Trabectedin for the treatment of advanced metastatic soft tissue sarcoma

Article history

The research reported in this article of the journal supplement was commissioned and funded by the HTA programme on behalf of NICE as project number 08/92/01. The assessment report began editorial review in July 2009 and was accepted for publication in July 2009. See the HTA programme website for further project information (www.hta.ac.uk). This summary of the ERG report was compiled after the Appraisal Committee’s review. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

none

Copyright statement

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2010 Queen’s Printer and Controller of HMSO

Description of the underlying health problem

Trabectedin is licensed for patients with advanced metastatic soft tissue sarcoma having failed anthracycline and ifosfamide or for whom these agents are unsuitable.

Soft tissue sarcomas (STS) constitute a heterogeneous group of malignancies arising in soft tissues of the body including muscle, fat and blood vessels. The most frequent types are leiomyosarcoma and liposarcoma, which account for approximately 40–50% of all STS. There is an estimated annual incidence of 2000 STS in England and Wales (including gastrointestinal stromal tumour, which is excluded from this report). 3 Approximately 50% of patients present with, or develop, advanced or metastatic disease.

Scope of the evidence review group report

The principal research question was to appraise the clinical effectiveness and cost-effectiveness of trabectedin within its licensed indication for the treatment of advanced metastatic soft tissue sarcoma. Trabectedin is licensed for use in patients with advanced metastatic STS who have failed anthracycline and ifosfamide, either in combination as first-line therapy or in sequence as first- and second-line therapy. No other chemotherapies are currently licensed in the UK for STS at this point in therapy. The comparator was best supportive care. Relevant outcomes were overall survival (OS), progression-free survival (PFS), response rates (including stabilisation), adverse effects of treatment, health-related quality of life, and cost per quality-adjusted life-year (QALY) gained.

The manufacturer submitted a state transition model developed in excel, with individuals followed up to 5 years (until death). The base case in the manufacturer’s submission assumed that patients treated with trabectedin enter the model in the progression-free state (PFS) while patients in the best supportive care (BSC) arm enter the model in the progressive disease (PD) state. The base case was limited to patients with leukaemia (L)-sarcomas. Additional analyses requested by the ERG adjust the base case to account for differences in the starting health state. In addition, the manufacturer presented three additional scenarios. The first scenario used the pooled effectiveness of trabectedin from three uncontrolled phase II studies which was not limited to patients with L-sarcomas. In the second and third scenarios, the manufacturer assumed that a proportion of patients in BSC would receive further chemotherapies (either 33% or 100% of patients).

Summary of submitted clinical evidence

Owing to the lack of any comparative trials comparing trabectedin and BSC, the main evidence in the manufacturer’s submission was derived from one phase II randomised trial, in which the licensed dose of trabectedin was compared with a different dose of trabectedin. In the randomised controlled trial (RCT), median OS was 13.9 months [95% confidence interval (CI) 12.5 to 18.6] for the licensed dose of trabectedin (24-hour regimen every 3 weeks), which was not significantly different (p = 0.1985) from that for the comparator dose of trabectedin (weekly 3-hour regimen) which was 11.8 months (95% CI 9.9 to 14.9). From the phase II uncontrolled trials, median OS was reported as 9.24 or 12.8 months. 5 Historical control data, presented by the manufacturer’s submission as equivalent to BSC, had median OS of 5.9–6.6 months. 6 The RCT reported significantly (p = 0.04) superior PFS for the licensed dose of trabectedin (median 3.3 months) over the comparator trabectedin dose (median 2.3 months). One phase II uncontrolled trial reported median PFS as 1.9 months in the licensed dose of trabectedin. 5 The RCT reported PFS rates at 6 months were 35.5% (95% CI 27.1 to 43.9) for the licensed dose of trabectedin, and 27.5% (95% CI 19.4 to 35.5) for the comparator dose of trabectedin. From the phase II uncontrolled trials, PFS rates at 6 months were 24.4%7 or 29%. 4 Historical control data, presented by the manufacturer’s submission as equivalent to BSC, reported PFS rates at 6 months of 14% for patients treated with ifosfamide or dacarbazine after failure of anthracycline or 8% for patients from pooled studies on ‘inactive’ regimens.

For the RCT, deaths attributed to trabectedin occurred in 3.1% of the licensed dose, and 2.3% of the comparator group. Safety data for the licensed dose of trabectedin from the included RCT and three phase II studies’ reported rates of grade 3/4 haematological events varied: neutropenia 34–61%; febrile neutropenia 0.8–7.0%; thrombocytopenia 12–19%; and anaemia 8–22%. Across the four included studies, rates of grade 3/4 non-haematological events varied: aspartate aminotransferase (AST) elevation 26–48%; alanine aminotransferase (ALT) elevation 20–57%; nausea 4–7%; vomiting 2–9%; and asthenia/fatigue 0–15%.

Summary of submitted cost-effectiveness evidence

In the latest manufacturer’s submission, the cost per QALY gained of trabectedin compared with BSC was estimated to be £56,985 for the base case using effectiveness from the STS-201 trial for trabectedin and a pool analysis of the European Organisation for Research and Treatment of Cancer data set for BSC. This analysis was constrained to patients with L-sarcomas only.

The ERG was concerned that patients in the trabectedin arm began in a different health state than those in the BSC arm, and that those on trabectedin were assumed to have a higher starting utility. An exploratory analysis by the manufacturers in amending this assumption raised the cost per QALY gained for trabectedin compared with BSC to £61,064.

In addition to the base case, the manufacturer presented three additional scenarios. The first used the pooled effectiveness of trabectedin from three uncontrolled phase II studies which was not limited to patients with L-sarcomas; this produced a cost per QALY gained of £50,017. In the second and third scenarios, the manufacturer assumed that a proportion of patients in BSC would receive further chemotherapies (either 33% or 100% of patients). The cost per QALY gained for these two scenarios was estimated to be £62,044 and £80,279 respectively. None of these three scenarios amended the model to take into consideration the different starting utilities between the trabectedin and BSC arms.

When the joint uncertainty between parameters was considered, the cost-effectiveness acceptability curve showed that trabectedin has a very low probability of being cost-effective at a threshold of £30,000 per QALY gained compared with BSC for any scenario.

Commentary on the robustness of submitted evidence

Limited data were available. The main evidence in the manufacturer’s submission was derived from one phase II randomised trial, in which the licensed dose of trabectedin was compared with a different dose of trabectedin. The population in this trial was limited to L-sarcomas. Supplementary data were presented from three uncontrolled phase II trials of the licensed dose of trabectedin. Owing to the lack of a relevant comparator group in the included trabectedin trials, the manufacturer’s submission reported data from a database of other studies that are suggested to equate to BSC. The manufacturer acknowledged there were limitations with these controls, which, in addition to being historical comparisons, were from studies with populations comprising types of STS not restricted to L-sarcomas, and Eastern Cooperative Oncology Group (ECOG) performance status not confined to 0–1. This would bias against these controls for effectiveness data. There were some data available for ifosfamide studies restricted to a population similar to the trabectedin trials. Data presented in the clinical effectiveness section did not have OS calculated appropriately in all cases, and for OS and PFS data, further chemotherapy was given to some patients, thus making treatment not just BSC.

Iterations were needed to amend errors found by the ERG, which included errors in the treatment cost and additional analyses to explore the likely impact of the different starting health states. The ERG, however, still had concerns regarding the structure of the model and its ability to capture the cost-effectiveness of trabectedin for adults with advanced soft tissue sarcoma after failure of anthracyclines and ifosfamide. Firstly, the ERG had concerns about the potential non-comparability between patients included in studies to derive the effectiveness for trabectedin and BSC despite the adjustment of the Weibull curves for age, gender, histopathology and World Health Organization performance score. Secondly, the base case focuses on patients with L-sarcomas only and may not be generalisable to patients with other forms of STS. Thirdly, despite the attempt to adjust for the differences in the starting health state, uncertainties still exist on the likely impact of such model structure. Fourthly, while no utility values are available for patients with STS, there are uncertainties about the appropriateness of using utility values for patients with lung cancer as a proxy for STS. Fifthly, the probabilistic sensitivity analyses did not capture all the uncertainty within the decision, for example, the model assumed no correlation between time to disease progression and OS, nor correlation between the utility estimates for health states or the number of 1-mg and 0.25-mg vials used. Finally, the proportion of patients treated did not vary according to the proportion of patients in PFS. It is unclear how incorporating these correlations would change the mean cost per QALY, although it is likely that the range in the results generated from the PSA would increase.

Disclaimers

The views expressed in this publication are those of the authors and not necessarily those of the HTA programme or the Department of Health.