocarcinoma patients in
Germany’
Katharina Schremser, Wolf H. Rogowski, Sigrid Adler-Reichel, Amanda L.H. Tufman,
Rudolf M. Huber, Björn Stollenwerk
1
Webtable 1 Akaike information criterion (AIC) as a measure of the goodness of fit for
progression-free survival (PFS) and overall survival (OS). Smaller AIC values indicate betterfitting models.
Model distribution
Exponential
Weibull
Log-logistic
Log-normal
Gompertz
Flexible parametric
proportional-hazards model
using the spline model of
Royston and Parmar
a
Base case model
b
Structural sensitivity analysis
PFS
1024.2
1016.7a
1024.2
1038.5
1024.3
1003.9b
AIC values
OS
615.8a
617.6
622.7
630.1
616.0
616.9b
2
Adverse events
Based on the clinical experience of our cooperation partners, we estimated the share of
outpatient treatment for each adverse event to enable a reliable presentation of clinical
practice. If no information on outpatient cost data was available, we used published literature
to estimate resource use [1].
Webtable 2 Health-care resource use per patient for treatment of adverse events
Grade 3/4 adverse event
Outpatient resource use
per patient and episode
Inpatient resource use
per patient and episode
Grade 3/4 rash
Proportion of patients
assumed to be treated as
outpatients
0.95
one additional outpatient
visit and one tube of
Cleocin T gel
one day hospital stay
(G-DRG J68B)
Grade 3/4 fatigue
0.75
one additional outpatient
visit
2-10 days of hospital
stay (G-DRG Z65Z)
Grade 3/4 diarrhea
0.05
one additional outpatient
visit and intake of
loperamide (30 capsules)
2-7 days of hospital stay
(G-DRG G67C)
Grade 3/4 febrile
neutropenia
0
Grade 3/4 neutropenia
0.98
one additional outpatient
visit and prophylactic GCSF (filgrastim 480 µg, 10
vials) (19.2% of patients)
one day hospital stay
(G-DRG Q60C)
Grade 3/4 anemia
0.95
one additional outpatient
visit and transfusion of
two red blood cell
concentrates
one day hospital stay
(G-DRG Q61D)
Grade 3/4
thrombocytopenia
0.95
one additional outpatient
visit and transfusion of one
platelet concentrate (20%
of patients)
one day hospital stay
(G-DRG )
Grade 3/4
aminotransferase rise
0.98
one additional outpatient
visit
one day hospital stay
(G-DRG Z65Z)
Grade 3/4 appetite loss
0.90
one additional outpatient
visit
2-11 days of hospital
stay (G-DRG K62B)
2-12 days of hospital
stay (G-DRG T64B)
G-CSF, granulocyte colony-stimulating factor; G-DRG, German Diagnosis Related Groups
3
Webtable 3 Details on parameters varied in one-way sensitivity analysis
Model input parameter
Probabilities
EGFR mutation prevalence in patients with
Adeno-NSCLC
Not enough tissue for EGFR testing
Base case
(mean)
Lower
0.128
0.115
0.184
Upper
95% CI
0.143
Reference
[2]
Clinical data do not support rebiopsy
0.1
0.151
0.222
Clinical expert
0.08
0.12
Non-informative rebiopsy
0.175
0.15
0.066
0.062
0.002
0.01
0.001
0.009
0.005
0.4
0.004
0.007
Clinical expert
0.10
0.50
0.061a
0.281a
0.492a
0.183a
0.035
0.207
0.423
0.148
95% CI
0.103
0.33
0.562
0.259
[7]
[7]
[7]
[7]
0.048
0.06
0.131
0.012
0.024
0.019
0.026
0.075
0.002
0.007
0.116
0.132
0.22
0.064
0.083
[8]
[8]
[8]
[8]
[8]
0.037
0.195
0.22
0.037
0.024
0.146
0.024
0.013
0.102
0.124
0.294
0.144
0.321
0.013
0.102
0.007
0.085
0.086
0.239
0.007
0.085
Clinical expert
Complications of biopsy procedures
Pneumothorax (percutaneous needle aspiration
biopsy)
Pneumothorax (bronchoscopic biopsy)
Severe hemorrhage (percutaneous needle
aspiration biopsy)
Severe hemorrhage (bronchoscopic biopsy)
Proportion of patients receiving chemotherapy in
inpatient settings
Proportion of patients receiving different
chemotherapeutic regimens
Cisplatin plus docetaxel
Cisplatin plus gemcitabine
Carboplatin plus docetaxel
Carboplatin plus gemcitabine
Grade 3/4 adverse event probabilities (total
reported)
Erlotinib (n=84)
Diarrhea
Fatigue
Rash
Anemia
Aminotransferase rise
Platinum-based chemotherapy (n=82)
Anemia
Fatigue
Neutropenia
Febrile neutropenia
Alopecia
Thrombocytopenia
Appetite loss
Proportion of patients assumed to be treated as
outpatients
Diarrhea
Fatigue
Rash
Anemia
Aminotransferase rise
Neutropenia
Febrile neutropenia
Thrombocytopenia
Appetite loss
0.20
95% CI
0.07
0.003
0.012
[3]
Thoracic Hospital
of Heidelberg
Thoracic Hospital
of Heidelberg
[4]
[5, 6]
[4]
[5, 6]
University Hospital
of Munich
[8]
[8]
[8]
[8]
[8]
[8]
[8]
University Hospital
of Munich
0.05
0.75
0.95
0.95
0.98
0.98
0
0.95
0.9
0
0.7
0.9
0.9
0.95
0.95
fixed
0.9
0.8
0.1
0.8
1
1
1
1
fixed
1
1
4
Model input parameter
Probabilities
Proportion of patients receiving second-line
chemotherapy within first-line chemotherapy
group
Proportion of patients receiving second-line
chemotherapy within first-line erlotinib group
Health state utilities
Stable disease while receiving oral therapy
Stable disease while receiving IV chemotherapy
Progressive disease
Disutilities related to adverse events
Diarrhoea
Fatigue
Rash
Neutropenia
Febrile neutropenia
Thrombocytopenia
Pneumothorax
Haemorrhage
Hair loss
Anemia
Costs
Drug acquisition
Erlotinib
Cisplatin plus docetaxel
Cisplatin plus gemcitabine
Carboplatin plus docetaxel
Carboplatin plus gemcitabine
1 tube of Cleocin T gel (60 g 1% cream)
Neupogen (480 µg), 10 vials
Loperamide (2 mg), 30 tablets
Medical services (outpatient)
Bronchoscopic biopsy of pulmonary nodules,
performed outpatient (EBM codes 13662, 13642)
EGFR mutation testing using DNA sequencing of
exons 19 to 21 (EBM 11212, EBM 11322)
Outpatient management of oral therapy (EBM
codes 13492, 13500, 13502, 86512)
Outpatient management of IV chemotherapy
(EBM codes 13492, 13500, 13502, GOP 86512,
86516)
Chemotherapy infusion, 4 hours (EBM code
01511)
Chemotherapy infusion, 30 minutes (EBM code
02100)
Outpatient visit (dermatology)
Outpatient visit (internal medicine)
Red blood cell transfusion (incl. EBM codes
02110, 02111, 32540, 32545, 32556)
Platelet transfusion (incl. EBM codes 02110,
32540)
Medical services (inpatient)
Bronchscopic biopsy of pulmonary nodules, with
one day hospital stay (or mean length of stay) (GDRG E71B)
Base case
(mean)
Lower
Upper
Reference
0.195
0.124
95% CI
0.294
[8]
0.627
0.490
0.747
[8]
0.672
0.653
0.473
0.627
0.609
0.412
0.718
0.696
0.533
[1, 9]
[9]
[9]
-0.047
-0.073
-0.032
-0.09
-0.09
-0.053
-0.023
-0.023
-0.045
-0.07
Unit costs
2014
-0.082
-0.114
-0.059
-0.122
-0.124
-0.064
-0.028
-0.028
-0.078
-0.084
Upper
-0.021
-0.041
-0.014
-0.062
-0.061
-0.043
-0.019
-0.019
-0.021
-0.057
Lower
[9]
[9]
[9]
[9]
[9]
[6]
[6]
[6]
[9]
[10]
Reference
€1,839
€1,529
€978
€1,710
€984
€43
€1,616
€6
€1,471
€1,223
€782
€1,368
€787
€34
€1,293
€5
± 20%
€2,206
€1,835
€1,173
€2,052
€1,180
€51
€1,939
€7
€121
€97
€146
[13]
€323
€258
€387
[13]
€100
€80
€119
[13]
€268
€215
€322
[13]
€97
€77
€116
[13]
€6
€5
€7
[13]
€19
€65
€155
€15
€53
€77
€23
€79
€232
[13]
[13]
[13]
€506
€405
€607
[13]
€796
(€1,992)
€636
(€1,594)
€955
(€2,390)
[14]
[11]
[11]
[11]
[11]
[11]
[12]
[1, 11]
[11]
5
Costs
Unit costs
2014
Upper
Percutaneous needle aspiration biopsy of
pulmonary nodules, with 1 day hospital stay (or
mean length of stay) (G-DRG E71A)
Biopsy of metastatic sites, with one day hospital
stay (or mean length of stay) (G-DRG E02C)
Hospitalization for pneumothorax (G-DRG
E76C)
Hospitalization for hemorrhage, with one day
hospital stay (G-DRG X62Z)
IV chemotherapy admission with one day
hospital stay (G-DRG E71B)
Oncology day fee
€1,645
(€4,328)
€1,316
(€3,462)
± 20%
€1,974
(€5,194)
€2,064.56
(€4,338)
€3,005
€1,653
(€3,470)
€2,404
€2,478
(€5,205)
€3,606
[14]
€695
€556
€833
[14]
€796
€636
€955
[14]
€150
€120
€180
1 day hospital stay for rash (G-DRG J68B)
Hospitalization for diarrhea (G-DRG G67C)
Hospitalization for fatigue (G-DRG Z65Z)
1 day hospital stay for anemia (Q61D)
1 day hospital stay for aminotransferase rise (GDRG Z65Z)
1 day hospital stay for non-febrile neutropenia
(G-DRG Q60C)
Hospitalization for febrile neutropenia (G-DRG
T64B)
1 day hospital stay for thrombocytopenia (GDRG Q60C)
Hospitalization for anorexia (G-DRG K62B)
€612
€1,402
€1,610
€944
€701
€490
€1,121
€1,288
€755
€561
€735
€1,682
€1,932
€1,133
€841
University
hospital of
Munich
[14]
[14]
[14]
[14]
[14]
€811
€649
€974
[14]
€3,289
€2,632
€3,947
[14]
€811
€649
€974
[14]
€1,957
Base case
(mean)
0.03
€1,566
Lower
€2,349
Upper
[14]
Reference
0.00
0.05
Discount rate (per annum)
Lower
Reference
[14]
[14]
a
Each probability was varied while the remaining proportions were adjusted by the same percentage to ensure
that the sum of probabilities adds up to one.
Adeno, adenocarcinoma; EBM, ambulatory physicians’ fee schedule (“Einheitlicher Bewertungsmaßstab”); GDRG, German Diagnosis Related Groups; GOP, fee schedule position ("Gebührenordnungsposition"); incl,
including; IV, intravenous; OS, overall survival; NSCLC, non-small cell lung cancer; PFS, progression-free
survival
6
Webfig. 1 Survival curves in patients with first-line erlotinib or chemotherapy in locally
advanced/metastatic non-small-cell lung cancer. The original curves from the clinical trial are
shown, together with the Weibull and Exponential model estimated for progression-free
survival (lower curves) and overall survival (upper curves) separately.
OS, overall survival; PFS, progression-free survival
7
Webfig. 2 Survival curves in patients with first-line erlotinib or chemotherapy in locally
advanced/metastatic non-small-cell lung cancer. The original curves from the clinical trial are
shown, together with the flexible spline model estimated for progression-free survival (lower
curves) and overall survival (upper curves).
OS, overall survival; PFS, progression-free survival
8
Webfig. 3 Two-way sensitivity analysis of EGFR mutation prevalence and costs of mutation
analysis. Base case values are indicated by horizontal and vertical lines, respectively. Shaded
areas represent specified ICER or dominance of individualized strategy vs. non-individualized
strategy.
EGFR, epidermal growth factor receptor; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted
life years
9
Webfig. 4 Probabilistic sensitivity analysis of individualized strategy versus nonindividualized strategy, assuming no uncertainty in the PFS and OS curves. Scatter plot based
on 10,000 replications.
Base case ICER was €15,577/QALY compared to non-individualized strategy. The 95% confidence interval
ranges from €131to €309 (mean €200) for incremental costs and from 0,009 to 0,017 (mean 0,013) for
incremental effects.
OS, overall survival; PFS, progression-free survival; QALYs, quality-adjusted life years
10
Webfig. 5 Cost-effectiveness acceptability curve (CEAC) of individualized strategy,
assuming no uncertainty in survival curves
11
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