Executive summary Overview

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Kristian Hunter
6 years ago
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1 Executive summary Overview In this appraisal, we have demonstrated that dasatinib is clinically more effective, as well as more cost effective, than imatinib, the current standard of care. In the pivotal clinical trial, 12-month data have shown that dasatinib is superior to imatinib in terms of complete cytogenetic response (CCyR) rates. CCyR rate is a reliable prognostic predictor for long-term clinical benefits in CML. Progression free survival (PFS) and overall survival (OS) are related to time to and length of such response. Patients who achieve CCyR early in treatment have improved PFS and OS, while those who do not respond to treatment early generally face disease progression. Dasatinib gives higher and faster CCyR and molecular response compared to imatinib, the current standard of care, and has the potential for improved OS. The narrower spectrum of mutations associated with resistance to dasatinib (compared with imatinib) suggests additional potential for less resistance to dasatinib. Because of better CCyR rate, dasatinib reduces the risk of progression to secondline treatment. Due to the expense of second-line treatment, this may result in a reduction in overall costs associated with treatment of CML. Further benefits of dasatinib include the fact that as a once daily oral therapy independent of meal-times, dasatinib is easy to self-administer and has minimal impact on service delivery. This could have consequences for improved patient compliance, which is known to be related to a better clinical outcome. Side effects of dasatinib are well characterised and easily managed. In particular there were no major grade 3/4 toxicities. There are no new safety signals associated with first-line compared with second-line treatment. Dasatinib is a designated orphan medicine, so comparative data to support this appraisal are inevitably scarce. However, there is robust clinical evidence that dasatinib is more effective than imatinib, and economic studies demonstrate that dasatinib is cost effective compared with standard-dose imatinib (400mg). Without a recommendation to allow first-line use of dasatinib, future CML patients in England and Wales may have to accept less effective therapy, a reduced quality of life and a diminished life expectancy, possibly at an increased cost to the NHS. BMS therefore request that dasatinib is recommended as a first-line treatment option for CML in England and Wales. The UK approved name, brand name, marketing status and principal mechanism of action of the proposed technology. Dasatinib, SPRYCEL. Dasatinib was first approved in the EU on 20 November 2006 for all indications except first-line treatment which was approved in the EU on 6 December Dasatinib is a highly-potent inhibitor in vitro of the BCR-ABL tyrosine kinase, an enzyme that plays a critical role in the pathogenesis of chronic myeloid leukaemia (CML). Dasatinib blocks these enzymes at nanomolar concentrations, binding to and inhibiting not only BCR-ABL and SRC family but also a number of other selected oncogenic kinases including c-kit, ephrin (EPH) receptor kinases, and PDGFβ

2 receptor (Sprycel SmPC 2010). This binding blocks phosphorylation of substrate proteins, which prevents the activation or over-expression of various pathways responsible for transforming normal cells into malignant cells. The formulation(s), strength(s), pack size(s), maximum quantity(ies), anticipated frequency of any repeat courses of treatment and acquisition cost. Film-coated tablet 20mg, available in packs of 60 tablets ( per pack) 50mg, 70mg available in packs of 60 tablets ( per pack) 80mg, 100mg, 140mg available in packs of 30 tablets ( per pack) The indication(s) and any restriction(s). Dasatinib is indicated for the treatment of adult patients with: newly diagnosed Philadelphia chromosome positive (Ph+) chronic myelogenous leukaemia (CML) in the chronic phase chronic, accelerated or blast phase CML with resistance or intolerance to prior therapy including imatinib mesilate. Ph+ acute lymphoblastic leukaemia (ALL) and lymphoid blast CML with resistance or intolerance to prior therapy Dasatinib is contraindicated in cases of hypersensitivity to the active substance or excipients. Caution is recommended in the following instances: concomitant use with drugs that potently inhibit cytochrome P450 (CYP) 3A4, patients with hepatic impairment, patients taking drugs that inhibit platelet function or anticoagulants, patients who have or may develop prolongation of QTc (including those with hypokalaemia or hypomagnesaemia, congenital long QT syndrome, patients taking anti-arrhythmic drugs or other drugs which lead to QT prolongation, and cumulative high dose anthracycline therapy), and patients who have, or with risk factors for, cardiac disease. Dasatinib should not be used in pregnant or lactating women. The recommended course of treatment. The recommended starting dose for chronic phase CML is 100 mg dasatinib once daily, administered orally. Treatment is continued until disease progression or until no longer tolerated by the patient, but is not continued until death. Dose escalation to 140 mg once daily is recommended in patients with chronic phase CML who do not achieve a haematological or cytogenetic response at the recommended starting dose. 140 mg once daily is the approved dose for accelerated and blast phase CML. The main comparator(s). Nilotinib, Imatinib (standard dose, 400mg daily). Whether the key clinical evidence in the submission comes from head-to-head randomised controlled trials (RCTs), from an indirect and/or mixed treatment comparison, or from non-randomised studies.

3 Key clinical evidence: a multinational open label randomised Phase III clinical study in patients newly diagnosed with chronic phase CML, comparing dasatinib at 100 mg once daily (OD) and imatinib at 400 mg OD (DASISION; Kantarjian et al 2010). This publication reports data from the 12-month analysis; data from the 18-month timepoint have since been presented in abstract form only (Shah et al 2010) and are not discussed further pending presentation of the full 18-month and 24-month analyses later in This study is supported by the results of a Phase IIb study with dasatinib (Radich et al 2010). The Phase III ENESTnd study compares nilotinib with imatinib in newly-diagnosed chronic phase CML (Saglio et al 2010). There are no studies that directly compare dasatinib and nilotinib head-to-head. Consequently, a mixed treatment comparison (MTC) was conducted. The main results of the RCTs and any relevant non-rct evidence. In the DASISION trial, dasatinib treatment produced a significantly higher CCyR rate by 12 months compared with imatinib (83% vs 72%, p <0.001) in newly diagnosed chronic phase CML. Dasatinib s superior efficacy over imatinib was also confirmed through subpopulation analyses and by secondary endpoints. MMR rate, a key secondary endpoint, was significantly higher by 12 months in dasatinib-treated patients compared with imatinib-treated patients (46% vs. 28%, p <0.0001). Dasatinib-treated patients also achieved cytogenetic and molecular responses significantly earlier compared with imatinib-treated patients. Time to events data with 12 months of follow-up showed a non-detrimental effect of dasatinib. Dasatinib demonstrated higher response rates, faster time to response and a safety profile that was similar to imatinib in newly diagnosed CML patients with a minimum of 12 months of follow-up. In the MTC, results for dasatinib and nilotinib showed no statistically significant differences between the two products on all endpoints. In relation to the economic evaluation, details of: the type of economic evaluation and justification for the approach used; the pivotal assumptions underlying the model/analysis; the mean costs, outcomes and incremental cost-effectiveness ratios (ICERs) from the evaluation. The approach used is similar to that presented by Botteman et al. in a review of methods for extrapolating CML related survival data (Botteman et al 2010) (Table 1). A time in state (area under the curve) model (Briggs et al 2006) was developed, with the health states representing the early (CP) and advanced (AP/BP) stages as well as death, and time being in blocks of one month. A schematic of the patient pathway is presented in Error! Reference source not found.. In addition, patients can be on either first, second or third line treatment in all phases; however, according to clinicians opinion, palliative care is only for patients in advanced phases (i.e. AP/BP). Note that the model distinguished between disease staging (CP, AP/BP) and line of treatment (first-line, second-line, third-line).

4 Table 1 Key assumptions in the economic model Assumption Disease prognosis is predicated on early cytogenetic response Long term benefit of treatment (progression free and overall survival) is based on response to first line treatment at one year Non-CML mortality included in addition to information from clinical trials Different data sources used to model treatment specific prognosis in patients who has a less than partial cytogenetic response to treatment at one year Individuals can switch treatment for response related reasons at 3, 12 and 18 months Individuals can switch treatment for other reasons during every month For 2 nd generation TKIs (dasatinib and nilotinib), the discontinuation rates due to adverse events are assumed to decrease over time; For 1 st generation TKI (imatinib), constant rates are assumed Permanent treatment cessation has not been included in the base-case of the model. No patients get the benefit of treatment without incurring the costs In deriving post progression costs, 2/3 of time is spent in the AP state and 1/3 in the BP state SCT occurs only in third line therapy 3 rd line treatment in the CP state is different to post progression treatment Vial sharing does not occur when deriving the cost of IFN based therapy Where an adverse event was not reported in the literature it was assumed not to occur Where no data on utility decrement were Rationale / justification Trial literature supports this hypothesis Long term response category specific ITT data used in model construction. Hence, the benefits incurred by patients switching treatment early are implicitly included in the reported Kaplan-Meier plots CML-related death is not a common event in early stages of CML in CP (e.g. 12 months). Clinical trial program recruited mainly young patients and so long term non-cml related death effectively not accounted for. Based on information provided by clinical advisory panel. Individuals who fail 2 nd generation TKI treatments (i.e. dasatinib and nilotinib) were assumed to have a poor prognosis In line with current ELN guidelines In line with what has been observed long term in clinical trials In line with comments from clinical advisory panel. Unlike the 1 st generation TKI, clinicians tend to keep patients on 2 nd generation TKIs as long as possible since the only option left post-2 nd line treatment would be BMSCT, which is not suitable for all patients, and is associated with high risk. Therefore, it is assumed that patients on 2 nd generation TKIs would have lower discontinuation rates than those on 1 st generation TKIs, other things being equal. Although there is evidence in high quality journals that permanent treatment cessation happens for patients on TKI treatment, it is still early stage and not yet the clinical practice. We therefore include such scenarios in the sensitivity analysis Broadly in line with the clinical literature In line with current ELN clinical guidelines In line with comments made by clinical advisory group. Post progression treatment (treatments for advanced phases of CML) can include acute myeloid leukaemia (AML) related treatment (a combination of chemotherapies) in addition to the 3 rd line treatment options In line with common modelling practice In line with common modelling practice In line with current modelling practice

5 Assumption identified, a nominal value (-0.05) was used Rationale / justification

6 Tabulation of the base-case results as follows: Table 2 Base-case cost-effectiveness results Technology acquisition cost Dasatinib 100mg Imatinib 400mg Nilotinib 600mg 283,209 84, ,887 Other costs 215, , ,726 Total costs 498, , ,613 Difference in total costs + 19,924-8,396 LYG LYG difference QALYs QALY difference ICER 26, ,778 LYG, life years gained; QALY(s), quality-adjusted life year(s); ICER, incremental cost-effectiveness ratio

Ponatinib for treating chronic myeloid leukaemia and acute lymphoblastic leukaemia

Ponatinib for treating chronic myeloid leukaemia and acute lymphoblastic leukaemia Single Technology Appraisal 2 nd Committee meeting: 16 March 2017 Committee C FOR PUBLIC Key issues Absence of direct