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[logo] TLV
TANDVÅRDS- OCH
LÄKEMEDELSFÖRMÅNSVERKET
[THE DENTAL AND PHARMACEUTICAL BENEFITS
AGENCY]
Zaltrap (aflibercept)
Health-economic supporting documentation
Evaluated indication
ZALTRAP combined with irinotecan/5-fluorouracil/folic acid (FOLFIRI) chemotherapy is
indicated for adult patients with metastatic colorectal cancer (MCRC) that is resistant to or
has progressed after treatment containing oxaliplatin.
September 2013
Clinical drug project
The Swedish Dental and Pharmaceutical Benefits Agency (TLV) has been commissioned by
the government to in the form of a pilot project implement health-economic assessments of
selected drugs used in inpatient care. Within the framework of the commission TLV will not
make any decisions, merely compile health-economic supporting documentation.
The NLT (New Drug Therapies) group indicates which drugs are to be assessed in the clinical
drugs project and provides recommendations to the county councils based on the healtheconomic supporting documentation.
The assessment is part of the national drugs strategy to develop a long-term, sustainable
pricing, priority and financial model for all pharmaceuticals.
The health-economic supporting documentation has been produced in accordance with TLV’s
general guidelines on health economics established methods.
Sofia Wallström
Director General, TLV
Project group:
Gustaf Befrits (Health Economist), Magnus Köping-Höggård (Medical Investigator) and Johanna Mörnefält (Lawyer).
Scientific experts:
Docent Gustav Ullenhag and Professor Roger Henriksson have acted as scientific experts in this matter. They have been
consulted regarding current clinical practice as well as in terms of interpretation of the medical basis in the material. TLV is not
bound by the expert’s statements, interpretations or opinions regarding which assumptions the cost-effectiveness analysis should
be based on.
Company: Sanofi-Aventis AB
Journal number: 1778/2012
Tandvårds- och läkemedelsförmånsverket
Address: Box 22520, 104 22 Stockholm
Street address: Fleminggatan 7, 4 trappor, Stockholm
Phone: 08 568 420 50
www.tlv.se
ii
TLV’s assessment and summary

Zaltrap(aflibercept) combined with chemotherapy (irinotecan/5-fluorouracil/folic acid,
FOLFIRI) is indicated for adult patients with metastatic colorectal cancer (MCRC) that is
resistant to or has progressed after treatment containing oxaliplatin.

Colon and rectal cancer (colorectal cancer) is the most common form of cancer in Sweden
after prostate and breast cancer. When the disease has progressed to metastases it is
usually terminal and palliative treatment is given. Second-line palliative treatment
includes combinations of chemotherapy, possibly combined with targeted biological
therapy, especially bevacizumab.

Aflibercept is a VEGF inhibitor (a type of targeted biological therapy) that blocks the
activation of VEGF receptors and thereby proliferation (growth) of the endothelium in
blood vessels, inhibiting the growth of new blood vessels that supply tumours with oxygen
and nutrients.

The VELOUR study evaluated the efficacy and safety of aflibercept in combination with
FOLFIRI compared to placebo in combination with FOLFIRI. The study included a total of
1,226 relatively young patients in good general health who had previously had oxaliplatinbased therapy. The primary measure of efficacy was the total survival and the secondary
measure of efficacy included progression-free survival.

Combination therapy with aflibercept and FOLFIRI significantly increased the total survival
compared to placebo and FOLFIRI, with a median survival of 13.50 and 12.06 months for
the respective therapies. Aflibercept also increased progression-free survival significantly,
with a progression-free median survival of 6.90 months compared to 4.67 months with
placebo.

The adverse reactions resulted in permanent discontinuation of treatment for 26.8% of
patients treated with aflibercept and FOLFIRI and 12.1% of patients with placebo and
FOLFIRI. The most commonly reported reactions of stage 3-4 were neutropaenia,
diarrhoea, hypertension, leukopaenia, stomatitis, fatigue, proteinuria.

The company’s health-economic analysis consists of a cost-minimisation analysis with the
rationale that the drug is as effective as currently available options. The company has
calculated the cost per treatment cycle for second-line treatment of metastatic colorectal
cancer with the existing biological drugs that can be used under these treatment
circumstances. The calculations include pharmaceutical costs as well as costs for treatment
of adverse reactions.

The cost per treatment cycle amounts to SEK 12,405 for aflibercept, SEK 13,324 for
bevacizumab (Avastin), SEK 21,036 for cetuximab (Erbitux) and SEK 20,751 för
panitimumab (Vectibix). Currently, bevacizumab in particular is used in second-line
treatment if not given in the first line.

TLV accepts a cost-minimisation analysis in this specific case.

The uncertainty in the cost-minimisation analysis is relatively low. Assumptions regarding
an equivalent effect must be sustained, otherwise the analysis is incorrect. Any price
reductions obtained alter the conditions in the analysis, which in such cases needs to be
recalculated based on current prices.
The findings in the documentation may be subject to change if the conditions that form the
basis of the health-economic analysis change significantly.
3
Contents
1
Clinical summary ............................................................................................................................... 1
1.1
The disease.................................................................................................................................................. 1
1.2
The drug ...................................................................................................................................................... 1
1.2.1 Indication ................................................................................................................................................ 1
1.2.2 Mechanism of action .............................................................................................................................. 1
1.2.3 Dosage/administration ............................................................................................................................ 2
1.2.4 Adverse reactions ................................................................................................................................... 2
1.3
Clinical documentation as a basis for the health-economic analysis .......................................................... 3
1.3.1 Method.................................................................................................................................................... 3
1.3.2 Results .................................................................................................................................................... 3
1.3.3 Other therapies for second-line treatment of metastatic colorectal cancer ............................................. 5
1.4
Current treatment recommendations and comparison options .................................................................... 7
1.4.1 Current treatment recommendations ....................................................................................................... 7
1.4.2 Comparators ............................................................................................................................................... 8
2
Health-economic analysis................................................................................................................... 9
2.1
2.2
2.3
Cost-minimisation analysis ......................................................................................................................... 9
Quality of life and cost-effectiveness ........................................................................................................ 11
Uncertainty in the results .......................................................................................................................... 11
3
Authority observations..................................................................................................................... 12
4
Further issues.................................................................................................................................... 13
5
Bibliography ..................................................................................................................................... 14
Appendix 1 ECOG performance status
Appendix 2 An introduction to health-economic evaluation
4
1 Clinical summary
1.1 The disease
Colon and rectal cancer (colorectal cancer) is the most common form of cancer in Sweden
after prostate and breast cancer. Every year, approximately 6,000 people become ill. Surgery
is the most important measure for curative purposes. Early-stage tumours can generally be
operated on. If the tumour has spread to other parts of the body (distant metastases), surgery
is usually not possible. When the disease has progressed to metastases it is usually terminal
and palliative treatment (end-of-life palliative care), in the form of chemotherapy and possibly
in combination with bevacizumab, should be considered. For most patients the most
important goals in palliative treatment of terminal cancer are prolonged survival and
enhanced quality of life.
If the disease continues to progress after the first treatment cycle with a drug (so-called firstline treatment), the treatment may be repeated with the same drug (if progression of disease
occurred only after discontinuation of treatment) or with another type of drug (so-called
second-line treatment, etc.).
Second-line treatment often includes a combination of chemotherapy, possibly with the
addition of targeted biological therapy. This documentation concerns second-line treatment of
metastatic colorectal cancer.
1.2 The drug
1.2.1 Indication
Zaltrap is indicated for combined use with chemotherapy (irinotecan/5-fluorouracil/folic acid,
FOLFIRI) in adult patients with metastatic colorectal cancer (MCRC) that is resistant to (no
treatment effect) or has progressed (continued to grow) after chemotherapy and treatment
containing oxaliplatin.
1.2.2 Mechanism of action
Background
Vascular endothelial growth factor A (VEGF-A), B (VEGF-B) and placental growth factor
(PlGF) belong to the family of vascular growth factors (VEGF) that occur naturally in the
body. Normally, VEGF binds and stimulates two different receptors on the surface of the
endothelial cells (VEGFR-1 and VEGFR-2). PlGF only binds to VEGFR-1, which is also found,
in addition to on the endothelial cells, on the surface of leukocytes (white blood cells). Strong
stimulation of these receptors (VEGFR-1 and 2) may lead to pathological vascularisation
(pathological neovascularisation) and extensive leakage from the blood vessels (vascular
permeability). PlGF enhances the effect of VEGF and promotes leukocyte infiltration (white
blood cells penetrate into tissue) and vascular inflammation (blood vessel inflammation).
How aflibercept works
Aflibercept is a recombinant fusion protein that acts as a “false” receptor that binds VEGF-A,
VEGF-B and PlGF in a more powerful way than the body’s own receptors (VEGFR-1 and VEGFR2). By aflibercept binding VEGF and PlGF, the body’s own receptors that bind VEGF/PIGF are
impeded, which leads to a reduced growth of the endothelium in blood vessels, reduced
formation of blood vessels and reduced leakage from the blood vessels.
a
Cell layers in the heart, blood and lymph vessels
1
1.2.3 Dosage/administration
The recommended Zaltrap dose is 4 mg/kg of body weight administered as an intravenous
infusion for 1 hour, followed by the FOLFIRI doseb. This is considered as one treatment cycle.
The treatment cycle should be repeated every two weeks.
Treatment with Zaltrap should continue until progression of disease or until unacceptable
toxicity occurs.
1.2.4 Adverse reactions
According to the SPC [1], the safety of aflibercept in combination with FOLFIRI has been
evaluated in a phase III study titled VELOUR [2] in 1,216 patients who have previously been
treated for metastatic colorectal cancer. Of these, 611 patients were treated with aflibercept 4
mg/kg every two weeks (one cycle) and 605 patients were treated with placebo. The patients
received an average of 9 cycles of aflibercept/FOLFIRI treatment.
Aflibercept gave rise to adverse reactions associated with treatment with VEGF inhibitors,
which include hypertension, bleeding and fistula formation. The addition of aflibercept also
increased the frequency of adverse reactions associated with treatment with FOLFIRI, such as
diarrhoea, neutropaeniac and stomatitisd.
The most common adverse reactions (all stages, ≥20% incidence) that were reported, with at
least 2 percentage points higher incidence for aflibercept/FOLFIRI compared to
placebo/FOLFIRI, were, in descending order of frequency: leukopaeniae, diarrhoea,
neutropaenia, proteinuriaf, elevated levels of ASTg, stomatitis, fatigue, thrombocytopaeniah,
elevated levels of ALTi, hypertension, weight loss, reduced appetite, epistaxisj, abdominal
pain, dysphoniak, increased serum creatinine and headache.
The most commonly reported reactions of stage 3-4 (≥5% incidence) reported, with at least 2
percentage points higher incidence for aflibercept/FOLFIRI compared to placebo/FOLFIRI,
were, in descending order of frequency: neutropaenia, diarrhoea, hypertension, leukopaenia,
stomatitis, fatigue, proteinuria and asthenial.
The adverse reactions resulted in permanent discontinuation of treatment for 26.8% of
patients treated with aflibercept/FOLFIRI and 12.1% of patients with placebo/FOLFIRI [2, 3].
The most common adverse reactions that resulted in permanent discontinuation of treatment
for ≥1% of patients treated with aflibercept/FOLFIRI were vascular diseases, including
hypertension, infections, asthenia/fatigue, diarrhoea, dehydration, stomatitis, neutropaenia,
proteinuria and pulmonary embolismm [1].
b
The FOLFIRI dose given at the same time on Day 1 consists of irinotecan 180 mg/m2 as an intravenous infusion
for 90 minutes and 400 mg/m2 of folic acid as an intravenous infusion for two hours. This should be followed by
5-fluorouracil (5-FU) 400 mg/m2 as an intravenous bolus dose, followed by 5-FU 2,400 mg/m2 as a continuous
intravenous infusion for 46 hours.
c
Abnormally low neutrophil count (a type of white blood cells in the blood).
d
Inflammation of the oral mucosa.
e
Reduction in number of circulating white blood cells (leukocytes).
f
The urine contains higher levels of protein than normal.
g
Aspartate aminotransferase, an enzyme (proteins that influence the rate of reactions in the body).
h
Lack of thrombocytes (platelets), resulting in an increased bleeding tendency.
i
Alanine aminotransferase, an enzyme in the body.
j
Epistaxis.
k
Dysphonia.
l
Weakness.
m
Pulmonary embolism.
2
In more than half of the cases, hypertension occurred during the first two treatment cycles
and the median time was comparable between patients treated with aflibercept/FOLFIRI and
placebo/FOLFIRI [3].
A higher number of patients treated with aflibercept/FOLFIRI died due to adverse reactions
compared to patients treated with placebo/FOLFIRI (2.3% vs. 0.7%) [3].
The company has submitted preliminary unpublished data (116 patients), based on the clinical
use of aflibercept, recorded in ASQoP (Aflibercept Safety and Quality of Life Program). Based
on these data, the adverse reaction complexity is slightly lower than what was reported in the
VELOUR study. The difference between the VELOUR study and ASQoP is that in the
VELOUR study all patients received full drug doses in the first course of treatment, while
ASQoP entailed the possibility to reduce the dose initially, depending on patient status and
how patients reacted to the first-line treatment. For the subsequent treatment courses there
was the opportunity to reduce the dose in both VELOUR and ASQoP.
1.3 Clinical documentation as a basis for the health-economic analysis
1.3.1 Method
The efficacy and safety of aflibercept was evaluated in a randomised, double-blind, placebocontrolled study (titled VELOUR) in patients with metastatic colorectal cancer who had
previously received oxaliplatin-based treatment with or without prior treatment with
bevacizumab [2].
In total 1,226 patients were randomised (1:1) to receive either


Aflibercept (612 patients; 4 mg/kg as a 1-hour intravenous infusion on
Day 1) + FOLFIRIn
Placebo (614 patients; as a 1-hour intravenous infusion on Day 1) + FOLFIRI.
The treatments were repeated every two weeks.
The patients were treated until progression of disease or until unacceptable toxicity occurred.
The primary measure of efficacy was total survival.
1.3.2 Results
The median age of the patients was 61 years; 58.6% were men. At baseline, 97.8% had a
performance status equivalent to ECOGo 0 or 1 and 2.2% had ECOG 2.
n
FOLFIRI: irinotecan 180 mg/m2 as an intravenous infusion for 90 minutes and 400 mg/m² of folic acid as an
intravenous infusion for two hours at the same time on Day 1 This was followed by 5-FU 400 mg/m² as an
intravenous bolus dose, followed by 5-FU 2,400 mg/m² as a continuous intravenous infusion for 46 hours.
3
The patients included in the study had received prior oxaliplatin-based chemotherapy and
approximately 30% of the patients had received prior oxaliplatin-based treatment in
combination with bevacizumab.
The patients were treated with an average of 9 cycles of aflibercept/FOLFIRI and 8 cycles of
placebo/FOLFIRI.
Statistically, combination therapy with aflibercept and FOLFIRI significantly increased the
total survival (1.44 months in median) compared to placebo and FOLFIRI (relative risk, 0.817;
95% CI, 0.713-0.937; p=0.0032), with a median survival of 13.50 and 12.06 months for the
respective therapies (Fig. 1).
Fig. 1 Total survival in the ITT population: Aflibercept/FOLFIRI compared to placebo/FOLFIRI
Statistically, aflibercept also increased progression-free survival significantly (relative risk,
0.758; 95% CI 0.661-0.869; p<0.0001), with a progression-free median survival of 6.90
months compared to 4.67 months with placebo (Fig. 2).
o
The ECOG (Eastern Cooperative Oncology Group) [sic: performance] status is a scale that measures
performance from 0 (fully active and able to perform activities that were performed before the disease) to 5
(death) (see Annex 1).
4
Fig. 2 Progression-free survival in the ITT population: Aflibercept/FOLFIRI compared to placebo/FOLFIRI
A similar trend in terms of the effect on overall and progression-free survival was seen in analyses
of prespecified subgroups, including patients previously treated with bevacizumab (Avastin).
The proportion of patients who responded to the treatment (objective responders, OR) was 19.8%
(95% CI 16.4-23.2%) with aflibercept/FOLFIRI compared to 11.1% (95% CI 8.5-13.8%) with
placebo/FOLFIRI (p=0.0001).
The survival rate after 24 months was 28.0% (95% CI, 23.7-32.4) for the group receiving
aflibercept, compared to 18.7% (95.34% CI, 14.9-22.5) for the group that received placebo. After 30
months the corresponding figures were 22.3% (95% CI, 17.8-26.8) with aflibercept, and 12.0%
(95% CI, 8.0-16.0) with placebo.
The effect of aflibercept in patients with a performance status of 2 or lower, as per ECOG, as well as
the effect in the elderly, cannot be considered established.
The adverse reactions resulted in permanent discontinuation of treatment for 26.8% of patients
treated with aflibercept/FOLFIRI and 12.1% of patients with placebo/FOLFIRI [2, 3].
1.3.3 Other therapies for second-line treatment of metastatic colorectal cancer
There are no comparative studies of aflibercept and other targeted biological treatment options.
In a literature review, the company has summarised results from studies in which the addition of
other targeted biological therapies to chemotherapy (irinotecan or oxaliplatin-based combination
chemotherapy such as FOLFIRI and FOLFOX) was investigated for second-line treatment of
metastatic colorectal cancer. Targeted biological therapy encompasses Avastin (bevacizumab;
VEGF inhibitor), Erbitux (cetuximab; EGFRp inhibitor) and Vectibix (panitumumab; EGFR
inhibitor). Table 1 summarises the studies in which the effect of targeted biological therapy has
been investigated as an addition to chemotherapy in second-line treatment of colorectal cancer.
5
Table 1 Summary of results from studies investigating the effect of targeted biological therapy as an
addition to chemotherapy in second-line treatment of colorectal cancer
Study
Treatment
Number
of
patients
Aflibercept
Cetuximab
Panitumumab
Bevacizumab
van Cutsem et al. [2].
Sobrero et al. [4]
Peeters et al. [5]
Bennouna et al. [6].
FOLFIRI +
Aflibercept
FOLFIRI
+
placebo
612
614
§
Irino- Irinotecan
tecan
+ cetuximab
648
§
650
§
FOLFIRI
+
Panitumumab
FOLFIRI
303
294
OSq median
(months)
13,50*
12,06
10,70
§
10,00
14,50
PFSr median
(months)
6,90*
4,67
4,00*
2,60
5,90*
Cytostatic Cytostatic
agent +
agent
bevacizumab
409
§
12,50
§
11,20*
§
3,90
§
5,70*
411
§
Bevacizumab
Giantonio et al.
[7].
FOLFOX
+
bevacizumab
FOLFOX
292
293
9,80
§
12,90*
§
10,80
§
4,10
7,30*
4,70
* Statistically significant difference compared to the control group (chemotherapy)
§ The primary measure of efficacy in the study
The company states that the overall survival is approximately 12 months in randomised,
controlled studies, in which current chemotherapy regimens used e.g. FOLFIRI and FOLFOX.
The addition of an EGFR inhibitor (cetuximab or panitumumab) did not show any significant
improvement of the total survival [4, 5]. The study by Sobrero et al. [4] also included cancer
patients with K-ras mutations. These patients (50% of those treated) showed no benefit from
EGFR inhibitors which means that the survival benefit with the addition of cetuximab is
underestimated.
The addition of bevacizumab to chemotherapy (either as oxaliplatin or irinotecan-based
treatment depending on what was used in the first-line treatment) resulted in a significantly
improved overall median survival of 1.4 months [6]. The median survival was 11.2 months
with bevacizumab and chemotherapy compared to 9.8 months with chemotherapy only.
The addition of bevacizumab to chemotherapy (FOLFOX) resulted in a significantly improved
overall median survival of 2.1 months [7]. The median survival was 12.9 months with
bevacizumab and FOLFOX compared to 10.8 months with FOLFOX only.
p
Epithelial Growth Factor Receptor.
OS is an abbreviation for Overall Survival.
r
PFS is an abbreviation for Progression Free Survival..
q
6
The company has in an analysis compared the adverse reaction profiles of aflibercept,
bevacizumab, cetuximab and panitumumab in combination with chemotherapy based on the
studies van Cutsem et al. [2], Sobrero et al. [4], Peeters et al. [5] and Bennouna et al. [6]. It is
noteworthy that partially different forms of chemotherapy were used as comparison options in
this analysis. In addition, the studies differ in terms of at which lowest frequency as well as
severity the adverse reactions were reported. According to the reported studies, treatment
with aflibercept is associated with a higher frequency of adverse reactions of stage 3-4 in the
form of hypertension, neutropaenia (including febrile neutropaenia), stomatitis and diarrhoea
(except in comparison to cetuximab) compared to other targeted biological therapies in
combination with chemotherapy. The company has not appended any estimation of the extent
to which the higher adverse reaction profile affects the patients’ quality of life.
TLV’s assessment: There are no direct comparative studies of aflibercept and other
targeted biological therapies. Consequently, there is uncertainty when making a statement on
the relative efficacy of various targeted biological therapies as additions to chemotherapy in
second-line treatment of metastatic colorectal cancer. The company and the experts in the
matter assigned by TLV believe that treatment with aflibercept provides almost the equivalent
effect to that of other targeted biological therapies in combination with chemotherapy. TLV
finds no reason to make any other assessment.
TLV assesses, in accordance with the company’s analysis, that treatment with aflibercept and
FOLFIRI is linked to a higher adverse reaction complexity compared to the alternative
treatment regimens.
1.4 Current treatment recommendations and comparators
1.4.1 Current treatment recommendations
Below is a colorectal cancer treatment summary from the preliminary version of the National
Guidelines for Breast, Prostate, Colon and Rectal Cancer 2013 from the National Board of
Health and Welfare [8].
Since 1990, cytostatic agents have been the established palliative form of treatment for
metastatic colorectal cancer. Cytostatic agents may cause disease regression, relieve tumourrelated symptoms and improve quality of life, prolong the time to disease progression, and
improve overall survival. There are three established forms of cytostatic agents to treat
metastatic colorectal cancer: fluoropyrimidine (FU, parenterallys 5-FU modulated with
calcium folinate or orallyt capecitabine), irinotecan and oxaliplatin. A combination of two
cytostatic agents generally has a better effect on the tumour than one single drug but also
gives rise to more adverse reactions.
In recent years, biological drugs (VEGF as well as EGFR inhibitors) have also been shown to
have positive effects on metastatic colorectal cancer and have therefore been used. These
biological drugs seemingly work best with one or several cytostatic agents. Targeted biological
therapy includes bevacizumab (VEGF inhibitor), cetuximab (EGFR inhibitor) and
panitumumab (EGFR inhibitor).
s
Taking drugs which entails penetration of the skin or mucous membranes, e.g intravenous administration, or
so-called intravenous infusion.
t
Taking oral medication.
7
If the disease continues to progress after the first treatment cycle with a drug (so-called firstline treatment), the treatment may be repeated with the same drug (if progression of disease
occurred after discontinuation of treatment) or with another type of drug (so-called secondline treatment, etc.).
First-line treatment is expected to provide the best opportunity for delaying disease
progression. In second and third-line treatment, the effect is generally weaker than in
previous treatments. This is due to the disease being more resistant to cytostatic agents, while
sometimes the general health of the ill patient gradually also deteriorates.
In first and second-line treatment of metastatic colorectal cancer to prolong survival or relieve
symptoms, the National Board of Health and Welfare recommends [8]:

fluoropyrimidine (modulated 5-FU) or oral capecitabine with the addition of
bevacizumab as first-line palliative treatment for patients with metastases
without significant tumour-related symptoms (priority 8)

cytostatic agents (fluoropyrimidine and irinotecan or oxaliplatin) with the
addition of bevacizumab as first-line palliative treatment for patients with local
recurrence or metastases (priority 9)

cytostatic agents with the addition of EGFR inhibitors as second-line palliative
treatment for patients with local recurrence or metastases (priority 9)

cytostatic agents (fluoropyrimidine and oxaliplatin or irinotecan) with the
addition of bevacizumab as second-line palliative treatment for patients with
local recurrence or metastases (priority 9)
In 2013, Gastrointestinal onkologisk förening (the Swedish Society of Gastrointestinal
Oncology, GOF) published updated recommendations for the use of targeted biological drugs
for colorectal cancer.
In palliative first-line treatment, in combination with oxaliplatin-based chemotherapy,
bevacizumab may be given after consideration. Treatment with bevacizumab in combination
with chemotherapy (with either irinotecan or oxaliplatin) may be considered in the second
line. In the second line, cetuximab or panitumumab may be given after consideration in
combination with irinotecan-based chemotherapy.
According to TLV’s expert, in the Uppsala-Örebro region EGFR inhibitors (cetuximab or
panitumumab) are recommended in a palliative situation at the earliest after the second-line
treatment.
1.4.2 Comparators
The NLT group has not submitted any specific requests comparators. The company assesses
that bevacizumab, cetuximab and panitumumab are comparators.
TLV’s assessment: In accordance with the preliminary version of the National Guidelines
for Breast, Prostate, Colon and Rectal Cancer 2013 from the National Board of Health and
Welfare, TLV assesses that the additions of cetuximab, panitumumab or bevacizumab to
cytostatic agents (fluoropyrimidine and oxaliplatin or irinotecan) are relevant comparators
when targeted biological therapy is considered in the second line.
According to TLV’s experts, bevacizumab in particular is used in second-line treatment if not
given in the first line. As with bevacizumab, there is no predictive factor for aflibercept, i.e.
which patients will benefit or not benefit from treatment cannot be determined beforehand.
8
2 Health-economic analysis
For an introduction to health economics and health-economic assessments, see
Appendix 2.
2.1 Cost-minimisation analysis
There are many types of health-economic evaluations. The most commonly occurring are the
cost-utility analyses where the result is expressed as a cost-effectiveness ratio, i.e. the cost per
QALY. However, there are also other types of analyses.
TLV’s General Guidelines on Economic Evaluations (LFNAR 2003:2) state the following as an
alternative in the selection of an analytical method:
If there is evidence to suggest that the drug the application concerns has the same health
benefit as best comparison option, a cost comparison may be enough.
This is called a cost-minimisation analysis.
The company argues that it has been shown that survival benefit from treatment with
aflibercept with FOLFIRI is at least as good as the addition of bevacizumab, cetuximab or
panitumumab in second-line treatment of metastatic colorectal cancer, and therefore argues
that a cost-minimisation analysis is sufficient. The company has therefore calculated the
pharmaceutical costs for treatment with the various drugs according to the studies carried out
with the various drugs in second-line treatment, and has set the dosage according to the mean
value (weight or equivalent body surface area) observed in the VELOUR study [2].
However, the adverse reaction frequency and intensity differ from treatment to treatment. The
company has made an effort to quantify and calculate the adverse reaction costs for the various
treatments based on the adverse reactions reported in the following studies (see also section
1.3):

Bennouna et al. [6] conducted an open-label, phase III study investigating secondline treatment of non-operable and histologically confirmed metastatic colorectal
cancer (MCRC) in patients who had discontinued first-line treatment. The study
compared treatment with bevacizumab + chemotherapy (409 patients) to treatment
with chemotherapy only (411 patients), and the patients were randomised 1:1 in both
arms. The chemotherapy was oxaliplatin-based if the first-line treatment was
irinotecan-based, and vice versa. Eight different chemotherapy regimens were used
in this study, and therefore the treatment was defined as bevacizumab +
chemotherapy in the analysis. Adverse reactions of grade 3-5 that occurred in at
least 2% of the patients were reported in the study. Four cases of grade 5 adverse
reactions were reported in the group that received bevacizumab + chemotherapy.

In a publication by Peeters et al., [5] panitumumab + FOLFIRI (fluorouracil,
leucovorin and irinotecan) (303 patients) was compared to FOLFIRI only (294
patients). This publication only reports adverse reactions where the frequency
differs by more than 5% between the two arms.
 In an open-label, randomised, multi-centre, phase III study, patients with epidermal
growth factor receptor-expressing MCRC without any response to first-line treatment
with oxaliplatin or fluoropyrimidine were investigated. The patients were randomised
to treatment with either cetuximab + irinotecan (648 patients) or irinotecan only (650
9
patients) [4]. The most common adverse reactions of non-haematological nature,
drug-related and of grade 3-4 were included. Laboratory deviations that occurred
during the study period were also included. This study reports adverse reactions that
were observed in more than 2% of patients in the study.

Adverse reaction frequencies for aflibercept + FOLFIRI (612 patients) have been
obtained from the clinical study VELOUR [2]. Adverse reactions of grade 3-5 that were
reported in at least 5% of the patients were included.
The company has set the costs for management of adverse reactions with the help of ICD-10u,
NordDrgv and DRG weightsw from the National Board of Health and Welfare. The basic
amount was multiplied by corresponding DRG weight to obtain a unit cost for each adverse
reaction. The costs of adverse reactions have been standardised so that the average adverse
reaction cost per cycle has been obtained. The costs are reported in Table 1. The drug prices in
the analysis are list prices.
Table 2 Drug costs and treatment of adverse reactions
Aflibercept + FOLFIRI Bevacizumab +
chemotherapy
Cetuximab +
irinotecan
Panitumumab + FOLFIRI
Costs: the patient’s
assumed weight is 75 kg,
with a body surface area
of 1.83 m2 (consistent with
VELOUR)
Drug costs/cycle
Cost/chemotherapy cycle
SEK 10,110
SEK 11,285
SEK 19,875
SEK 19,492
SEK 1,553
SEK 1,553
SEK 467
SEK 743
SEK 11,663
SEK 12,838
SEK 20,341
SEK 20,235
SEK 743
SEK 487
SEK 695
SEK 516
SEK 12,405
SEK 13,324
SEK 21,036
SEK 20,751
Total drug costs/cycle
Adverse reactionrelated cost per cycle
Total cost per cycle
TLV’s assessment: TLV assesses that the company has shown that drug costs per treatment
cycle are lowest for treatment with aflibercept compared to established targeted therapies (see
section 1.4.2).
The company is practically carrying out a cost comparison of the treatment of adverse
reactions based on an indirect comparison between studies with setups that differ in many
respects. This is a source of uncertainty.
u
The International Classification of Diseases, ICD, is a statistical classification with diagnostic codes for grouping diseases and causes of death.
v
The DRG (Diagnosis-Related Group) system means that patients with a similar diagnosis and resource consumption are grouped into one. DRG is a way of
perspicuously describing the patient composition at different hospitals and in different counties. NordDRG is used in Sweden and has been jointly developed by
the Nordic countries.
w
A DRG weight is a relative measure of care and treatment costs for an average patient in each DRG group. A higher weight means higher costs.
10
Table 2 above clearly indicates that even if all the costs of adverse reactions are excluded for the
three comparison options bevacizumab, cetuximab and panitumumab, but included for
aflibercept, the treatment with aflibercept still has the lowest cost per treatment cycle.
The company has chosen to price aflibercept in such a way that treatment with aflibercept costs
less than the relevant comparison options per treatment cycle.
2.2 Quality of life and cost-effectiveness
Treatment with aflibercept as an addition to FOLFIRI in metastatic colorectal cancer appears
to have a higher adverse reaction frequency than other available treatment options. In a costminimisation analysis, the company has attempted to quantify the costs arising from the
management of adverse reactions. However, it is also likely that these adverse reactions may
affect the patient’s quality of life negatively.
Chemotherapy in itself causes significant adverse reactions. The addition of VEGF or EGFR
inhibitors, so-called angiogenesis inhibitors, is known to potentiate these adverse reactions.
There are limited data on the impairment of quality of life that may be linked to the treatment.
There are no direct comparison studies of the available options. In the studies carried out
regarding treatment with biological drugs as additions in the second line, there are differences
in the chemotherapy treatments, as well as in the patient populations, and several other
parameters.
A cost-effectiveness analysis based on such inadequate data would be very unreliable.
TLV’s assessment: Normally, TLV requires a cost-effectiveness analysis when the effect
differs between two treatments. It is not improbable that there may be some further
impairment in the quality of life due to adverse reactions from treatment with aflibercept in
relation to the comparison option. The magnitude of this impairment is unknown and would
in an analysis be based on mere presumptions. It is questionable whether it would be of value
in a decision process.
Given that the treatment is associated with lower costs per treatment cycle, and that the effect
seems equivalent, TLV deems that the cost-minimisation approach is acceptable in this case.
2.3 Uncertainty in the results
There is relatively low uncertainty in terms of the results in this cost-minimisation analysis.
Any discounts obtained in the procurement of bevacizumab, cetuximab or panitumumab
may affect the outcome.
Assumptions regarding equivalent treatment efficacy in the treatment with aflibercept as
with bevacizumab, cetuximab or panitumumab are fundamental. If the assumptions are not
reliable, neither are the results in the analysis.
11
3 Authority observations
Observations from Läkemedelsverket [the Swedish Medical Products Agency]:
“The supporting documentation is well written. An estimate of the costs compared to the
treatment effect could be considered.”
TLV’s comments: According to TLV, an applicable decision situation arises when decisions
about treatment with targeted biological therapy have already been made. The decision is then
to select additions with bevacizumab, cetuximab or panitumumab in accordance with the
preliminary version of the National Guidelines for Breast, Prostate, Colon and Rectal Cancer
2013 from the National Board of Health and Welfare, or with the additional option of
aflibercept. Under these circumstances, a cost-minimisation analysis is sufficient in Sweden.
According to TLV’s experts, bevacizumab in particular is used in the second line if not given in
the first line.
NICE [National Institute for Health and Care Excellence] in the UK has published costeffectiveness analyses of both bevacizumab and aflibercept in relation to chemotherapy in
second-line treatment.
According to these, treatment with the addition of bevacizumab compared to FOLFOX only
costs GBP 70,500 per QALY (approx. SEK 710,000 at the September 2013 exchange rate). The
cost per QALY for treatment with bevacizumab has been calculated for first-line treatment.
This means that the cost-effectiveness ratio is not directly comparable. Given that the cost of
bevacizumab is the same regardless of at what level the treatment is given, the costeffectiveness ratio is affected primarily by the treatment effect. The patient access scheme that
NICE considered is associated with a lower price than the list price. A similar calculation at
the list price would most likely increase the cost per QALY.
Treatment with aflibercept as an addition to FOLFIRI compared to FOLFIRI only costs GBP
62,900–66,500 per QALY (approx. SEK 636,000–670,000 at the September 2013 exchange
rate). The cost per QALY generated by NICE is still preliminary. The final cost will be
published shortly.
TLV has clarified the text in accordance with specific instructions from the company.
12
4 Further issues
NICE (National Institute for health and Care Excellence) does not recommend the use of
aflibercept in the treatment of metastatic colorectal cancer. This is based on a costeffectiveness analysis where aflibercept plus FOLFIRI is compared to treatment with FOLFIRI
only. NICE also do not recommend treatment with bevacizumab, which is why the decision
situation differs from the one in Sweden.
SMC (Scottish Medicines Consortium) also do not recommend treatment with aflibercept for
the same reasons given by NICE.
IQWIG (Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen [Institute for
Quality and Efficiency in Health Care]) has evaluated aflibercept for the treatment of
metastatic colorectal cancer and found that it has little additional benefit (geringer
Zusatznutzen) beyond treatment with FOLFIRI only. IQWIG has not made any statement on
aflibercept in relation to other angiogenesis inhibitors.
13
5 Bibliography
1] EMA, “Zaltrap Summary of Product Characteristics,” EMA, 2013.
[2] E. Van Cutsem , J. Tabernero, R. Lakomy, H. Prenen, Prausova J, et al., “Addition of
aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III
randomized trial in patients with metastatic colorectal cancer previously treated with an
oxaliplatin-based regimen,” J Clin Oncol, vol 30, pp. 3499-3506, 2012.
[3] EMA, “Zaltrap Assessement Report,” EMA, 2012.
[4] A.F. Sobrero, J. Maurel, L. Fehrenbacher, W. Scheithauer, Y.A. Abubakr, et al., “EPIC:
phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in
patients with metastatic colorectal cancer,” J Clin Oncol, Vol 26, pp. 2311-2319, 2008.
[5] M. Peeters, T.J. Price, A. Cervantes, A.F. Sobrero, M. Ducreux, et al., “Randomized phase
III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared
with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer,” J
Clin Oncol, Vol 28, pp. 4706-4713, 2010.
[6] J. Bennouna, J. Sastre, D. Arnold, P. Osterlund, R. Greil, et al., “Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase
3 trial,” Lancet Oncol Vol 14, pp. 29-37, 2013.
[7] B.J. Giantonio, P.J. Catalano, N.J. Meropol, P.J. O’Dwyer, E.P. Mitchell, et al., “Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology
Group Study E3200,” J Clin Oncol Vol 25, pp. 1539-1544, 2007.
[8] Socialstyrelsen, “Nationella riktlinjer för bröst-, prostata-, tjocktarms- och ändtarmscancervård 2013 – Stöd för styrning och ledning – Preliminär version,” 2013.
14
Appendices
Appendix 1 ECOG performance status
Grade ECOG*
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work
of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities.
Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking
hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
*
As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T.,
Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the scale, please cite the
reference above and credit the Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair.
Appendix 2 An introduction to health-economic evaluation
What is health economics?
Health economics is used to analyse healthcare from a national-economic perspective. The
basis for national economy is that resources in society are limited and therefore the needs and
desires of everyone cannot be satisfied. In healthcare, this becomes increasingly clear in line
with medical technologies getting more and more advanced and therefore more costly, while
the demand for healthcare increases. By using economic methods, different health
interventions can be evaluated and thus a better basis for prioritising the alternatives is
obtained.
What is health-economic evaluation?
Health-economic evaluation is a tool to assess the costs and health effects in connection with
the use of resources in healthcare. Health-economic evaluations are usually used in order to
find out if a medical treatment is cost-effective or not, i.e. if the treatment is a reasonable cost
for society in relation to the health benefits that it provides. However, the goal is not to save
money but to use the available resources in a way that provides as much health[care] as
possible for the population. This is usually determined by a so-called cost-effectiveness
analysis, where costs associated with an intervention are weighed against its effects.
Cost-effectiveness is a relative concept and to decide whether a treatment is cost-effective or
not, an alternative to compare with is needed. A comparator may be e.g. a drug therapy, other
type of healthcare or no treatment at all. By using a cost-effectiveness analysis, a new and
more expensive and effective treatment option can be compared to a traditional treatment,
thereby obtaining an answer to the question whether the new approach is worth the increased
cost compared to the traditional treatment, and also compared to other healthcare
interventions.
Quality of life and survival set against costs
Normally a distinction is made between four different types of health-economic evaluations.
All measure the costs in SEK, while the health effects can be measured in different ways.
Which method is the most appropriate is controlled by the issue of the analysis and the
availability of data.
The cost benefit analysis is the only one of the four methods that measures costs as well as
effects in SEK. It is, however, used to a relatively small extent due to the practical difficulties
in placing a monetary value on health benefits.
The three other analytical methods are in actual fact variations on the same methodology. The
cost-effectiveness analysis measures the health effects in e.g. number of symptom-free days
or number of life years gained. However, two problems are associated with this type of
method. Firstly, healthcare interventions may affect health on several dimensions
simultaneously, and a measure of the number of life years gained and the number of days
without worry or anxiety measures health quantitatively but says little about the patient’s
perceived quality of life. Moreover, in the cost-effectiveness analysis, it is difficult to compare
treatments from different therapeutic areas. For example, there is no obvious way to measure
the health benefit of a prevented heart attack in relation to the health benefit of a year without
pain for a rheumatoid patient. The cost-minimisation analysis is a version of the costeffectiveness analysis that can be used when the comparable treatments have the same effect.
What we are left with is a cost comparison, where the treatment with the lowest cost is
considered to be the most cost-effective.
The cost-utility analysis, which currently is the predominant form of health-economic
evaluation and the method that is referred to in the rest of this document, resembles the costeffectiveness analysis but includes both life years and quality of life as endpoints. The results
therefore provide a more comprehensive picture of the overall health effects of a treatment.
QALYs measures health effects in the cost-utility analysis
In the cost-utility analysis, the most commonly used measure of healthcare effects is qualityadjusted life years, QALYs. The measure is constructed so that a life year is multiplied by a
quality of life weight between 0 and 1, where 0 equals death and 1 equals good health. For
instance, if a person has five years of good health it equals five QALYs. In contrast, if a person
has five years with a 50% life quality, this equals 2.5 QALYs. In this way, life years as well as
quality of life are captured in a general measure, which also makes it possible to compare
treatments from different therapeutic areas.
The cost-utility analysis results in an incremental cost-effectiveness ratio, also called ICER,
which is calculated based on the difference in costs in relation to the difference in health
outcomes. The ratio is expressed as cost per QALY. This can be interpreted as the price at
which society buys a life year of good health for one of its citizens, a life year which the citizen
would not have had without treatment.
Societal perspective required
There are many different costs and health effects of interventions and morbidity that can be
taken into account in health-economic evaluations. Which ones to include are determined by
the perspective chosen for the analysis. A healthcare perspective includes only the costs and
effects relevant to healthcare, while a societal perspective includes all costs and effects,
regardless of who they apply to (county, state, patient, family member). In terms of drugs, this
means e.g. that the analysis in addition to direct costs as well as pharmaceutical costs should
also take into account indirect costs and benefits, such as loss of production due to sick-leave,
or an increase in productivity when the patient can return to work because of the health
benefits that a treatment provides.
In Sweden, a societal perspective in health-economic evaluations is generally pursued. One
advantage of the societal perspective is that the benefits of an intervention within healthcare
can be weighed against potential interventions in other sectors of society.
Models facilitate the calculations
Health-economic evaluations are based on data on the costs and effects of healthcare
treatments. However, often there are not enough supporting data, e.g. when the evaluation
involves a new method or when the costs and longer term effects than those possible in a
clinical study are to be included. In order to comment on the cost-effectiveness in these cases,
a so-called model analysis is often applied. Based on the data available, assumptions are made
about future sequences of events and a mathematical model based on these assumptions is
then constructed. The purpose of model analyses is not to replace empirical studies, but to
highlight a decision issue based on the best available information . In “General Guidelines on
Economic Evaluations” TLV recommends that the model analysis should be used to try to
predict the events following the completion of the clinical follow-up.
Making decisions with cost per QALY as a basis
Decisions made within healthcare are not based solely on cost per QALY. A combined
weighting is carried out according to an ethical platform with three main principles:

Human dignity: All humans have equal value and equal rights regardless of
personal qualities and functions in society.

Needs and solidarity: The resources should primarily be allocated to the areas
where the need is the greatest.

Cost-effectiveness: When choosing between different areas of activity or
measures, there should be a reasonable relationship between cost and
effect, measured in improved health and increased quality of life.
When the combined weighting between the different principles is done, the willingness to
pay is determined for the need for care that the treatment provides, i.e. the level of
increased cost per QALY that is acceptable to TLV. For a high degree of severity, or if there
are few other treatments available, a higher cost per QALY is generally accepted. The
combined weighting also means that treatments for mild discomforts are sometimes
deprioritised in publicly-funded healthcare to give way for more urgent treatments.