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a coST-uTiliTy aNalySiS of NaB-PacliTaXel (aBraXaNe) PluS GeMciTaBiNe iN MeTaSTaTic PaNcreaTic caNcer iN SlovaK rePuBlic
radovan Stetka1, Maria Psenkova1, Martina ondrusova1, Tomas Pastorek2, Tomas Salek3
1
Pharm-In ltd., Karadzicova 16, Bratislava, Slovakia, 2Celgene Ltd., Bratislava, Slovakia, 3Narodny onkologicky ustav, Bratislava, Slovakia
ISPOR 18th ANNUAL EUROPEAN CONGRESS, 7-11 NOVEMBER 2015, MILAN
PCN193
In the clinical trial, Nab-paclitaxel + gemcitabine patients were on treatment longer than patients treated with gemcitabine. The same approach
was undertaken and the stratified gamma model was selected, Figure 4.
Pancreatic cancer has the worst survival rate amongst all cancers. The average survival rate is between 3 and 6 months from diagnosis with a 1
year survival rate of between 10% and 23% (1). The poor prognosis of pancreatic cancer is partly attributed to the disease being extremely
difficult to treat as well as patients being diagnosed at a late stage with over 55% of patients presenting with stage IV at the time of diagnosis
(2). The severity of pancreatic cancer, in combination with the limited number of effective treatments, results in a high level of unmet need.
ePiDeMioloGy
The annual incidence of pancreatic cancer in the United States (US) (2013) and Europe (2012) is estimated at 45,220 and 78,654, respectively
(3), (4). Estimated incidence in Slovakia for 2015 was calculated using Join-point regression analysis and represents 942 new cases (crude rates
of incidence 17.3/100,000; age-standardized incidence to the World standard population 9.1/100,000) (5). Slovakia is according to the IARC
WHO the leading European country in estimated incidence of pancreatic cancer for 2012 (6). Although pancreatic cancer has a lower incidence
than other common cancers, it is increasing steadily, and is the fourth-leading cause of cancer death in Slovakia.
Figure 4.
Percentage On Treatment
overview
Comparative Survival: Nab-paclitaxel + Gemcitabine vs. Gemcitabine Alone including the
ToT modelled in the patient flow
Nab -paclitaxel + gemcitabine
100%
KM Nab -pac + gem
Gemcitabine
3
4
KM Gem
80%
60%
40%
20%
0%
0
1
2
Years
5
ProGNoSiS aND TreaTMeNT
Gemcitabine monotherapy is the current standard of care for the first-line treatment of unresectable metastatic pancreatic cancer in the Slovakia.
Alternatives include a range of treatments used in combination with gemcitabine (“gem doublets”) (7). FOLFIRINOX is used as the first-line
treatment in less than 5% of patients eligible for chemotherapy, and its use is typically only for very fit patients due to tolerability concerns (8).
Nab-paclitaxel is a solvent-free paclitaxel formulation approved for first-line treatment of patients with metastatic pancreatic cancer (MPC) in
combination with gemcitabine. Treatment with Nab-paclitaxel and gemcitabine has been shown to be clinically effective in this area of high
unmet need. Patients treated with Nab-paclitaxel and gemcitabine had an increase in median overall and progression free survival of 1.8 months
and 3.3 months in patient subgroup with Karnofsky Performance Score 70-80, compared to those treated with gemcitabine alone (9).
coST-uTiliTy aNalySiS
This poster presentation outlines a cost-utility analysis of Nab-paclitaxel + gemcitabine regimen for the first-line treatment of metastatic
pancreatic cancer in specific patient population with a KPS 70-80 in whom the clinical- and cost-effectiveness of Nab-paclitaxel can be
demonstrated to be particularly favorable in Slovak settings.
coST-effecTiveNeSS MoDel
Figure 1. Model schema
Pre p
progression:
rogression:
O
On
n fi
first-line
rst-line
Trea
Treatment
tment
Pre progression:
progression:
rst-line
Off
first-line
O
ff fi
Trea
tment
Treatment
There are four main model states Figure 1.:
• pre-progression: on treatment,
• pre-progression: off treatment
• post-progression or
• death.
weeks
4w
eeks
tto
o death
death
Post
P
ost
progressio
p
rogressio
coMParaTor
Table 1.
The first-line treatments under consideration are:
• Nab-paclitaxel + gemcitabine
• Gemcitabine monotherapy
4w
weeks
eeks
death
to
to d
eath
OS parameters
Gemcitabine monotherapy
Observed OS
11.82%
0.70%
NA
Figure 2.
Modelled PFS
9.24%
0.64%
0.03%
Gemcitabine monotherapy
Observed PFS
2.54%
NA
Nab-paclitaxel + gemcitabine
(Total = 38%)
1%
17%
4%
7%
4%
1%
0%
8%
7%
13%
3%
4%
3%
1%
0%
6%
Romanus et al. (2012)
Local Quality of life data are not published in Slovakia. Therefore, in the base case,
Romanus et (11) al utility values were used. This was the only study reporting
Mean
SE
separate utility values by disease stage for advanced pancreatic cancer patients.
Pre-progression: Stable Disease
0,80
0,01
Utilities were valued using EQ-5D with TTO values from the general population. The
Progressive disease
0,75
0,02
study reported utility values for the pre-progression and post-progression health
states at baseline and eight weeks. In order to calculate the utility value for each of the respective states an average of the baseline and eight
week value for the pre-progression (0.79,0.81) and post-progression (0.77,0.73) health states were used.
Modelled PFS
2.05%
0.15%
0.00 %
KM Gem
Costs
LY
€ 9,912.13
0.808
€ 3,969.52
0.534
€ 5,942.61
0.274
€ 27,769
Nab-paclitaxel + gemcitabine
Gemcitabín
Increment
ICER
Table 8.
Table 7.
Base case results
0.231
0.147
0.252
0.629
0.193
0.049
0.173
0.415
One way sensitivity analysis (OWSA) was conducted
to determine the key input parameters in the model.
This analysis was conducted by varying each input
to their upper and lower 95% sequentially and
recording the results at each stage. The ten most
influential parameters are shown in Table 9.
coNcluSioN
Breakdown of base case cost results
(discounted)
Nab-paclitaxel
+ gemcitabine
Gemcitabine
€ 6,376.83
€ 615.04
€ 147.40
€ 134.99
Pre Progression: Drug Cost
Pre Progression: Administration Costs
Pre Progression: Monitoring Costs
Nab-paclitaxel Gemci+ gemcitabine tabine Difference
SeNSiTiviTy aNalySiS
The stratified gamma survival extrapolation were
used in the model, Figure 2, Figure 3
QALY
0.629
0.415
0.214
Breakdown of base case QALY results
(discounted)
Pre-progression: First-line treatment
Pre-progression: Off treatment
Post progression
Total
Data from MPACT study were used to estimate
the efficacy of treatment with Nab-paclitaxel +
gemcitabine and gemcitabine monotherapy (10).
Parametric survival models were estimated for the
three endpoints of overall survival (OS),
progression free survival (PFS) and time on
treatment (ToT), Table 2 and 3. The survival models
enable the cost-effectiveness model to
incorporate outcomes which occur after the trial
period.
Gem
Table 6.
Heath state/treatment
Comparative Overall Survival: Nab-pac + Gemcitabine vs. Gemcitabine Alone
Nab -pac + gem
Percentage Survival
Modelled OS
13.11%
0.70%
0.02%
PFS parameters
Observed PFS
8.97%
NA
NA
Gemcitabine
(Total= 42%)
cliNical efficacy
Nab-pac + gemcitabine
1 year
3 years
5 years
Patients moving onto second-line therapies (%)
Fluorouracil (5-FU)
Fluorouracil (5-FU) + Oxaliplatin
Capecitabine + gemcitabine
Capecitabine
Erlotinib + gemcitabine
Erlotinib
Nab-paclitaxel + gemcitabine
FOLFIRINOX
Nab-pac + gemcitabine
Table 3.
Utilities for Each Health State
Official ICER threshold for regular access of medicines to the Reimbursement List in Slovakia for 2015 is € 19,776 and € 28,840 for conditional
access. Results for the base case against gemcitabine show an ICER of € 27 769 (discounted), Table 6. Treatment with Nab-paclitaxel + gemcitabine
results in an incremental increase of 0.214 QALYs and incremental total cost € 5,942.61. A breakdown of costs and QALYs is given in Table 7 and
Table 8.
Death
Death
Second-line treatment
Second-line treatment
The eight most prevalent second-line treatments
reported in the MPACT study have been included in
the model and have been adjusted to reflect the
difference in the overall percentage of patients
moving on to second-line therapy in each arm (i.e.
adjusted such that the sum of eight selected therapies
is equal to total percentage moving on to second-line
treatment in each arm). Patients who do not move on
to active second-line therapy move on to palliative
care.
1 year
3 years
5 years
Table 4.
reSulTS
The model takes a Slovak health insurance perspective. The only costs accrued in the model are therefore direct costs of the health insurance. The
model takes a life-time time horizon. Due to the severity of the condition a 10-year time horizon is long enough to model the cohort of patients
until the to death. Costs and health gains are discounted at 5 % per annum in line with the Slovak methodological guideline.
Modelled OS
27.84%
2.28%
0.15%
QualiTy of life (Qol)
Routine care costs as well as treatment costs are applied to each health state and discounted with 5% discount rate defined in the
methodological guideline of Slovak Ministry of Health. Costs associated with MPC were derived from a local cost study (12). The cost study was
designed to measure the resource utilization and the direct costs associated with health-care management of patients with MPC in Slovakia
and to provide a basis for cost-effectiveness evaluations. Dosing information for each of the first-line therapies was taken from studies on each
of the relevant interventions. Dosing for most of the interventions is based on body surface area (BSA) as mg/m2 and as such the weekly dose
was adjusted to account for the average BSA, which was assumed to be 1.7 m2 for Slovak pancreatic cancer population. The dosing used for
each of the treatments in second-line treatment was assumed to be the same as those identified in first line.
PerSPecTive aND DiScouNT raTe
Observed OS
31.78%
3.97%
NA
The type, severity and rate of adverse events can vary between chemotherapy treatments leading to differences in overall HRQL, resource use
and costs. In order to capture these differences, treatment emergent adverse events of grade three and above that occur in over 5% of patients,
on either arm, were included in the model.
coSTS
The cost-effectiveness analysis evaluates Nab-paclitaxel + gemcitabine
in the first-line treatment of metastatic pancreatic cancer. The model
uses an “area under the curve” modelling approach to estimate patients
transitions between defined health states from beginning of the
treatment to death. Patients enter the model in the “Pre progression:
on first line treatment” state. All patients remain there for the duration
of the first cycle which is one week.
Table 2.
aDverSe eveNTS
0.038
0.098
0.079
0.214
Table 9.
€ 1,076.25
€ 977.95
Pre Progression: Adverse Event Costs
€ 232.31
€ 308.56
Off Treatment: Monitoring Costs
€ 128.55
€ 42.63
Post Progression: Drug Cost
€ 416.52
€ 424.09
€ 67.15
€ 64.91
Post Progression: Monitoring Costs
€ 755.23
€ 699.56
Post Progression: Terminal Care
€ 540.30
€ 545.92
Post Progression: Adverse Events
€ 171.60
€ 155.86
€ 9,912.13
€ 3,969.52
Post Progression: Administration Costs
Total
OWSA Analysis: ten most influential parameters in CUA
Parameter
OS Gamma-Treat
PFS Stratified Gamma-Ln (sigma) treat
PFS Stratified Gamma-Kappa treat
OS Gamma-Kappa
OS Gamma-Ln(sigma)
Administration costs chemotherapy
per treatment (simple)
OS Gamma-Cons
PFS Stratified Gamma-Treat
Utility in pre-progression health state
Cycle Probability Abraxane armFebrile Neutropenia
Lower bound Upper bound Difference
€ 45,390
€ 26,181
€ 29,180
€ 28,755
€ 28,525
€ 21,097
€ 29,558
€ 26,313
€ 26,546
€ 26,473
€ 24,293
€ 3,377
€ 2,867
€ 2,209
€ 2,052
€ 27,639
€ 28,403
€ 764
€ 28,218
€ 28,152
€ 27,541
€ 27,479
€ 27,540
€ 30,322
€ 739
€ 612
€ 581
Nab-paclitaxel + gemcitabine fulfils an unmet clinical
need in MPC patients offering the high-level efficacy
€ 27,438
€ 28,954
€ 516
combined with acceptable tolerability. The extension
of life shown in the MPACT study translates to an
increase of 0.214 QALYs. An increase of total costs of € 5,942.61 results in an ICER of € 27,769; which is below the threshold set in Slovakia. Nabpaclitaxel + gemcitabine met very strict criteria for approving the conditional access to the Reimbursement List in Slovakia.
SourceS
KM Nab -pac + gem
1. Malvezzi M, Bertuccio P, Levi F, et al. European cancer mortality predictions for the year 2013. Annals of oncology : official journal of the European
Society for Medical Oncology / ESMO. 2013; 24(3):792-800.
100%
80%
2. Seufferlein T, Bachet JB, et al. Pancreatic adenocarcinoma: ESMO-ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals
of oncology : official journal of the European Society for Medical Oncology/ESMO. 2012; 23 Suppl 7:vii33-40.
60%
3. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008 v2.0. Cancer Incidence and Mortality Worldwide: IARC CancerBase No.
10 2010 http://globocan.iarc.fr.
40%
20%
4. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur.J
Cancer. 2013;49(6):1374-1403.
0%
0
1
2
Years
3
4
5
5. Safaei-Diba, Ch., Pleško, I. (eds.): Cancer incidence in the SR in 2008. NCZI, Bratislava 2014, 175 s. ISBN 978-80-89292-37-0.
6. Ferlay, J., Soerjomataram, I., Ervik, M., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D.M., Forman, D., Bray, F.: GLOBOCAN 2012 v1.0. Cancer
Incidence and Mortality Worldwide: IARC CancerBase No. 11. [Online] 30. 10 2015.
Figure 3.
Comparative Progression Free Survival: Nab-pac + Gemcitabine vs. Gemcitabine Alone
Nab -pac + gem gamma curve fit
Percentage PFS
100%
KM Nab -pac + gem
KM Gem
7. Heinemann V, Boeck S, Hinke A, et al. Meta-analysis of randomized trials: evaluation of benefi t from gemcitabine-based combination
chemotherapy applied in advanced pancreatic cancer. BMC Cancer. 2008;8:82.
gem gamma curve fit
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9. Hidalgo M, et al. SPARC Analysis in the Phase III MPACT Trial of nab-Paclitaxel Plus Gemcitabine vs Gem Alone for Patients With Metastatic
Pancreatic Cancer. ESMO 16th World Congress on Gastrointestinal Cancer 2014; June 25-28; Barcelona, Spain.
80%
60%
10. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. The New England journal of
medicine. 2013; 369(18):1691-703.
40%
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randomized phase III trial CALGB 80303. Journal of pain and symptom management. 2012; 43(2):205-17.
20%
0%
0
1
2
Years
3
4
5
12. Ondrušová M, Pšenková M. Vybrané ukazovatele deskriptívnej epidemiológie pri karcinóme pankreasu. Pharm-In, spol. s r. o., Bratislava.
http://pharmin.sk/sk/epidemiologicke-studie/
Address for correspondence: Maria Psenkova, Pharm-In, spol. s r.o., Karadzicova 16, City Business Center V, 821 08 Bratislava, e-mail: [email protected]