Trabectedin for the treatment of relapsed ovarian cancer

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1 National Institute for Health and Clinical Excellence Summary form Comment 1: the draft remit Trabectedin for the treatment of relapsed ovarian cancer Appropriateness (Royal Marsden Hospital/Institute of Research) Yes Comment noted Royal College of Nursing (RCN) National Research Insititute (NCRI) Gynaecology Clincial Studies Group/Royal College of Physicians/Royal College of Radiologists/Joint Collegiate Council on Oncology/Association of Physicians Until all the evidence is available for the ovarian cancer indication, we cannot comment how likely it may result in guidance which is helpful to NHS in England and Wales. A submission to the EMEA is anticipated for December Seems appropriate Trabectedin is another novel marine derived compound where promising early benefit has been seen. We believe the trial combining it with caelyx vs caelyx alone is due to be presented at ESMO This will give clearer indications of its likely role and use in subgroups. Any activity over 25-30% RR in Pt Resistant disease would merit attention. Having a novel action and being a non platinum drug it is worthy of further development and assessment in relapsed ovarian cancer. Comment noted Availability of evidence and subgroups were discussed at the scoping workshop. Guidance will only be issued in accordance with the marketing authorisation The scope has been updated to reflect this.

2 Summary form Wording The remit is clear and accurate. There is no real need to pursue the platinum refractory group in this context provided that the platinum-resistant group are clearly identified. The degree of platinum sensitivity is an important factor. The comparator - caelyx/doxil - is acceptable, as long as the platinum-free interval is less than 12 months which should be the case in most patients. Please note that the sensitive population in our pivotal study includes the partially sensitive population. The definitions used for the purpose of inclusion of patients into the pivotal study were: 1) Previously treated with only 1 platinum-based chemotherapy regimen and had experienced either recurrence or progression after more than 6 months from the beginning (first dose) of the initial line of platinum-based chemotherapy for ovarian cancer. 2) Recurrence or progression after 6 full cycles of a complete 6 cycle initial treatment regimen or 6 months after the beginning (first dose) of the initial treatment line of platinum-based chemotherapy for ovarian cancer to include: Subjects with platinum-resistant disease (platinum-free interval from the end of first-line treatment less than 6 months) Subjects with platinum-sensitive disease (platinum-free interval from the end of first-line treatment equal to or more than 6 months) who are not expected to benefit from or who are ineligible for or who are not willing to receive retreatment with platinum-based chemotherapy; Comments noted. Women whose ovarian cancer is platinum refractory are not included in the scope. Comments noted. Guidance will only be issued in accordance with the marketing authorisation The scope has been updated to reflect this.

3 Summary form Timing Issues Reasonably urgent as the trial reports in September This will be the first randomized trial involving a non-platinum based combination in this population of patients. As mentioned in the appropriateness of the appraisal, please note that we are currently in the process of evaluating the data. A submission to the EMEA is anticipated in December Please note that the basis for the application for approval in this indication is progession free survival as primary endpoint. Overall survival data will not become available until 2010/2011.Therefore, it might be difficult to perform appropriate comparisons when complete information is not yet available. Scheduling of appraisals are dependant on the Department of Health referring a topic and consideration of the work carried out across NICE programmes. Evidence on progression free survival data would be considered in appraisal of this technology. Additional comments on the draft remit Yondelis is given through a central line, and any additional toxicity relating to this has to be documented. Adverse effects of treatment are included in the scope.

4 Summary form NCRI There is a large interest in drugs for platinum-resistant ovarian cancer. The current drugs used for this indication (liposomal doxorubicin, topotecan etc) are both unpleasant and of limited effectiveness. Caelyx is rarely used at 50 mg/m2 unless mandated in a trial protocol. Best supportive care is probably not an issue. For both of these drugs, a phase II single agent trial that demonstrated any form of activity would be followed by comparative phase III trials. For trabectidin, the most likely trial would be a straight comparison with Caelyx. We think this is probably more logical than adding it into Caelyx but we will be interested to hear what is presented at ESMO. The Aflibercept vs Avastin trial is unlikely ever to happen, but if Aflibercept were to show promise in phase II, without significant bowel toxicity, then moving straight to phase III in first line treatment with carboplatin/taxol would seem obvious. This is what has happened with Avastin, despite the significant bowel toxicity seen in phase II in relapsed disease. Guidance will only be issued in accordance with the marketing authorisation. Comment (on Aflibercept) noted. Aflibercept is not a comparator for trabectedin, so will not be considered in this appraisal.

5 Summary form Comment 2: the draft scope Background information Accurate: results of trial will be available very soon (within 2-3 weeks) and probably should be included. Trial results are not normally included in scope documents. The technology appraisal, once initiated, will consider such evidence. Considered correct. The technology/ intervention Yes Yes, the draft scope accurately describes trabectedin and its use in treating women who have failed a first-line platinum based chemotherapy regimen. Population Yes. If any patients had platinum-free interval more than 12 months they should be identified since carboplatinwould more often be given to them. Of course the patients will be subdivided into platinum resistant/sensitive using the conventional 6 months threshold. The population defined is appropriate. RCN Think this reads betters as follows: Women with ovarian cancer that has relapsed following first-line platinum-based chemotherapy regimen Wording in scope has been revised to improve readability. Comparators Yes (for doxil) The comparators are adequate.

6 Outcomes Yes The primary endpoint of the pivotal trial is progression free survival. The secondary endpoints are OS, response rate and safety. Health related quality of life is also being collected. Summary form Comments noted. These outcomes are reflected in the scope. Economic analysis n/a We cannot comment as yet to the appropriate time horizon. The scoping workshop participants discussed time horizon and agreed that a life time may be the most appropriate. Equality n/a Such consideration do not appear relevant The scoping workshop participants discussed equalities issues and agreed that none were relevant to this appraisal. Other considerations n/a No further suggestions at this point. Questions for consultation as above

7 GlaxoSmithKlin e It would seem sensible to review trabectedin through the Single Technology Appraisals process in order to provide timely and relevant guidance to the NHS. Summary form In our pivotal study - refractory patients were not included. Therefore, platinum refractory disease should not be included. The platinum-free interval is important for determining the reponse to futher treatment after patients have relapsed. We have not yet started with any cost-effectiveness study. OS data will only be avaible in 2010/2011. Therefore there is not enough information yet avaible to define which process is more suitable. Guidance will only be issued in accordance with the marketing authorisation. Availability of overall survival data would not normally justify delay of an appraisal and the potential to issue guidance to the NHS. Scheduling of appraisals are dependant on the Department of Health referring a topic and consideration of the work carried out across NICE programmes. The scoping workshop participants discussed the technology appraisal processes in use at NICE and agreed that the single technology appraisal process would be suitable.

8 Additional comments on the draft scope. We are currently in the process of collecting all information and analysing the data of our pivotal ovarian cancer study and would therefore prefer to comment in detail at a later stage once all information is available to us No further comments Comments noted. Summary form The following consultees/commentators indicated that they had no comments on the draft remit and/or the draft scope Department of Health National Collaborating Centre for NHS Quality Improvement Scotland National Public Health Service for Wales Royal College of Pathologists RICE - The Research Institute for the Care of Older People (The Research Institute for the Care of the Elderly) Royal Pharmaceutical Society