Eli Lilly and Company Ltd

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1 Eli Lilly and Company Limited Lilly House Priestley Road Basingstoke Hampshire RG24 9NL Medical and Product Information: +44 (0) February 2007 Mr Christopher Feinmann Technology Appraisal Project Manager National Institute for Health and Clinical Excellence MidCity Place 71 High Holborn London WC1V 6NA Dear Mr Feinmann Response to the Erlotinib Appraisal Consultation Document on Non-Small Cell Lung Cancer Lilly appreciates the opportunity to comment on the evidence base used to inform NICE s preliminary decision regarding erlotinib for use in patients with non-small cell lung cancer (NSCLC) in England and Wales. Lilly agree with the Appraisal Committee s (AC) preliminary recommendations given in paragraph 1.1 of the ACD that erlotinib is not an alternative to docetaxel in second-line treatment. However, it is of concern that the AC is not minded to recommend erlotinib for the treatment of patients with locally advanced or metastatic NSCLC who have relapsed following prior exposure to docetaxel. These patients would be considered third line and there is no current active therapy for these patients. The erlotinib registration study (BR21) has shown that patients who have received more than two lines of chemotherapy (i.e. third line) receive significant survival and symptomatic benefits from active therapy compared to Best Supportive Care (BSC). Lilly are also concerned about the many discrepancies in the manner in which the pemetrexed and the erlotinib submissions were reviewed by the Liverpool Reviews and Implementation Group (ERG). In a separate response to NICE, we have addressed each of the criticisms raised by the ERG report (ERGR) in relation to our submission on pemetrexed. The aim of this response is to bring to the attention of the Appraisal Committee key points to consider in reviewing the evidence on erlotinib which ERGR on erlotinib has failed to highlight. Lines of therapy Second line versus third-line treatment of advanced NSCLC With respect to lines of therapy in advanced non-small cell lung cancer, it would appear the ERG has adopted an inconsistent approach between the erlotinib and pemetrexed assessment of evidence. In the ERGR for pemetrexed there are several statements which

2 demonstrate confusion on the part of the ERG with respect to lines of therapy (i.e second-line versus third-line), in that the ERG makes a comment that all three agents (erlotinib, pemetrexed and docetaxel) could potentially be used third-line. This is incorrect with respect to the licence for pemetrexed and docetaxel. As NICE s guidance is constrained to statements around licensed products, it needs to be clear that docetaxel and pemetrexed are not licensed third-line treatments. The only treatment which is indicated for second and third line treatment of advanced NSCLC is erlotinib (EPAR, EMEA 2005). Survival benefit with erlotinib in patients with one prior chemotherapy (i.e second-line) The BR.21 trial is a randomised controlled phase III clinical trial comparing erlotinib with placebo/best supportive care in patients with locally advanced or metastatic non-small lung cancer in 17 countries around the world none of which are in the UK. Patients eligible for inclusion in the trial were restricted to having previously received one or two previous chemotherapy regimen and who were not suitable for further chemotherapy (PBAC Public Summary Document, EMEA EPAR and Shepherd et al, 2005). Median survival data for patients treated with one prior regimen compared to those patients with 2 or more previous chemotherapy regimens are available from BR.21 study. In the registration trial comparing pemetrexed to docetaxel (JMEI), only patients with one prior chemotherapy were included (hence the indication for pemetrexed (as with docetaxel) in second-line treatment of advanced NSCLC). Lilly would like to draw the committee s attention to the survival benefit and confidence intervals seen in patients treated with one prior chemotherapy regimen in the BR.21 study the survival benefit of erlotinib over placebo in patients treated with one prior chemotherapy regimen (i.e. second-line) in a sample size of 364 patients is less than one month (erlotinib: 6.3 months and placebo: 5.5 months). The following slide is from the presentation of the BR.21 results presented at the Annual meeting of ASCO (2004): In the erlotinib submission, the overall survival in the erlotinib arm of the BR21 trial (6.7 months) was used to compare to docetaxel (which is indicated for second-line therapy). This in fact may bias against docetaxel (if it is accepted docetaxel is a suitable comparator to

3 erlotinib in the second-line setting) and not against erlotinib, as suggested by the manufacturer. Suitable comparators to erlotinib in the second-line treatment of advanced NSCLC The primary basis of the marketing authorisation (licence) of erlotinib in the second and third line treatment of advanced NSCLC, is the BR.21 trial. As mentioned above, one of the inclusion criteria for the trial was patients who are not suitable for chemotherapy. Therefore the most suitable comparator for erlotinib should be best supportive care, and this evidence is again available directly from the BR.21 trial. As shown above, the survival data can be disaggregated into results specific for second and third-line patients. As almost 50% of advanced NSCLC patients who relapse after 1 st line chemotherapy will get BSC, it is most appropriate to compare erlotinib to BSC. Registration study for erlotinib BR.21 Lilly wish to draw the attention of the committee to the following points relating to this trial: The trial included patients with good performance status, in spite of the eligibility criteria being patients not suitable for chemotherapy. According to the EMEA there are concerns about the potential lack of efficacy in the EGFR-negative patients particularly for a compound targeting this signalling pathway. The EMEA go on to conclude the following: In view of the overall positive results of the trial and the need to take into account all positive and negative predictive factors, the CHMP supported a recommendation for a therapeutic indication, but with mentioning that no survival benefit or other clinically relevant effect of erlotinib has been observed in EGFR-negative patients (defined by IHC using EGFR pharmdx kit and defining EGFR-negative as less than 10% tumour cells staining), and that prescribing physicians should refer to the results of the subgroup analysis in section 5.1 for deciding what patients should receive treatment with Tarceva. (EPAR, EMEA 2005). In the BR.21 trial response was higher among Asians, women, patients with adenocarcinoma and lifetime nonsmokers (Shepherd et al, 2005). Selection bias regarding efficacy data for docetaxel Roche excluded highly relevant phase III trial data from 4 studies on the second-line use of docetaxel in NSCLC patients from their base case economic evaluation (namely, Schuette et al., (2005), Ramlau et al., (2005), Fossella et al., (2000) and Gridelli et al., (2004)). This is most likely to have reduced the efficacy estimates for docetaxel thus falsely inflating the clinical and cost effectiveness estimates for erlotinib. Clinical management of patients treated with erlotinib Roche fail to mention the additional need for (and costs of) CT scanning which according to expert clinical opinion is required prior to commencing treatment with erlotinib. The availability of erlotinib as an oral therapy does not eliminate the need for patients to attend hospital as assumed by Roche. If this were true, then it would not be possible for a. Patients with NSCLC to be seen by their oncologist b. The effectiveness and tolerability of treatment with erlotinib to be monitored c. Routine tests and investigations to be performed d. Patients to get access to further supplies of erlotinib e. Compliance to treatment to be managed.

4 It is not the case therefore that erlotinib poses no burden on NHS resources because as with docetaxel, pemetrexed and best supportive care, patients still need to attend hospital. It is important to determine the extent to which erlotinib reduced the burden on NHS resources because of avoiding time spent receiving intravenous chemotherapy and incorporated these costs accordingly. Presently, the costs are underestimated in favour of erlotinib and the clinical importance of monitoring these patients is unclear in the ACD recommendations. Costing methodology employed in the MS on erlotinib None of the unit costs used within the model have been inflated to present values. The unit costs employed within the model were two-three years out of date. Comment on the implications for further research as advised by the ERG A full systematic review of all the available and relevant evidence on chemotherapy options and best supportive care has already been performed in the Lilly submission on pemetrexed. The ERG alludes to the possibility of a meta-analysis of the available data; however, there are not a sufficient number of head-to-head clinical trials to permit such an analysis at this time. Had this been the case, then such a meta-analysis would have formed an integral part of the Lilly submission on pemetrexed. Coverage of databases employed in the systematic literature review The ERG state [page 19 of 67] in their report on erlotinib that appropriate databases and conference proceedings were searched. It is worthy of note that that the coverage of databases used in the literature review performed by Roche on erlotinib neither included searches of the Web of Science, ISI Proceedings or the European Society for Medical Oncology (ESMO) proceedings. Furthermore, the literature review of clinical evidence performed by Roche used very subjective inclusion / exclusion criteria that were not sufficiently explicit so as to avoid selection bias. It would be impossible for this review to be reproduced as described. None of these shortcomings are mentioned in the ERGR on erlotinib. Conclusion With regards to general second-line treatment, we do not believe all the relevant evidence has been taken in to account and would ask that NICE review the evidence on erlotinib specific to the second-line setting i.e. comparison with BSC using efficacy data from the patients who received one prior chemotherapy in the BR21 trial. Lilly would also encourage NICE to recommend erlotinib in patients who have never smoked and have not benefited from first-line chemotherapy. In patients who have smoked, have a good performance status, and cannot tolerate docetaxel, then treatment with pemetrexed is a clinically effective option for patients with advanced NSCLC. In conclusion, we believe erlotinib is a clinically efficacious treatment for patients requiring third-line treatment for advanced NSCLC. As erlotinib is the only third line agent available, we would urge NICE to it available for patients who otherwise would have no other alternative other than BSC. Yours sincerely Manager, HTA and Health Outcomes, UK

5 References Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. Journal of Clinical Oncology 2000;18(12): Gridelli C, Gallo C, Di Maio M, Barletta E, Illiano A, Maione P, et al. A randomised clinical trial of two docetaxel regimens (weekly vs 3 week) in the second-line treatment of non-small-cell lung cancer. The DISTAL 01 study. British Journal of Cancer 2004;91(12): Public summary document for Tarceva, PBAC Australia available on Ramlau R, Gervais R, Kzakowski M et al. Oral topotecan demonstrates clinical activity in relapsed non-small cell lung cancer. Results from an open-label, phase III study (387) comparing oral topotecan to intravenous docetaxel. Proc Am Soc Clin Oncol. 2005; Abs Schuette W, Nagel S, Blankenburg T, Lautenschlaeger C, Hans K, Schmidt E-W, et al. Phase III study of second-line chemotherapy for advanced non-small-cell lung cancer with weekly compared with 3-weekly docetaxel. Journal of Clinical Oncology 2005;23(33): Shepherd FA, Pereira J, Ciulianu T et al, A randomized placebo-controlled trial of erlotinib in patients with advanced non-small cell lung cancer (NSCLC) following failure of 1st line or 2nd line chemotherapy. A National Cancer Institute of Canada Clinical Trials Group (NCIC Meeting: Presented at the 2004 ASCO Annual Meeting. Shepherd FA, Rodrigues Pereria J, Ciuleanu T, et al. Erlotinib in previously treated nonsmall-cell lung cancer. New England Journal of Medicine, 2005, 14: (353) 2, Tarceva EPAR. Available on