trabectedin, 0.25 and 1mg powder for concentrate for solution for infusion (Yondelis ) SMC No. (452/08) Pharma Mar S.A. Sociedad Unipersonal

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1 trabectedin, 0.25 and 1mg powder for concentrate for solution for infusion (Yondelis ) SMC No. (452/08) Pharma Mar S.A. Sociedad Unipersonal 08 October 2010 The Scottish Medicines Consortium (SMC) has completed its assessment of the above product and advises NHS Boards and Area Drug and Therapeutic Committees (ADTCs) on its use in NHS Scotland. The advice is summarised as follows: ADVICE: following a re-submission trabectedin (Yondelis ) is not recommended for use within NHS Scotland. Indication under review: the treatment of patients with advanced soft tissue sarcoma, after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents. Efficacy data are based mainly on liposarcoma and leiomyosarcoma patients. In a phase II randomised study in patients with advanced leiomyosarcoma and liposarcoma in which two trabectedin dose schedules were used, the licensed 3-weekly schedule was superior to the alternative one for the primary endpoint, time to progression. The manufacturer s justification of the treatment s cost in relation to its health benefits was not sufficient to gain acceptance by SMC and in addition, the manufacturer did not present a sufficiently robust economic case to gain acceptance by SMC. Overleaf is the detailed advice on this product. Chairman Scottish Medicines Consortium Published 08 November

2 Indication Trabectedin is indicated for the treatment of patients with advanced soft tissue sarcoma, after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents. Efficacy data are based mainly on liposarcoma and leiomyosarcoma patients. Dosing Information Trabectedin must be administered under the supervision of a physician experienced in the use of chemotherapy. Its use should be confined to qualified oncologists or other health professionals specialised in the administration of cytotoxic agents. The recommended dose is 1.5 mg/m 2 body surface area, administered as an intravenous infusion over 24 hours with a three-week interval between cycles. Administration through a central venous line is strongly recommended and pre-treatment with 20mg of intravenous dexamethasone is advised for anti-emetic and hepatoprotective effects. Product availability date 17 September 2007 The EMA designated trabectedin an orphan medicinal product for this indication on 31 May Summary of evidence on comparative efficacy Trabectedin is a tetrahydro-isoquinoline originally extracted from the marine tunicate Ecteinascidia turbinate, or sea squirt. It is now manufactured synthetically. The proposed mode of action is blockage of the transcriptional activation of a subset of inducible genes, without their constitutive expression being affected. One phase II randomised open-label study has been conducted in adult patients with; measurable advanced leiomyosarcoma or liposarcoma (L-sarcomas); relapsed or progressive disease despite prior treatment with an anthracycline and ifosfamide (given in combination or sequence); an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 1; and adequate organ function. Patients were randomly and equally assigned to receive either trabectedin 1.5 mg/m 2 administered as a 24-hour intravenous (IV) infusion every 21 days (24-hr q3wk) or trabectedin 0.58 mg/m 2 administered as a 3-hour IV infusion on days 1, 8 and 15 of a 28-day cycle (3-hr qwk). Patients received dexamethasone 10 to 20mg IV as anti-emetic prophylaxis. The all randomised set was used for the primary analysis (n=270). Following initial favourable efficacy results in 80 patients the study was extended to allow a formal comparison between the trabectedin schedules. The primary endpoint of the extended study was time to progression (TTP), defined as the time between randomisation and the first documentation of disease progression or death due to progressive disease. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and best objective response. The 24-hr q3wk arm was significantly superior to the 3-hr qwk arm in terms of TTP: median TTP 3.7 months versus 2.3 months, hazard ratio The 24-hr q3wk schedule was significantly superior and numerically superior to the 3-hr qwk schedule, for PFS and OS, 2

3 respectively. The objective response rates assessed by Response Evaluation Criteria in Solid Tumors (RECIST) were 1.6% in the 3-hr qwk arm versus 5.6% in the 24-hr q3wk arm. Results for primary and secondary endpoints are included in the table below. Table: primary and secondary endpoints for pivotal trial for the all randomised population. Trabectedin schedule 24-hr q3wk n=136 3-hr qwk n=134 Hazard ratio (95% confidence interval) P- value Primary TTP, median (months) (0.55 to 0.97) Secondary PFS, median (months) (0.57 to 0.99) OS, median (months) (0.65 to 1.09) TTP, time to progression; PFS, progression free survival; OS, overall survival; 24-hr q3wk, 24 hour infusion given every 3 weeks; 3-hr qwk, 3 hour infusion given weekly for 3 weeks of a 4 week cycle. Summary of evidence on comparative safety Significant haematological and hepatic toxicity has been observed, although toxicity was usually reversible and cumulative toxicity has not been observed. Other than laboratory abnormalities the most common drug related adverse events were fatigue, nausea and vomiting. In an integrated database of 1018 patients, rhabdomyolysis was associated with death in 5 patients (0.5%), none from the pivotal trial. The summary of product characteristics (SPC) stipulates strict treatment criteria to minimise the risk of rhabdomyolysis. The European Medicines Agency (EMA) commented that the results regarding dose reductions, cycle delays and treatment discontinuations confirm that the treatment schedule (24-hr q3wk) is close to the threshold where a majority of patients would experience dose-limiting toxicity. They note that the available safety data show that despite being manageable, the toxicity of trabectedin is undoubtedly significant and appears to be similar to other antineoplastics in terms of nausea, vomiting, asthenia, anorexia and haematological toxicity. The SPC includes criteria for haematological, hepatic and renal function (similar to those used in the clinical study) that have to be satisfied prior to initial treatment and re-treatment with trabectedin. Summary of clinical effectiveness issues Outcomes in advanced soft tissue sarcomas are poor and there has been little progress with respect to new active compounds since the introduction of ifosfamide in the late 1980s. Median overall survival in studies of treatments for advanced disease has been around six months. In the pivotal study median overall survival with the licensed dose of trabectedin was 13.9 months. However objective response rates were low with stable disease being the most common best response. 3

4 The marketing authorisation for trabectedin, an orphan medicine for advanced soft tissue sarcoma, was granted under exceptional circumstances. The clinical data supporting its use in this indication are limited to a phase II randomised study and three phase II non-comparative open label studies. There are no comparisons with best supportive care and other chemotherapy regimens that may be used at this stage of treatment are unlicensed or investigational. It may, therefore, be difficult to evaluate the additional clinical benefit of trabectedin over current standard practice in patients who have failed on anthracycline/ifosfamide treatment. In the pivotal study only patients with L-sarcomas and an ECOG PS of 0 or 1 were included. The three phase II non-comparative studies did include patients with other subtypes of STS. Nevertheless there are limited data to quantify the benefit of trabectedin in patients with a poorer performance status and in soft tissue sarcomas other than L-sarcomas. The use of a central venous access is strongly recommended as severe injection site reactions may occur when trabectedin is administered through a peripheral venous line. This may have implications for the patient as well as for service delivery. Summary of comparative health economic evidence The manufacturer presented a cost-utility analysis comparing trabectedin with best supportive care (BSC) for the treatment of patients with advanced soft tissue sarcoma, after failure of anthracyclines and ifosfamide, or who are unsuitable to receive these agents. A Markov model was used where patients on trabectedin started in the progression free health state and BSC patients entered the model in the progressive disease state. The analysis was conducted over a lifetime horizon with patients assumed to receive a mean of 7 cycles of trabectedin based on the trabectedin clinical trial. Clinical data in relation to time to progression, progression free survival and overall survival were taken from the trabectedin study. For the BSC arm clinical data were based on four studies selected from the European Organisation for Research and Treatment of Cancer (EORTC) soft tissue sarcoma group database. Resource use associated with progressive disease was taken from a cost of illness study which estimated the management costs of metastatic soft tissue sarcoma from diagnosis of metastatic disease until death. Half of this cost was also applied to the progression free health state to account for disease management costs in this state of the model. The utility values for progression free and progressive disease were taken from a study of second-line advanced non-small cell lung cancer patients as no values specific to patients with soft tissue sarcoma were available. Costs and disutilities associated with adverse events were also included in the analysis. In the base case, the manufacturer estimated a cost per quality adjusted life year (QALY) of 46,282 based on an increased cost of 24,756 and a QALY gain of In addition to the high base case cost per QALY estimate, the following issues were noted: A formal indirect comparison was not conducted and there were some differences between the trial population and the BSC studies that have not been fully adjusted for. Notable differences relate to performance status, previous treatment and soft tissue sarcoma subtype. 4

5 Sensitivity analysis showed that the results were sensitive to the overall survival estimates. Using the most pessimistic estimate of overall survival in the trabectedin arm increased the cost per QALY to 121k. Using the most optimistic estimate of overall survival in the BSC arm increased cost per QALY to 70k. Only with very optimistic estimates of survival with trabectedin did the cost per QALY fall to 27k. The results were relatively sensitive to the utility values used in the model. In the base case it was assumed that patients in the progressive disease health state only experienced one month of poor quality of life before death. However, in an alternative scenario analysis where patients entering the progressive disease health state experienced a linear decline in utility over 5 cycles, the cost per QALY increased to 56k. Due to the high cost per QALY and the uncertainties outlined above, the economic case has not been demonstrated. Summary of patient and public involvement A Patient Interest Group Submission was received from Sarcoma UK. Additional information: guidelines and protocols The European Society for Medical Oncology (ESMO) produced clinical practice guidelines for diagnosis, treatment and follow-up of soft tissue sarcomas in May 2010 via a consensus process. These guidelines state that standard chemotherapy is based on anthracyclines as first line treatment. Evidence is lacking to guide treatment choice where anthracyclines have failed or cannot be used. Second line options would include ifosfamide if it has not been used previously or high dose ifosfamide in patients who have already received the drug. Trabectedin, which has been shown to be effective in leiomyosarcoma and liposarcoma, is recommended as an alternative second line option. Responses to trabectedin have also been seen in synovial sarcoma and in myxoid liposarcoma, although a peculiar pattern of tumour response was noted in myxoid liposarcoma. Additional second line options are given but the guidelines advise that, in general, advanced pretreated patients are candidates for clinical studies and also give best supportive care as an option for advanced patients especially if they have failed on further line therapies. The Scottish Sarcoma Network published guidelines for the treatment of soft tissue sarcomas on their website in September The algorithm suggests that all patients should be discussed at the sarcoma MDT and entered into the appropriate clinical trial if possible. The only specific trial discussed is the EORTC study which is investigating single agent doxorubicin versus a combination of doxorubicin and ifosfamide. No specific chemotherapy regimen is suggested if this is unsuccessful or not suitable. Additional information: comparators There are no other established treatments for advanced STS in clinical practice in Scotland. 5

6 Cost of relevant comparators Drug Dose regimen Cost per cycle ( ) Cost for 5* cycles ( ) trabectedin 1.5 mg/m 2 as a 24-hour infusion every 3 weeks 3,821 19,105 Doses are for general comparison and do not imply therapeutic equivalence. Costs from evadis on 26 July Costs based on a body surface area of 1.8m 2. *Based on the median number of cycles in pivotal trial. Additional information: budget impact The manufacturer estimated the net budget impact would be 122k in year 1 rising to 335k in year 5. These estimates were based on 6 patients being treated in year 1 (20% uptake) rising to 16 in year 5 (50% uptake). 6

7 References The undernoted references were supplied with the submission. The reference shaded in grey is additional to the reference supplied with the submission. Demetri GD, Chawla SP, von Mehren M et al. Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of prior anthracyclines and ifosfamide: results of a randomized phase II study of two different schedules. Journal of Clinical Oncology 2009; 27 (25): The European Medicines Agency (EMEA) European Public Assessment Report. Trabectedin (Yondelis ). EMEA H-C This assessment is based on data submitted by the applicant company up to and including 17 September Drug prices are those available at the time the papers were issued to SMC for consideration. These have been confirmed from the evadis drug database. SMC is aware that for some hospital-only products national or local contracts may be in place for comparator products that can significantly reduce the acquisition cost to Health Boards. These contract prices are commercial in confidence and cannot be put in the public domain, including via the SMC Detailed Advice Document. Area Drug and Therapeutics Committees and NHS Boards are therefore asked to consider contract pricing when reviewing advice on medicines accepted by SMC. Advice context: No part of this advice may be used without the whole of the advice being quoted in full. This advice represents the view of the Scottish Medicines Consortium and was arrived at after careful consideration and evaluation of the available evidence. It is provided to inform the considerations of Area Drug & Therapeutics Committees and NHS Boards in Scotland in determining medicines for local use or local formulary inclusion. This advice does not override the individual responsibility of health professionals to make decisions in the exercise of their clinical judgement in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. 7