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Brentuximab vedotin in relapsed/refractory Hodgkin lymphoma post-autologous stem

cell transplant: a cost-effectiveness analysis in Scotland

Authors:

Christopher Parkera, Beth Woodsb, James Eatona, Esprit Mac, Ross Selbyd, Eugene Bensond,

Andreas Engstrome, Peter Sajosif, Andrew Briggsa,g, Vijayveer Bonthapallyf

Author affiliations:

aICON Health Economics, Abingdon, UK; bCentre for Health Economics, University of

York, York, UK; cCenter for the Evaluation of Value and Risk in Health, Institute for Clinical

Research and Health Policy Studies, Tufts Medical Center, Boston, MA, USA; dTakeda UK

Ltd, Buckinghamshire, UK; eTakeda Pharma AB, Stockholm, Sweden; fMillennium

Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda

Pharmaceutical Company Limited; gInstitute of Health and Wellbeing, University of

Glasgow, Glasgow, UK.

Address for correspondence:

Christopher Parker, ICON Health Economics, 100 Park Drive, Milton Park, Abingdon, OX14

4RY, UK. Tel: +44 (0)1865 324930. Email: [email protected]

Keywords:

Suggested keywords: Health technology assessment; orphan medicine; decision analysis;

health utility; quality-adjusted life year

Short title (limit 60 characters): 53

Brentuximab vedotin cost-effectiveness in Hodgkin lymphoma

1

Prior presentation: Poster presentation at the American Society of Clinical Oncology

Quality Care Symposium, 26–27 February, 2016, Phoenix, AZ, USA.

Journal: Journal of Medical Economics

Article type: Original article

Total word count: 7,226

Body text word count: 4,790 words

Abstract word count (limit 300 words): 299

Figures/Tables (limit not specified): 3/4

References (limit not specified): 43

2

Abstract (limit 300 words): 300

Objective:

Evaluate cost-effectiveness of brentuximab vedotin in patients with relapsed/refractory

Hodgkin lymphoma who have received autologous stem cell transplantation, from a Scottish

healthcare payer perspective.

Methods:

A Microsoft Excel-based partitioned survival model comprising three health states

(progression-free survival [PFS], post-progression survival, and death) was developed.

Relevant comparators were chemotherapy with or without radiotherapy (C/R) and C/R with

intent to allogeneic hematopoietic stem cell transplantation (alloSCT). Data were obtained

from the pivotal phase II single-arm trial in 102 patients (SG035-0003; NCT00848926), a

systematic literature review and clinical expert opinions (where empirical evidence

unavailable). PFS and overall survival for brentuximab vedotin were estimated using 5-year

follow-up data from SG035-0003, and extrapolated using event rates observed for comparator

treatments from published survival data. Resource use included drug acquisition and

administration; alloSCT; treatment of adverse events; and long-term follow-up. Deterministic

and probabilistic sensitivity analyses were conducted to evaluate the impact of uncertainty.

Results:

In the base case, the incremental cost-effectiveness ratio (ICER) for brentuximab vedotin was

£38,769 per quality-adjusted life year (QALY) vs C/R, whereas C/R with intent to alloSCT

was dominated by brentuximab vedotin. ICERs for brentuximab vedotin generated by the

deterministic sensitivity analysis ranged between £32,000 – £54,000 per QALY. Including

productivity benefits reduced the ICER to £28,881 per QALY.

Limitations:

3

Limitations include lack of comparative data from this single arm study and the

heterogeneous population. Inconsistent baseline characteristic reporting across studies

prevented complete assessment of heterogeneity and the extent of potential bias in clinical

and cost-effectiveness estimates.

Conclusions:

Although the base case ICER is above the threshold usually applied in Scotland, it is

relatively low compared with other orphan drugs, and lower than the ICER generated using a

previous data cut of SG035-0003 that informed a positive recommendation from the Scottish

Medicines Consortium, under its decision-making framework for assessment of ultra-orphan

medicines.

4

Introduction

Classical Hodgkin lymphoma (HL) is a rare cancer of the immune system that usually affects

adults aged 20–24 years, followed by another peak in adults aged ≥70 years1. Data from the

Scottish Cancer Registry indicate that there were 161 new cases of HL diagnosed in Scotland in

20132. In 2009, HL was estimated to affect approximately 1 in 10,000 people in the European

Union (EU), which is well below the threshold (5 people in 10,000) for designation as an orphan

indication3.

Chemotherapy with or without radiotherapy (C/R) is the standard of care for limited-

stage HL4. However, around 15% of patients are refractory or relapse following frontline

treatment5. Standard treatment for relapsed or refractory (R/R) HL is high-dose chemotherapy

followed by autologous stem cell transplant (ASCT)4, but data from a number of studies suggest

that up to 50% of R/R HL patients will ultimately relapse after ASCT6. Patients who fail ASCT

have a very poor prognosis, with a median overall survival (OS) of 2.4 years, which falls to only

1.2 years in patients who relapse within one year of ASCT7, 8.

Treatment guidelines and observational data indicate that, historically, the most

commonly used treatment in these patients was multi-agent C/R, which may be followed by

allogeneic stem cell transplant (alloSCT) in eligible patients4, 9. However, these approaches are

increasingly being challenged by the introduction of novel agents.

Brentuximab vedotin (ADCETRIS1a, Seattle Genetics, Inc., Bothell, WA, USA) is an

antibody–drug conjugate with a distinct mechanism of action that results in selective apoptosis

of CD30-expressing tumor cells10. CD30 is consistently expressed in patients who are refractory 1a ADCETRIS is a registered trademark.

5

to multi-agent chemotherapy, regardless of prior transplant status11. In the USA, brentuximab

vedotin received accelerated approval by the Food and Drug Administration for the treatment of

patients with classical HL after failure of ASCT or after failure of at least two prior multi-agent

chemotherapy regimens in patients who are not ASCT candidates, and is approved for classical

HL at high risk of relapse or progression post-ASCT10. In addition, brentuximab vedotin has

received conditional approval from the European Medicines Agency for the treatment of adult

patients with R/R CD30-positive HL following ASCT; or following failure of at least two prior

therapies where ASCT or multi-agent chemotherapy is not a treatment option11. The approval of

brentuximab vedotin in HL was based on data from a pivotal phase II, open-label, single-arm,

multi-center study in 102 patients with R/R HL after ASCT (SG035-0003; NCT00848926).

Eligible patients were aged ≥12 years with R/R HL after ASCT, and patients with prior alloSCT

were ineligible. Patients received brentuximab vedotin 1.8 mg/kg IV once every 3 weeks for up

to 16 cycles12-15. The objective response rate (ORR) per the independent review facility (IRF)

was 75%; 34% of patients achieved a complete remission (CR) and 40% achieved a partial

remission (PR)15. Follow-up data from SG035-0003, based on a median follow-up of 32.7

months, indicate a median OS of 40.5 months, with an estimated 3-year survival rate of 54%13.

The median OS was also confirmed in the 5-year follow-up data from this study, based on a

median follow-up of 35.1 months (range 1.8–72.9 months)12. This finding compares favorably

with the median OS reported in the literature for such patients (around 1–2 years)7, 8.

Recommendations for the use of new therapies by some health technology assessment

(HTA) bodies — such as the UK National Institute for Health and Care Excellence (NICE) and

Scottish Medicines Consortium (SMC) — depend not only on the efficacy and safety of such

treatments but also their cost-effectiveness, expressed in terms of an incremental cost-

effectiveness ratio (ICER)16. In 2015, the SMC made a positive recommendation for

6

brentuximab vedotin in patients with R/R HL who have received ASCT17, which was informed

by 3-year follow-up data from SG035-0003. Here, we present the cost-effectiveness analysis

that informed this recommendation, updated with 5-year follow-up data from SG035-0003.

Patients and methods

Population

In line with SG035-0003, the model evaluates brentuximab vedotin in patients who have failed

high-dose chemotherapy and ASCT. Patients entered the trial within one year of ASCT relapse

in 71% of cases. Of the 56% patients who had received post-ASCT treatment, 42% were

refractory to their last treatment and 14% had relapsed after their last treatment. Patients had

received one, two, and three or more post-ASCT treatments in 20%, 17%, and 20% of cases,

respectively. Clinicians suggested that brentuximab vedotin may therefore be used in three

patient groups post-ASCT failure, which the SG035-0003 study population are split across: (1)

first-line post-ASCT relapse in patients not eligible for alloSCT (those aged >60–70 years or

with significant comorbidities); (2) first-line post-ASCT relapse, as an induction treatment for

alloSCT in patients eligible for an alloSCT; and (3) second or subsequent line post-ASCT

relapse.

Comparators

Treatment guidelines do not recommend a specific chemotherapy regimen for post-ASCT

relapse4; therefore, chemotherapy consisting of a range of regimens was considered as a

composite comparator. This was considered reasonable as little is known about their relative

efficacy and all the chemotherapies considered are associated with similar costs.

7

The cost-effectiveness analysis compared brentuximab vedotin with C/R and C/R with

intent to alloSCT. Analyses are presented with and without the latter comparator, as for some

patients this treatment would be precluded at baseline due to age or comorbidities.

Model structure

A partitioned survival model was developed using Microsoft Excel 2010 to project the costs and

outcomes for adult patients with R/R CD30-positive HL following ASCT failure over a lifetime

(40-year) time horizon. Three health states were included: progression-free survival (PFS); post-

progression survival (PPS); and death. The proportion of patients in the PFS state over time was

estimated directly from the PFS curves and the proportion of patients in the PPS state was

estimated as the difference between the OS curve and the PFS curve. Costs and quality-adjusted

life years (QALYs) were accrued according to the proportion of patients in the PFS and PPS

states over time.

The analysis was conducted from the perspective of the National Health Service (NHS)

in Scotland. The year of the cost analysis was 2013. For accuracy, costs and outcomes were

evaluated on a daily basis and were discounted at a rate of 3.5% per annum18. The model

estimates these outcomes for three cohorts: (1) patients who received only brentuximab vedotin;

(2) patients who received only C/R; and (3) patients who received only alloSCT.

Not all patients intended to receive alloSCT actually receive a transplant. In order to

generate outcomes for the C/R with intent to alloSCT comparator, the long-term outcomes

associated with the C/R and alloSCT cohorts were weighted according to the estimated

proportion of patients eligible for alloSCT who ultimately receive alloSCT. In the base case, this

weighting was based on data from a retrospective study in which 56% of 185 patients intended

8

for transplant (as indicated by human leukocyte antigen [HLA] typing within 30 days of ASCT

relapse) were actually allografted19.

Model inputs

Clinical data

Data from the SG035-0003 study were used to inform the efficacy and safety of brentuximab

vedotin12, 13. The efficacy and safety of the comparator treatments was informed by a systematic

review as discussed in Supplementary Data 1. Patient and disease characteristics for each data

source that informed the clinical outcomes in the model are shown in Table 1. Demographic and

clinical characteristics were similar across the three study populations.

Progression-free survival

PFS for brentuximab vedotin was estimated based on the observed PFS Kaplan-Meier curve up

to the maximum of 6.1 years of follow up of SG035-000312, 13. Investigator-assessed data rather

than IRF were used in the base case, as few studies in the available literature for the

comparators include an independent assessment.

For C/R, PFS was estimated using data from SG035-0003 patients collected during the

period following the most recent prior post-ASCT therapy. These data were selected in

preference to data from the literature which were from small studies and unlikely to be

representative of the heterogeneous set of regimens received by these patients. Moreover, use of

self-control data may have controlled for some of the inherent bias associated with conducting

naïve comparisons. Patients in the alloSCT cohort were assumed to remain progression-free for

the average chemotherapy duration period (3.9 months), calculated based on the mean number

of cycles reported in the literature for each of the modelled chemotherapy regimens20-26.

9

Thereafter, PFS was assumed to follow the experience of patients in the European Group for

Blood and Marrow Transplantation (EBMT) registry, as described in a study of reduced-

intensity conditioning (RIC) alloSCT in 285 HL patients that captures data across the main

European countries. This study was selected as it is the largest study of RIC alloSCT identified

by the systematic review and is based on the EBMT registry which is thought to capture the

majority of transplants conducted in the main European countries. Follow-up data for 5.2 years

are available from this study27.

To generate lifetime estimates of costs and QALYs, extrapolation of the PFS data for the

brentuximab vedotin and alloSCT cohorts was necessary, as not all patients still being followed-

up had experienced an event. For alloSCT, EBMT registry data suggest that the risk of

progression stabilized during the last ~40 months of follow up27. Therefore, a constant risk of

progression beyond the 5.2 year period described above was assumed for this cohort. For

brentuximab vedotin, the risk of progression following the maximum 6.1-year follow-up in the

SG035-0003 study12 was assumed to be equal to alloSCT, as limited data on PFS in non-

alloSCT treated patients are available.

Overall survival

OS for brentuximab vedotin was estimated directly from SG035-0003 study data, based on the

Kaplan-Meier curve for the maximum 6.1-year follow-up period12. However, in the base case

analysis, the OS Kaplan-Meier curve was only used up to 296 weeks due to rapid loss to follow

up after this time point.

Data for the other comparators were taken from another EBMT observational cohort

study (reported by Martinez et al.9, 28) that provided 6-year Kaplan-Meier OS curves for patients

10

who receive C/R (n=294), or RIC or myeloablative alloSCT (n=133), stratified according to

whether patients had 0, 1 or ≥2 of the following risk factors: relapse within 6 months of ASCT;

Ann Arbor Stage IV disease at ASCT relapse; bulky disease; age >50 years; and poor

performance status9. This study was selected as it is the largest available and allows for some

level of adjustment for differences in the population with regards to the SG035-0003 study

using the published data.

The OS Kaplan-Meier curves were adjusted for the risk-factor distribution in the SG035-

0003 study by weighting the EBMT data to reflect the proportion of patients with 0, 1 and ≥2

risk factors in SG035-0003. The adjusted curves were used directly for the maximum follow-up

period of 71.79 months in the Martinez et al. study9.

The probability of death beyond the 71.79 months of follow up was estimated based on

an OS curve that represented a weighted average of the adjusted survival curves for C/R and

RIC alloSCT (weighted by the proportion of patients receiving each treatment in the EBMT

study)9. Inspection of the probability of death associated with the resulting weighted survival

curve during each 6-month period, indicated that the probability of death was relatively constant

from 30 months to 66 months. In the base case analysis, the probability of death observed over

this period was therefore applied to the model as a constant rate to patients in the alloSCT and

C/R-only cohorts beyond the maximum follow-up in the EBMT study9. As a sensitivity

analysis, a Weibull survival model was fitted to the aggregate data to predict long-term OS.

Beyond the SG035-0003 study period (6.08 years), brentuximab vedotin treatment was assumed

to be associated with a hazard ratio (HR) of 1.00 compared to the other comparators (i.e.,

patients in the brentuximab vedotin cohort were considered to experience the same probability

of death as patients receiving the other comparators).

11

Adverse events

Adverse events (AE) were included in the model if they satisfied at least one of the following

criteria: grade 3–4 event that occurred for any comparator in ≥5% of patients (or cycles if

percentage of patients not reported); or grade 1–2 event occurring in ≥20% of patients (or

cycles). AEs were also required to have material implications for cost or quality of life. Event

rates for brentuximab were taken from the SG035-0003 study and rates for the comparators

were taken from the literature12, 21, 24, 25, 29-31 (Supplementary data 2).

Resource use and costs

A detailed summary of costs is presented in Supplementary Data 2. Resource use included drug

acquisition and administration, concomitant medications, radiotherapy, alloSCT, AEs and long-

term follow-up. Drug costs were taken from British National Formulary, March 201432. Unit

costs for all other resources were sourced from the NHS Reference Costs 2012–201333. All drug

cost calculations were made assuming vial wastage (as patient numbers in each center would be

likely to be too low to allow any vial sharing).

Patients receiving brentuximab vedotin required a single infusion per cycle to administer

the drug. Brentuximab vedotin was supplied as 50 mg vials (£2500 per vial) and was

administered in the SG035-0003 study on an outpatient basis at a dose of 1.8 mg/kg, every 21

days for an average of 9.7 cycles. The reported relative dose intensity (RDI) was 93.5%. The

weight distribution in the SG035-0003 study was used to estimate the number of vials required

per patient, based on the per-kg dosage, RDI and patients’ weights.

12

The cost of chemotherapy was estimated based on clinical expert opinion regarding the

frequency of use of different treatment regimens in the UK. Scottish specialists confirmed

similar usage in Scotland to the rest of the UK. In addition, 10% of patients were assumed to

require radiotherapy as adjunct to their chemotherapy based on clinical input. This was allocated

as a one-off cost at the beginning of treatment.

Delivery of chemotherapy was assumed to occur on an outpatient basis for all

comparators. In addition, the following concomitant medications were captured in the model:

anti-emetics for all chemotherapy and brentuximab vedotin treatments, and immunosuppressive

treatment for patients who receive an alloSCT.

A weighted cost of alloSCT (£108,052) for sibling donors and volunteer unrelated

donors was provided by the Bone Marrow Transplant Unit at the Beatson West of Scotland

Cancer Centre (WoSCC), Glasgow, based on the assumption that two-thirds of alloSCTs

undertaken in Scotland involve an unrelated donor.

Due to the lack of data available, assumptions on AE-related resource use were obtained

from clinical experts in the UK (Supplementary Data 2).

Follow-up care before progression comprised outpatient visits, blood counts,

biochemistry, and computed tomography (CT) scans. Corresponding resource use was estimated

based on clinical opinion and was stratified according to whether patients received alloSCT and

were on or off treatment. In the ‘post-progression’ state, patients were assumed to experience a

one-off cost of treatment on progression (equal to the chemotherapy acquisition and

administration cost, as well as the total cost of AEs associated with standard chemotherapy).

13

The long-term follow-up cost for post-progression patients was assumed to be equal to the cost

for the on-treatment period for chemotherapy.

Health-related quality of life

Utility data were taken from a vignette study34 that elicited time trade-off valuations from 100

members of the general public in the UK. Disease state vignettes (for CR, PR, stable disease

[SD] and progressive disease [PD]) were developed based on a review of the literature and on

patient and clinician interviews, to represent the experience of both post-ASCT HL patients’ and

patients with R/R systemic anaplastic large cell lymphoma34.

In order to capture the impact of the different response rates on quality of life, the utility

level in the PFS state was weighted according to the proportion of patients in each response

category for each comparator (Supplementary Data 2). For brentuximab vedotin, investigator-

assessed response rates were used. For C/R, response data were taken from the response to prior

post-ASCT treatment in SG035-0003. For RIC alloSCT, response rates at 100 days post-

transplant were obtained from the report by Robinson et al.27 and applied from the time of

transplant until progression27. Prior to 100 days post-transplant, alloSCT patients were assumed

to experience the same response rates as when treated with chemotherapy.

For AEs, utility decrements were combined with estimated event durations to generate a

QALY decrement for each event (Supplementary Data 2). These effects were assumed to be

independent for each event hence were modelled additively. Where data were not collected from

the vignette study, utility decrements obtained from similar studies in other cancers were

applied,34-36 and event durations were based on clinical input.

14

Sensitivity analyses

Extensive deterministic sensitivity analyses were conducted to evaluate the robustness of the

cost- effectiveness model. These included assuming a level of ‘catch up’ (HR > 1.00) between

brentuximab vedotin and the comparators for PFS and OS after the SG035-0003 study follow-

up; varying the relative effects of brentuximab vedotin vs the comparators for PFS and OS over

lifetime; use of IRF-assessed response and PFS data for brentuximab vedotin; use of the

maximum follow-up from SG035-0003 for OS for brentuximab vedotin; and varying the cost of

alloSCT.

A scenario analysis was also conducted, incorporating the potential productivity benefits

of treatment. Based on expert clinical opinion, the productivity scenario analysis assumed that

40%, 15%, and 10% of patients in the CR, PR, and SD health states, respectively, return to work

in the PFS state. This corresponded to a productivity benefit of £18,172, £2,567 and £19,034 for

brentuximab vedotin, C/R, and alloSCT, respectively. Patients were not able to return to work

for one year following alloSCT and could not return to work in the PPS state. For each year

patients are able to return to work, they accrue a productivity benefit (the average annual wage)

of £26,52237. Additional detail on the corresponding inputs for the productivity scenario

analyses are presented in Supplementary Data 3 and response rates in the PFS state for each

comparator are presented in Supplementary Data 2.

A probabilistic sensitivity analysis (PSA) was also conducted by assigning distributions

to all input parameters and randomly sampling from these distributions over 5000 Monte Carlo

simulations to calculate the uncertainty in the cost and health outcome measures.

15

Results

Clinical outcomes

Long-term outcomes predicted by the model show PFS for brentuximab vedotin that is superior

to that observed with C/R and, by a lesser margin, to that observed following C/R with intent to

alloSCT. Brentuximab vedotin also showed an OS advantage over C/R with or without intent to

alloSCT. These survival advantages were observed within the trial period (Figure 1); however,

the majority of the OS (and to some extent the PFS) gain was driven by the period beyond the

SG035-0003 study follow-up (Figure 2).

Brentuximab vedotin-treated patients accrued total QALYs of 3.36, yielding incremental

QALYs of 1.58 vs C/R and 0.85 vs C/R with the intent to alloSCT. QALY gains for

brentuximab vedotin and C/R with intent to alloSCT compared to C/R were both driven by

gains in the PFS state. The gains associated with C/R with intent to alloSCT vs C/R only were

offset to some extent by the QALY decrement associated with alloSCT-related AEs.

Costs

Patients treated with brentuximab vedotin incurred total costs of £88,572, yielding incremental

costs of £61,179 vs C/R and –£6,421 vs C/R with intent to alloSCT (Table 2). The incremental

costs of brentuximab vedotin compared to C/R were driven by the acquisition cost of

brentuximab vedotin treatment. The incremental costs of C/R with intent to alloSCT were

driven by both the cost of transplantation and the higher cost of AEs.

16

Cost-effectiveness

For some patients alloSCT would be precluded at baseline due to age or comorbidities;

therefore, analyses were conducted including and excluding C/R with intent to alloSCT from the

comparator set. The ICER for brentuximab vedotin was £38,769 per QALY gained vs C/R when

excluding C/R with intent to alloSCT (Table 3). For patients eligible for alloSCT, C/R with

intent to alloSCT was dominated by brentuximab vedotin. The prior cost-effectiveness estimate

is therefore applicable to all patients, regardless of eligibility for alloSCT. The same pattern of

results was observed in the analysis of cost per life-year (LY), in which the ICER for

brentuximab vedotin was £47,593 per LY gained vs C/R.

Sensitivity analyses

When considering all comparators, the ICER for brentuximab vedotin ranged between £38,000

and £50,000 per QALY for the majority of the analyses (Table 4). The following scenarios

yielded ICERs above or below these boundaries: assuming 18% of patients receiving

brentuximab vedotin go on to receive alloSCT (£53,030 per QALY), use of IRF data for PFS

and response to brentuximab vedotin (£51,937 per QALY), assuming all patients achieve a CR

utility until progression (£34,097 per QALY), and assuming all patients receive the most

expensive chemotherapy regimen (£32,998). C/R with intent to alloSCT remained dominated or

extended dominated in all analyses. Hence, the ICERs for brentuximab vedotin are applicable

regardless of eligibility for alloSCT.

The alloSCT cohort had the greatest productivity benefit (–£19,034), which was driven

by its superior response profile (Supplementary Data 3). When accounting for the proportion of

patients who proceed to transplant in the C/R with intent to alloSCT comparator, brentuximab

vedotin has the greatest productivity benefit (–£18,172) compared to C/R (–£2,567) and C/R

17

with intent to alloSCT (–£11,824). Incorporating these productivity benefits reduced the ICER

for brentuximab vedotin to £28,881 per QALY vs C/R.

The probability that brentuximab vedotin is cost-effective depends on the cost-

effectiveness threshold. Figure 3 shows the probability that brentuximab vedotin is cost-

effective at a range of cost-effectiveness thresholds.

Discussion

The base case ICER for brentuximab vedotin estimated by this analysis is £38,769 per QALY

compared to C/R17. This result was robust to a wide range of scenario analyses, including

analyses assuming that brentuximab vedotin is associated with higher rates of PFS or OS events

than the comparators beyond the trial follow-up. Only two scenarios increased the ICER to

above £50,000 per QALY. For patients eligible to receive alloSCT, C/R with intent to alloSCT

was dominated by brentuximab vedotin.

This evaluation compared brentuximab vedotin with two treatments recommended for

use in patients with R/R HL post-ASCT over a lifetime time horizon, based on the best available

evidence for these treatments. Data for brentuximab vedotin were taken from the SG035-0003

study which informed expedited approval from the regulatory authorities in Europe and the

USA for patients with R/R HL post-ASCT. Data for the comparators were taken from a

combination of SG035-0003 and EBMT observational cohort studies, the latter of which is the

largest available study of chemotherapy with or without radiotherapy in R/R HL. In addition,

the EBMT study provided information on risk factors, which allowed the observational data to

be adjusted according to baseline prognosis, in line with SG035-0003 data.

18

Drugs for rare diseases (orphan drugs) are often expensive and do not prove to be cost-

effective based on standard methods of HTA, which may mean that funding and patient access

are limited. However, the cost-effectiveness estimate for brentuximab vedotin (£38,769 per

QALY gained) is relatively low compared to other orphan drugs that are recommended in the

UK, examples of which include ipilimumab for advanced/metastatic melanoma (at around

£42,200 per QALY gained), and pemetrexed as maintenance therapy in non-small cell lung

cancer (between £41,300 and £51,000 per QALY gained)38, 39. The SMC made its positive

recommendation for brentuximab vedotin in 2015 under its decision-making framework for the

assessment of ultra-orphan medicines. The associated criteria include the nature of the

condition, the impact of the new technology, value for money and impact beyond direct health

benefits and on specialist services17. In addition, current HTA methodology by NICE in the UK

effectively recommends a higher decision threshold for end-of-life treatments (those that offer

an extension to life and are indicated for small patient populations with a short life

expectancy)40. This extended threshold has previously been estimated at around £50,000 per

QALY41. Brentuximab vedotin meets the SMC criteria for both an ultra-orphan and an end-of-

life medicine, as validated by the SMC17. In the present study, probabilistic sensitivity analyses

found that at a willingness-to-pay threshold greater than £50,000, the probability of brentuximab

vedotin being cost-effective is 82% respectively vs C/R, regardless of whether C/R with intent

to alloSCT was included as a comparator.

Prior to the availability of brentuximab vedotin there was no viable treatment option for

R/R HL other than to attempt ASCT, with a very low probability of success, or to resort to best

supportive care42, 43. Evidence for brentuximab vedotin in R/R patients who have not received

ASCT is limited to phase I/II studies, a Japanese-only study (TB-BC010088) and Named Patient

Programs. Data derived from these studies, based on 40 patients who received the licensed dose,

19

showed an ORR of 54% and a CR rate of 22%44. In addition, 19% of patients went on to receive

stem cell transplantation (SCT)44, which can potentially lead to prolonged PFS and cure. This

evidence was considered in the SMC recommendation, which includes adult patients with R/R

HL following at least two prior therapies when ASCT or multi-agent chemotherapy is not a

treatment option17.

There are a number of limitations to the analysis that largely stem from a lack of

comparative data and the heterogeneity of the SG035-0003 population. Ideally, data used in the

model would reflect the efficacy in each of the populations in which brentuximab vedotin may

be used, namely first-, second- or subsequent line post-ASCT; and patients eligible/ineligible for

alloSCT. However, due to the size of the available population, the model was based on the

entire SG035-0003 population (that reflects patients across these strata) and observational data

(that follows patients from ASCT relapse or from commencement of a subsequent line of post-

ASCT therapy).

The source of efficacy data for brentuximab vedotin (SG035-0003) was a single arm

study, which meant that direct or adjusted indirect comparisons were not possible. As such, a

naïve indirect comparison was conducted based on the published survival data for the

comparators. This may have biased the estimates of clinical outcomes and, hence, cost-

effectiveness due to differences in prognostic factors across the trial arms used.

Where patient characteristics were reported consistently across studies enabling a

comparison across cohorts for either PFS or OS, there was some observable heterogeneity. In

Robinson et al., only 80% of patients had previously received ASCT, compared to 100% of

patients in SG035-0003, which may have biased PFS in favor of alloSCT27. For OS, Martinez et

20

al. included higher proportions of patients with Stage III–IV disease at initial diagnosis (52% vs.

46%) and with baseline B-symptoms (49% vs. 34%) compared to SG035-0003, which may have

biased this outcome against C/R and alloSCT. Conversely, SG035-0003 included a higher

proportion of patients who were refractory to their most recent therapy (42% vs. 15% in

Martinez et al.) 9.

In addition, Martinez et al. did not report characteristics for the alloSCT and C/R cohorts

separately hence these data include 8% patients who received a second ASCT9. Moreover, a

number of characteristics were not reported consistently across studies, including; ECOG

performance status, Karnofsky status, histologically confirmed CD30-expression, bulky disease,

and disease status following frontline or most recent therapy. Consequently, it was not possible

to determine the extent of heterogeneity across studies for these characteristics. A Multivariate

analysis reported by Robinson et al. identified poor performance status, defined by Karnofsky

score and ECOG score, and disease status at transplant as significant predictors of PFS and

OS27. Similarly, Martinez et al. identified poor performance status, early relapse, stage IV, bulky

disease, and age as significant predictors of OS9. As such, any heterogeneity in these

characteristics would likely bias mean time-in-state and hence the cost-effectiveness estimates,

increasing uncertainty in the indirect comparison. An attempt was made to adjust for case-mix

to reflect the SG035-0003 population, however it was not possible to adjust PFS for alloSCT,

and the risk factor classification used for OS is simplistic. However, any bias may have been

conservative, as patients in the Robinson et al.27 study may have had a better prognosis on

average than those enrolled in SG035-0003, based on a comparison of median time from ASCT

to relapse (9 months in the study by Robinson et al.27 compared with 6.7 months in SG035-

0003). Moreover, both the PFS and OS outcomes for brentuximab vedotin used in this analysis

reflect survival following the most recent therapy13, 15; whereas the self-control data from

21

SG035-0003 reflect PFS following the most recent prior post-ASCT therapy and both of the

EBMT studies measured PFS and OS from the time of ASCT9, 27. The model can therefore be

thought of as comparing a mix of first-, second- and subsequent line post-ASCT patients to less

heavily treated patients, which may underestimate the incremental life-years for brentuximab

vedotin. Scenario analyses increasing and decreasing the PFS and OS hazards by 10% for both

comparators over lifetime yielded ICERs within the range of those generated by the SMC

analysis. These results indicate the potential impact of bias in the relative effects of brentuximab

vedotin on PFS and OS on cost-effectiveness, despite not being able to evaluate the full extent

of heterogeneity across the studies and the impact of this on clinical outcomes and cost-

effectiveness.

The base case analysis extrapolates both PFS and OS for brentuximab vedotin using the

hazard for alloSCT and a weighted hazard of alloSCT and C/R, respectively. Extrapolation of

the treatment effect observed within the trial periods would have been less conservative;

however, this was not pursued given the non-randomized nature of the evidence base.

Although clinicians indicated that brentuximab vedotin followed by alloSCT may be

pursued as a treatment option for adequate responders, this comparator was not modelled as

only eight patients in the SG035-0003 study received alloSCT as their first treatment after

brentuximab vedotin. All of these patients were first-line post-ASCT relapse; representing 8%

of all patients included in the trial and 18% of first-line patients included in the trial, and the

associated outcomes are captured in the observed OS data used. When including the associated

costs for 8% and 18% of patients, the ICER for brentuximab vedotin increased to £45,107 and

£53,030 per QALY respectively. However, patients were censored for progression upon

receiving alloSCT in SG035-0003; hence, these results may not fully reflect the health effects of

22

alloSCT and therefore the cost-effectiveness of brentuximab vedotin. More recently, Chen et al.

45published extended follow-up from a retrospective analysis comparing outcomes of two

consecutive case series; 21 patients who received brentuximab vedotin followed by RIC

alloSCT and a historical cohort of 23 patients who received RIC alloSCT in the pre-

brentuximab vedotin era. The authors cited these cohorts as being essentially matched aside

from their exposure to brentuximab vedotin, and found that salvage brentuximab vedotin

yielded an improvement in 2-year PFS. A potential further development of the cost-

effectiveness analysis would be to incorporate brentuximab vedotin with intent to alloSCT as a

comparator based on the data reported by Chen et al.45.

Due the relatively early age of presentation compared with many other adult cancers,

Hodgkin lymphoma can incur considerable societal costs including loss of productivity46.

Incorporating productivity benefits reduced the ICER for brentuximab vedotin to £28,881 per

QALY vs C/R. Currently there is no consensus on how to incorporate indirect external effects in

cost-effectiveness analyses of health care technologies. The human capital approach

implemented here may overestimate the value of productivity by using gross earnings and

failing to recognize that additional production may be consumed by the individual47.

Furthermore, this method does not reflect the productivity ‘opportunity costs’ of brentuximab

vedotin that will occur if brentuximab vedotin is funded (and other productivity-enhancing

interventions are therefore displaced). Alternatively, the impact of toxicity on ability to return to

work independent of response profile was not modelled hence the incremental productivity

benefit of brentuximab vedotin may be underestimated. However, this result highlights the

potential impact of incorporating benefits associated with patient’s ability to return to work in

this population.

23

Conclusions

Although the base case ICER for brentuximab vedotin estimated by this analysis exceeds the

decision threshold usually applied in Scotland, this result is modest for an orphan medicine that,

as recognized by HTA bodies, is unlikely to reach conventional cost-effectiveness thresholds48.

When other considerations are included (such as the ultra-orphan decision-making framework

for SMC, or the extended threshold applied by NICE for end-of-life treatments), brentuximab

vedotin may still be considered an appropriate use of UK healthcare resources. This is reflected

in the positive recommendation from the SMC, based on a previous data cut of SG035-0003,

under its decision-making framework for the assessment of ultra-orphan medicines.

Transparency

Declaration of funding:

The analysis was funded by Millennium Pharmaceuticals Inc., a wholly owned subsidiary of

Takeda Pharmaceutical Company Limited.

Declaration of financial/other relationships:

CP is an employee of ICON plc an international clinical research organization that has received

funding for this work from Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly

owned subsidiary of Takeda Pharmaceutical Company Limited.

BW is a former employee of ICON plc that received funding for this work from Millennium

Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda

Pharmaceutical Company Limited.

JE is an employee of ICON plc an international clinical research organization that received



24

EM was an employee of Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly

owned subsidiary of Takeda Pharmaceutical Company Limited, at the time of the study.

RS is an employee of Takeda UK Ltd, Buckinghamshire, UK.

EB is an employee of Takeda UK Ltd, Buckinghamshire, UK.

AE is an employee of Takeda Pharma AB, Stockholm, Sweden.

PS is an employee of Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned

subsidiary of Takeda Pharmaceutical Company Limited

AB is an employee of ICON plc an international clinical research organization that received



VB was an employee of Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly

owned subsidiary of Takeda Pharmaceutical Company Limited, at the time of the study

Acknowledgments

The authors acknowledge the writing assistance of Fiona Scott of FireKite, an Ashfield

company, part of UDG Healthcare plc, during the development of this manuscript, which was

funded by Millennium Pharmaceuticals, Inc., and complied with Good Publication Practice 3

ethical guidelines (Battisti WP, et al. Ann Intern Med 2015;163:461–4).

Supplementary Data

Supplementary data 1: Systematic review methodology

Supplementary data 2: Chemotherapy costs, alloSCT costs, safety costs and QALY decrements,

health state costs and health state utilities

Supplementary data 3: Productivity data

25

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31

Figure legends

Figure 1. Kaplan-Meier estimates of PFS and OS, by comparator.

33

(a) Brentuximab vedotin: PFS (investigator-assessed) and OS were taken from

SG035-000312, measured from trial entry. (b) C/R: PFS was taken from SG035-0003

for the most recent prior post-ASCT therapy (n=56), measured from trial entry12; OS

was taken from Martinez et al., 2013 for C/R, measured from ASCT failure and

adjusted for case mix9. (c) AlloSCT: PFS was taken from Robinson et al., 2009 for

RIC alloSCT, measured from ASCT failure27; OS was taken from Martinez et al.,

2013 for RIC and myeloblative alloSCT, measured from ASCT failure and adjusted

for case mix9.

alloSCT, allogenic stem cell transplant; ASCT, autologous stem cell transplant; C/R,

chemotherapy +/- radiotherapy; PFS, progression-free survival; OS, overall survival;

RIC, reduced-intensity conditioning.

34

Figure 2. Long term extrapolations of PFS and OS, by comparator.

(a) PFS: 0–6.08 years, brentuximab vedotin SG035-0003 data12 were compared with

self-control and Robinson et al., 2009 data27; 6.08 years–lifetime, all comparators

were assumed to have the same constant risk of progression. (b) OS: 0–5.67 years,

brentuximab vedotin SG035-0003 data12 were compared directly with Martinez et al.,

2013 data9; 5.67–6.0 years, brentuximab vedotin data12 were extrapolated with a

hazard ratio of 1.0 applied to the Martinez et al., 2013 hazard9; 6.0–lifetime, all

comparators were assumed to have the same constant risk of death.

alloSCT, allogenic stem cell transplant; C/R, chemotherapy +/- radiotherapy; OS,

overall survival; PFS, progression-free survival.

Figure 3. Cost-effectiveness acceptability curve (alloSCT eligible patients).

AlloSCT, allogenic stem cell transplant; C/R, chemotherapy +/- radiotherapy; QALY,

quality-adjusted life year.

36

Table 1. Demographic and clinical characteristics of patients enrolled in clinical

studies informing the cost-effectiveness model.

SG035-0003 study12, 13, 15

Robinson et al., 200927

Martinez et al., 20139, 28

Cohort (endpoints used in the model)

Brentuximab vedotin (PFS, OS); C/R (PFS)

AlloSCT (PFS) AlloSCT (OS); C/R (OS)

Maximum follow-up, years

PFS = 6.08

OS = 6.08

5.19 AlloSCT = 6.04

C/R = 6.04

Number of patients

102 285 AlloSCT = 133;

C/R = 294;

2nd ASCT = 35*

Median age, years (range)

31 (15–77) 31 (18–57) † 31 (18–72) †

Gender, male/female (n)

48/54 163/122 268/194

ECOG PS, n (%)

0 42 (41) NR NR

1 60 (59) NR NR

Karnofsky status, n (%)

≥80 NR NR 212 (75)

<80 NR NR 72 (25)

Prior ASCT, n (%)

102 (100) – (80) 462 (100)

Median number of prior chemotherapy regimens (range)

3.5 (1–13) 4 (1–8)‡ NR

Number of therapy lines before ASCT, n (%)

1–2 57 (56) NR 288 (62)

37

SG035-0003 study12, 13, 15

Robinson et al., 200927

Martinez et al., 20139, 28

>2 42 (34) NR 131 (28)

Median time from ASCT to first post-transplant relapse, months (range)

6.7 (0–131) § 9 7 (1–78)

Median time from diagnosis to transplantation, months (range)

17.9 (5–115) § NR 21 (5–244)

Histologically confirmed CD30-expressing disease, n (%)

102 (100) NR NR

Primary refractory to frontline therapy, n (%)

72 (71) NR NR

Refractory to most recent therapy, n (%)

43 (42) NR – (15)

Baseline B symptoms, n (%)

35 (34) NR 168 (49)

Bulky disease NR NR – (7)

Stage III at initial diagnosis, n (%)

27 (26) 56 (20) NR

Stage IV at initial diagnosis, n (%)

20 (20) 72 (25) NR

Stage III–IV at ASCT failure, n (%)

NR NR 235 (67)

alloSCT, allogenic stem cell transplant; ASCT, autologous stem cell transplant; C/R,

chemotherapy +/- radiotherapy; ECOG PS, Eastern Cooperative Oncology Group

38

Performance Status; NR, not reported; OS, overall survival; PFS, progression-free

survival.

*Characteristics include patients who received a second ASCT who were not

modelled †Median age at transplant; ‡All prior therapies; §11 patients (11%) received 2

prior ASCTs, in these patients, ASCT refers to the most recent ASCT.

39

Table 2. Discounted life years (LYs), QALYs and costs by resource category.

LYs QALYs Costs

Comparator Total PFS PPS AEs Total

Acquisition (£)

Admin (£)

Health state (£)

AEs (£)

Total (£)

Brentuximab vedotin 5.43 2.51 0.89 -0.04

3.36 69,335 3160 15,766 312 88,572

C/R 4.15 0.46 1.35 -0.03

1.79 3,823 3885 18,551 1,134 27,393

C/R with intent to alloSCT

4.41 1.69 0.90 -0.08

2.51 67,779 17,707 9,507 94,993

AlloSCT, allogenic stem cell transplant; AEs, adverse events; C/R, chemotherapy +/-

radiotherapy; LYs, life years; PFS, progress-free survival; PPS, post-progression

survival; QALYs, quality-adjusted life year.

40

Table 3. Base case cost-effectiveness.

Patients eligible for alloSCT Patients ineligible for alloSCT

Comparator ICER (£/QALY) ICER (£/LY) ICER (£/QALY) ICER (£/LY)

Brentuximab vedotin £38,769 £47,593 £38,769 £47,593

C/R Referent Referent Referent Referent

C/R with intent to alloSCT Dominated Dominated Not applicable

alloSCT, allogenic stem cell transplant; C/R, chemotherapy +/- radiotherapy; ICER, incremental cost-effectiveness ratio; LY, life year; QALY,

quality-adjusted life year.

Table 4. Deterministic sensitivity analyses.

Parameters explored Justification ICER(£/QALY)

C/R C/R with intent to alloSCT

Brentuximab vedotin (£)

Brentuximab vedotin % change vs base case

Base case For comparison Referent Dominated 38,769 0

Named patient program data used for weight distribution

May be more reflective of real world data

Referent Dominated 39,630 2

8% of patients in brentuximab vedotin arm receive alloSCT

Percent of patients receiving alloSCT in SG035-0003

Referent Ext Dominated

45,107 16

18% of patients in brentuximab vedotin arm receive alloSCT

Percent of first-line post-ASCT patients receiving alloSCT in SG035-0003


53,030 37

30% patients progress to alloSCT Alternative estimate provided by clinical experts


38,769 0

IRF PFS and response rates for brentuximab vedotin

Alternative PFS assessment from SG035-0003


HR for PFS beyond trial period 1.5 for brentuximab vedotin or C/R vs alloSCT

Explore scenario whereby PFS outcomes during trial are followed by ‘catch-up’ relative to alloSCT


HR for PFS beyond trial period 2.0 for brentuximab vedotin or C/R vs alloSCT

More extreme version of scenario above


42


Log-normal model used to extrapolate brentuximab vedotin or C/R

Extrapolation based on within trial curve fitting


Maximum follow-up used for OS Use of full follow-up from SG035-0003 Referent Dominated 38,073 –2

Weibull used to extrapolate OS Use of alternative approach to estimating baseline OS


HR for OS beyond trial period 1.5 for brentuximab vedotin vs C/R or alloSCT

Explore scenario whereby OS outcomes during trial are followed by ‘catch-up’ relative to comparators


HR for OS beyond trial period 2.0 for brentuximab vedotin vs C/R or alloSCT

More extreme version of scenario above


Increasing comparator hazards for PFS and OS by 10%

Explore potential bias in relative treatment effects for brentuximab vedotin resulting from naïve comparison

Referent Dominated £34,800 -10

Decreasing comparator hazards for PFS and OS by 10%

Explore potential bias in relative treatment effects for brentuximab vedotin resulting from naïve comparison

Referent Dominated £45,457 17

All patients achieve CR utility until progression

Address lack of time-dependency in proportion of CRs in PFS state

Referent Dominated 34,097 –12

All patients assumed to receive most expensive chemotherapy

Alternative cost scenarios Referent Dominated 32,998 –15

43


All patients assumed to receive least expensive chemotherapy


Post-progression cost increased by 100% Referent Dominated 38,279 –1

Post-progression cost set to zero Referent Dominated 39,260 1alloSCT, allogenic stem cell transplant; C/R, chemotherapy +/- radiotherapy; CR, complete remission; HR, hazard ratio; ICER, incremental cost-

effectiveness ratio; IRF, independent review facility; OS, overall survival; PFS, progression-free survival; QALY, quality-adjusted life year.

44

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