Trabectedin for the treatment of relapsed ovarian cancer

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 08/212/01. The assessment report began editorial review in June 2010 and was accepted for publication in October 2010. 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. The views expressed in this publication are those of the authors and not necessarily those of the HTA programme or the Department of Health.

Declared competing interests of authors

none

Copyright statement

© Queen’s Printer and Controller of HMSO 2011. This work was produced under the terms of a commissioning contract issued by the Secretary of State for Health. This journal is a member of and subscribes to the principles of the Committee on Publication Ethics (COPE) (http://www.publicationethics.org/). This journal may be freely reproduced for the purposes of private research and study and may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NETSCC, Health Technology Assessment, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

2011 Queen’s Printer and Controller of HMSO

Description of the underlying health problem

Trabectedin (Yondelis^®, PharmaMar) in combination with pegylated liposomal doxorubicin hydrochloride (PLDH) (Caelyx^®, Schering-Plough) is licensed for patients with platinum-sensitive ovarian cancer (OC). 3 OC is asymptomatic in the early stages, with diagnosis in ≥ 75% cases made when OC is at an advanced stage (stage III/IV disease). Of women with OC, 80% will relapse and require second-line chemotherapy; the long-term prognosis is poor, with the UK 5-year survival rate reported as around 30%. 4 The number of new cases of OC in 2010 was estimated as 5423, based on Cancer Research UK incidence rates. 5 The estimated number of stage III/IV OC cases will be 4067; the number who will relapse will be 3253. Expert opinion2,6 suggests that, of those patients who relapse, 15–25% are platinum refractory (OC that does not respond to initial platinum-based chemotherapy). Of the remaining patients, expert opinion in the UK indicates that 20–25% are platinum resistant (i.e. relapse within < 6 months), 25–30% (813–976 in 2010) are partially platinum sensitive (relapse within 6–12 months) and 50% (1626 in 2010) are fully platinum sensitive (relapse > 12 months after initial chemotherapy). In total, therefore, 75–80% of relapsing patients are potentially eligible for treatment: 2440–2602 patients in 2010. 2,6

Scope of the evidence review group report

The principal research question was to appraise the clinical effectiveness and cost-effectiveness of trabectedin in combination with PLDH within its licensed indication for the treatment of relapsed cases of platinum-sensitive OC. The comparator defined in the NICE scope was platinum-based chemotherapy (single agent or in combination) for the fully and partially platinum-sensitive populations. Additional comparators for the partially platinum-sensitive population were single-agent PLDH, paclitaxel or topotecan. Relevant clinical outcomes were overall survival (OS), progression-free survival (PFS) and overall response rate, with the last two outcomes being measured by three types of assessor – independent radiologists, independent oncologists and an investigator – and adverse effects of treatment. Health-related quality-of-life outcomes were measured by subscales from two cancer-specific quality-of-life instruments [European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and the EORTC QLQ-QV28], and the EQ-5D (European Quality of Life-5 Dimensions). Cost per quality-adjusted life-year (QALY) gained was the relevant outcome for the cost-effective analysis.

The manufacturer submitted a cost-effectiveness model developed in Microsoft^© excel (Microsoft Corporation, Redmond, WA, USA). The main analysis compared trabectedin in combination with PLDH versus paclitaxel, topotecan and PLDH (each as monotherapy) in the entire platinum-sensitive population only (> 6-month relapse) using results estimated from a mixed treatment comparison (MTC). Additional analyses were presented by the manufacturer comparing trabectedin in combination with PLDH versus PLDH as monotherapy using direct evidence from the ET743-OVA-301 trial7 for the fully, partially and entire platinum-sensitive populations. The model used a lifetime horizon and the main outcome was the cost per QALY gained.

Summary of submitted clinical evidence

The main evidence in the manufacturer’s submission (MS)6 is derived from one phase III randomised controlled trial (RCT) comparing the efficacy and safety of a combination of 1.1 mg/m² trabectedin and 30 mg/m² PLDH with 50 mg/m² PLDH. 7 Table 1 presents the OS and PFS data for the trial. The largest and only significant effect on OS was seen within the partially platinum-sensitive subgroup, for which the median OS for the trabectedin plus PLDH arm was 23.0 months compared with 17.1 months for patients treated with PLDH alone.

The MS presented PFS results from the independent radiologists’ assessment. Within the partially platinum-sensitive subgroup, there was a significant effect on PFS where the median PFS for the trabectedin and PLDH arm was 7.4 months compared with 5.5 months for PLDH alone [hazard ratio 0.65 (95% confidence interval 0.45 to 0.92); p = 0.0152]. Significant effects were also seen in the entire platinum-sensitive population but not in the fully platinum-sensitive population.

Progression-free survival results from assessments by the independent oncologists and the investigator are available in the ERG report. 2

Discontinuation of treatment owing to adverse events and most grade 3 and 4 adverse events were higher in the trabectedin and PLDH combination arm than in the PLDH monotherapy. The main adverse events were neutropenia, febrile neutropenia, thrombocytopenia, anaemia, elevated aminotransaminase levels, fatigue, fever, diarrhoea, nausea and vomiting.

The MS also presented the results of an MTC to allow a coherent comparison of trabectedin and PLDH with PLDH, paclitaxel and topotecan (each as monotherapy). This was undertaken for the entire platinum-sensitive population only, and based on an MTC that had previously been performed as part of a NICE Multiple Technology Assessment (TA) – NICE TA91. 4

Summary of submitted cost-effectiveness evidence

The model structure was derived from a previously published NICE Multiple TA (TA914), and the effectiveness was modelled using the mean survival time derived from the median survival time, using an assumption that data were exponentially distributed. Utilities were extracted from the OVA-301 trial,7 and costs were assessed from an NHS perspective. In the main analysis, the manufacturer reported that paclitaxel provided the least number of QALYs, followed by topotecan, PLDH as monotherapy and trabectedin in combination with PLDH. The incremental cost-effectiveness ratio (ICER) for trabectedin in combination with PLDH versus PLDH as monotherapy was estimated to be £70,076 per QALY gained.

The manufacturer also presented the ICERs for the three direct comparisons for the entire, partially and fully platinum-sensitive populations. The ICERs between trabectedin in combination with PLDH versus PLDH as monotherapy, using the independent radiologists’ assessment, were £94,832, £43,996 and £31,092 by population, respectively. Results using the independent oncologists’ assessment and the investigator’s assessment are available in the clarification letter provided by the manufacturer. 8

Uncertainties were examined in univariate sensitivity analyses only for the main analysis, whereas probabilistic sensitivity analyses (PSA) were undertaken for each scenario.

Commentary on the robustness of submitted evidence

Limited data were available and the MS addressed only one part of the final scope issued by NICE, i.e. trabectedin and PLDH versus PLDH alone for the partially platinum-sensitive population. The remainder of the final scope issued by NICE was not addressed within the MS, i.e. trabectedin and PLDH versus platinum-based chemotherapy (single agent or in combination) in the fully or partially platinum-sensitive populations, and trabectedin and PLDH versus paclitaxel or topotecan monotherapy in the partially platinum-sensitive population.

The main evidence in the MS is derived from one phase III RCT that is of reasonable methodological quality and measured a range of outcomes that were appropriate and clinically relevant. The included RCT is not an absolute reflection of the population with advanced relapsed OC in the UK, hence its external validity may be questionable. There appeared to be a high degree of censoring within the PFS analysis; reasons for censoring a large number of trial participants (n = 178) were not made explicitly clear within the MS. PFS analysis was also based on the independent radiologists’ assessment. Clinical advice sought by the ERG suggested that the independent oncologists’ assessment of PFS was more appropriate. OS results presented in the MS are based on an interim analysis.

The ERG did not believe that the MTC was necessary to answer the scope set by NICE. This is because PLDH had previously been estimated to be the most clinically effective and cost-effective treatment within the platinum-sensitive population when compared with paclitaxel or topotecan monotherapy,4 and clinical advice sought by the ERG indicated that in instances whereby PLDH monotherapy is contraindicated, a trabectedin and PLDH combination would also be contraindicated. Therefore, the relative cost-effectiveness of trabectedin and PLDH compared with paclitaxel or topotecan monotherapy is not needed, as there would never be a choice between these interventions. As such, a direct comparison of trabectedin and PLDH was deemed sufficient to address the decision problem.

The ERG requested individual patient data from the manufacturer. From these it was shown that the PFS and OS data were not exponentially distributed, and the ERG conducted analyses using alternative distributions. Secondly, the use of the average number of cycles of treatment across all the populations included in the trials for the main analysis only (i.e. platinum-sensitive and platinum-resistant individuals) is likely to have biased the cost-effectiveness estimate. Thirdly, there was uncertainty regarding the estimates of the mean dose per cycle. Fourthly, the ERG was concerned about the absence of discounting for costs and an incorrect approach used to discount health outcomes. Finally, there were problems concerning the implementation of the PSA, which limit its interpretation. This notably included the lack of variation for some main parameters, the choice of distribution and assumptions used.

Additional work was undertaken by the ERG only for the partially platinum-sensitive population. This included fitting more appropriate distributions for PFS and OS using individual patient-level data and estimating the mean dose per cycle from the mean number of cycles and mean cumulative dose from the trial, discounting costs and health outcomes using a conventional methodology, and amending the PSA. Assuming a Weibull or Gompertz distribution for both OS and PFS, and using the independent oncologists’ assessment, the ERG estimated that the ICER of trabectedin in combination with PLDH when compared with PLDH as monotherapy would range from £46,503 to £54,607, respectively, in the partially platinum-sensitive population. The ICER reported by the manufacturer was £39,262 using the independent oncologists’ assessment.

Disclaimers

The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Department of Health.