Oxford Outcomes ltd Project no. 1449/1450 TABLE OF CONTENTS INTRODUCTION...4 METHODS...5. Identification of trials...5. Statistical analysis...
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- Dortha Cannon
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3 TABLE OF CONTENTS INTRODUCTION...4 METHODS...5 Identification of trials...5 Statistical analysis...7 RESULTS...10 Identification of trials...10 Statistical analysis...11 DISCUSSION...13 TABLES...14 FIGURES...20 REFERENCES...22 APPENDICES...24 Appendix 1: Search strategy...24 Appendix 2: Jadad score...28 CONFIDENTIAL: Evidence synthesis to support erlotinib in NSCLC 3
4 INTRODUCTION Non-small cell lung cancer (NSCLC) is a leading cause of death in the UK with approximately 32,000 new patients diagnosed annually. The majority of patients diagnosed with advanced or metastatic disease will die within 18 months. As first-line treatment NICE have recommended platinum-based chemotherapy (in combination with gemcitabine, paclitaxel or vinorelbine) followed by docetaxel upon disease relapse. Besides docetaxel (taxotere), a range of other treatments are currently licensed in the UK as second-line treatment for NSCLC, in patients who have relapsed after prior chemotherapy. These consist of pemetrexed (alimpta) chemotherapy and the epidermal growth factor receptor (EGFR) inhibitors, erlotinib (tarceva) and gefitinib (iressa). However, no randomised controlled trials have been conducted which include all four treatments, rather trials of pairwise comparisons have been conducted between some of these treatments or best supportive care (BSC). In order to assist healthcare decision makers making choices between these licensed treatments, we have conducted a network meta analysis to compare each of the treatments by taking account all of the available published evidence in an evidence synthesis. Network meta-analysis (NMA) is an extension of conventional, pairwise, metaanalysis. It allows the results from trials comparing different sets of treatments to be statistically combined to produce comparable estimates of effects for all treatments. Network meta-analysis is based on the assumption that, on a suitable scale, we can add and subtract the within-trial estimates of relative treatment effects. In which case, the difference in effect between treatments A & B is equal to the difference in effects between treatments A & C and B & C; a difference in differences model. This is the methodology adopted when making simple indirect comparisons. In NMA these simple indirect comparisons are extended to include more complex networks of evidence using meta-regression techniques. We therefore used the NMA to provide comparable estimates of the hazard ratio for each active treatment compared to BSC or placebo based on a synthesis of the available direct and indirect trial evidence. This technique is increasingly being used to inform clinical decision making when there is an absence of or inadequate direct evidence (Cooper 2006; Griffin 2006; Nixon 2006). CONFIDENTIAL: Evidence synthesis to support erlotinib in NSCLC 4
5 We conducted a systematic review to identify all published randomised controlled trials which compared the above treatments at licensed dosages to each other or BSC as second-line treatment for advanced or metastatic NSCLC. METHODS Identification of trials We undertook a systematic review to identify RCTs of the following treatments: erlotinib, docetaxel, gefitinib or pemetrexed, administered as second-line therapy to stage III/IV NSCLC patients. The search was conducted in three electronic databases: EMBASE (OVID), MEDLINE (OVID) and MEDLINE in process (OVID). Our search terms comprised of disease terms, a study design filter and drug terms. The disease terms included a combination of free-text and index terms and were constructed by an Information Officer at the University of York. The study design filters were designed to identify randomised controlled trials, again using a combination of index and free text terms; these were taken from the recent NICE Guidance for Lung Cancer (National Collaborating Centre for Acute Care, 2005). A further study design filter was applied using the OVID review limit to identify, and consequently exclude, review articles. For the drug terms both brand and chemical names were used as free text items for each treatment. Full search syntax is provided in Appendix 1. Searches were limited to English language publications pertaining to human subjects published since January 1, Searches were conducted on October 24, All records were entered into a Reference Manager database and deduplicated. The title and abstract of each record was then reviewed against the following inclusion criteria: Study Design: Randomised Controlled Trials (RCTs) at any phase. Patient population: NSCLC patients where at least some proportion of patients have stage IIIB/IV disease. Patients were required to have received previous chemotherapy. CONFIDENTIAL: Evidence synthesis to support erlotinib in NSCLC 5
6 Intervention: Included trials must compare two or more of the following treatments: docetaxel, erlotinib, gefitinib, pemetrexed or best supportive care/placebo. Trials were required to compare treatments at their licensed dosages. Trials examining combined modality interventions were excluded. Endpoints reported: Trials were required to report data on the survival endpoint. Potentially relevant articles were ordered and their full text assessed for inclusion. Reference lists of included studies were also checked for relevant trials. In addition to the search of the published literature, a search was conducted of relevant presentations made at recent high profile oncology conferences to identify studies in the publication process. The search focused on conference presentations rather than abstracts as it was deemed unlikely that the latter would provide sufficient data to be incorporated into the network meta-analysis. The following conferences were searched to identify online presentations of clinical trials that met our inclusion criteria: - ASCO Annual Meeting 2007 oral presentations within the Lung Cancer Track were searched th European Cancer Conference (2007) th World Conference on Lung Cancer (2007) - Comprehensive Symptom Management in Advanced Lung Cancer educational session, Advances in Management of NSCLC Presidential Session, and Presidential Symposium presentations were searched 3. The following data was extracted from each included study: Study Descriptors and Trial Characteristics: o Author and date o Trial name 1 ASCO Annual Meeting 2007, Virtual Meeting: Lung Cancer Track: eb61a7010VgnVCM100000ed730ad1RCRD&vmview=vm_track_sessions_view&index=y&confID= 47&trackID=8. Accessed 1/11/ th European Cancer Conference, Webcast: Events/ECCO-14/Web-capturing/page.aspx/418. Accessed 1/11/ th World Conference on Lung Cancer: Accessed 1/11/07 CONFIDENTIAL: Evidence synthesis to support erlotinib in NSCLC 6
7 o Country o Trial Design Patient Population: o Demographics (age, sex) o Disease stage o Performance Status o Previous chemotherapy regimes (number of lines and type of previous chemotherapy) Intervention: o Treatment o Dose and regimen o Median number of cycles administered o Number of patients randomised to each arm Survival Data: o Hazard ratio o Confidence interval and/or p-value for hazard ratio. In addition, a quality assessment for each trial was performed using the Jadad scale (Jadad 1996; Moher 1999). Results of the assessment are presented both as the separate components of the scale and an overall score. The separate components of the scale are: Randomisation - Whether trial is stated to be randomised - Whether randomisation method is appropriate Blinding - Whether trial is states to be double-blind - Whether blinding method is appropriate Withdrawals - Whether number and reasons for withdrawals are stated. The scoring method is presented in Appendix 2. Statistical analysis The meta-analysis was based on the assumption that the estimates of the within trial log-hazard ratios are exchangeable between trials and that we can add and subtract estimates of the log-hazard ratios to obtain indirect estimates of treatment effects. CONFIDENTIAL: Evidence synthesis to support erlotinib in NSCLC 7
8 Estimates of the mean and standard error for the log hazard ratio between comparators for each trial were required for the analysis. Where the mean hazard ratio with the 95% confidence interval (UPPCI and LOWCI) were reported, the mean log hazard ratio was estimated as: ln( UPPCI ) + ln( LOWCI ) ln( hr) i = 2 and the standard error of the mean log hazard ratio as: s i UPPCI LOWCI = Where the mean hazard ratio and a p-value P were reported, the mean log hazard ratio was estimated as: ln( hr ) = ln( hr i i ) and the standard error of the mean log hazard ratio as: s i ln( HR) 1 Φ (1 P / 2) = where theta is the cumulative distribution function of the normal distribution. A Bayesian hierarchical model was used to synthesise the relative treatment effects observed within the trials. The model has a regression-like structure with the log hazard ratio for a study comparing treatments r and s equal to the difference between the treatment coefficients β and β. r s ln( HR, r s ) = β β r s The co-efficient for placebo is set to zero so that the effect estimates for active treatments are relative to placebo. CONFIDENTIAL: Evidence synthesis to support erlotinib in NSCLC 8
9 The trial data are included in the model using a normal likelihood function. With standard error model using a s i for the log hazard ratio, the observed data are included in the ln( hr) i ~ N 2 ( β β, s ) r s i The meta-analysis was conducted using WinBUGS 1.4 (Medical Research Council Biostatistics Unit, Cambridge). A burn-in period of 10,000 simulations was used to allow convergence, followed by 100,000 simulations for estimation. Caterpillar plots of the estimated parameters were checked to ensure that the model converged satisfactorily and residual plots were examined. CONFIDENTIAL: Evidence synthesis to support erlotinib in NSCLC 9
10 RESULTS Identification of trials The search of the published literature, after deduplication, identified 1,625 studies. Review of each record by title and abstract resulted in five potentially relevant studies being identified (Cufer 2006; Hanna 2004; Shepherd 2000; Shepherd 2005; Thatcher 2005). The full text of each of these studies was ordered and reviewed. All five met our inclusion criteria. The full texts of two papers (Karrison 2007; Scagliotti 2005) were ordered to assess whether trials referenced in their abstracts were suitable for inclusion. Trials thus identified were either not relevant or had already been captured by our review. Our review of conference presentations identified two potentially relevant trials: the Japanese V trial presented at ASCO (Niho 2007) and the INTEREST trial presented at both the European Cancer Conference and the World Conference on Lung Cancer (Douillard 2007). Review of the full presentations resulted in one trial (Douillard 2007) being included. The Niho (2007) trial was excluded as patients allocated to the docetaxel arm did not receive treatment at the licensed dosage. An additional trial comparing erlotinib to docetaxel or pemetrexed (Tarceva in the Treatment of Advanced NSCLC in the Second Line Setting (TITAN)), currently underway, was referenced in a discussion presentation at the World Conference on Lung Cancer (Shepherd 2007). Thus six studies were identified by our review. Tables 1 and 2 present the study and patient characteristics, respectively, for each of the included trials. The six trials comprised a total of 4,672 patients; the smallest trial was TAX 317 (Shepherd 2000) with 104 patients and the largest with 1,692 patients was the ISEL study (Thatcher 2005). Patient characteristics across studies were generally comparable. The median ages of patients was similar across studies (59-63 years) and between 31-36% of patients were female. Whilst some patients included in the studies had received more than one previous line of chemotherapy, the majority of patients were true second line patients. Only in the ISEL study (Thatcher 2005) had CONFIDENTIAL: Evidence synthesis to support erlotinib in NSCLC 10
11 50% of patients received two previous lines of chemotherapy. In terms of performance status, again the pattern was similar across studies with the majority of patients being ECOG status 0-1. Table 3 presents the results of the quality assessment for the included trials. The relatively low quality scores can partly be attributed to three of the trials using an open-label design (Cufer 2006; Douillard 2007; Hanna 2004). The low score attained by the INTEREST trial (Douillard 2007) is in part due to less information being available for this trial (extractions were performed from the conference presentation). Table 4 below presents the survival data reported for each study which was used to inform the network meta-analysis. Statistical analysis The network meta-analysis thus includes six trials: SIGN (Cufer 2006): Gefitinib vs Docetaxel INTEREST (Douillard 2007): Gefitinib vs Docetaxel JMEI (Hanna 2004): Pemetrexed vs Docetaxel BR21 (Shepherd 2005): Erlotinib vs Placebo TAX 317 (Shepherd 2000): Docetaxel vs BSC ISEL (Thatcher 2005): Gefitinib vs Placebo The network of evidence formed by these trials is shown in Figure 1. The hazard ratio data reported in each of the studies alongside the derived log hazard ratios are shown in Table 5. The hazard ratio is given for each treatment compared to the comparator treatment (placebo or docetaxel) used in each study. A hazard ratio less than 1 indicates that a treatment reduces the mortality rate and increase survival compared to the study comparator. Considering just the placebo controlled trials, docetaxel has the lowest hazard ratio compared to placebo (0.48). The hazard ratios estimated for each treatment from the NMA are shown in Table 6. The hazard ratio is given for all active treatments compared to placebo. A lower hazard ratio indicates that a treatment is associated with increased survival. Based on the NMA, when taking account of all the evidence, erlotinib has the lowest hazard ratio relative to placebo (0.70) and is also statistically significant. The results of the meta-analysis are also shown graphically in Figure 2. CONFIDENTIAL: Evidence synthesis to support erlotinib in NSCLC 11
12 A number of p-values are reported for the Shepherd (2000) study. The base analysis is based on the value of given for the intention-to-treat population. Table 7 shows the analysis repeated based on the p-value of given for the multivariable survival regression. The results of this analysis are similar those of the base case. Table 8 shows a further analysis excluding the unpublished INTEREST study. The mean results for erlotinib, pemetrexed and docetaxel are now similar albeit erlotinib has a tighter confidence interval. CONFIDENTIAL: Evidence synthesis to support erlotinib in NSCLC 12
13 DISCUSSION Our systematic review identified six randomised controlled trials each comparing two of our five treatments at licensed dosages as second line treatment in patients with stage III/IV NSCLC. On inspection, the patient characteristics in these six studies appeared generally comparable. We used a network meta analysis to combine all the evidence from all six studies comparing our five treatments, thus permitting comparisons of treatments not addressed directly within any of the individual trials. Our analysis found that erlotinib had the most favourable hazard rate relative to placebo. The hazard ratio estimate for erlotinib compared to placebo obtained from the network meta-analysis, 0.70 (95% CI 0.58, 0.85), was similar to that seen in the Shepherd (2005) study, 0.70 (95% CI 0.58, 0.85). Likewise, the hazard ratio estimate for gefitinib compared to placebo from the network meta-analysis, 0.88 (95% CI 0.78, 0.99) was similar to that reported in the ISEL study, 0.89 (95% CI 0.079, 1.01). However, the hazard ratio estimate for docetaxel compared to placebo from the network meta-analysis, 0.86 (95% CI 0.73, 1.01), is markedly different from that seen in the Shepherd (2000) study, 0.48 (p=0.039). This is because both the INTEREST and SIGN studies have hazard ratios for gefitinib compared to docetaxel close to one, 1.02 (95% CI 0.91,1.15) and 0.97 (95% CI 0.61,1.52), respectively. This suggests that gefitinib is similar to docetaxel. Combining the studies in a network, draws the estimate for the effect of docetaxel compared to placebo towards the estimate for gefitinib compared to placebo obtained from the ISEL trial. As the INTEREST study is large and provides relatively precise estimates of treatment effect, particularly compared to the smaller Shepherd (2000) study, it is influential when the studies are combined in the network meta-analysis. It could be argued that these findings support an argument for including indirect evidence when there is no or insufficient direct evidence (Lu & Ades 2004; Song 2003). If we had relied purely on direct evidence the results would have been quite different with docetaxel appearing to be the most favourable treatment relative to placebo which could have led to an inefficient allocation of scarce resources. CONFIDENTIAL: Evidence synthesis to support erlotinib in NSCLC 13
14 TABLES Table 1: Study Characteristics of Included Trials Study Characteristics Intervention Author & Date Trial Name Country Trial Design Treatment Dose Regimen Median cycles administered No. randomised Shepherd BR21 International Randomised, Erlotinib 150mg Daily Not stated double-blind trial. Placebo 243 Hanna 2004 JMEI International Phase III, Pemetrexed 500mg/m2 Every 21 days. 4 [range: 1-20] 283 randomised, openlabel Docetaxel 75mg/m2 Every 21 days. 4 [range: 1-14] 288 trial. Shepherd TAX 317 International Randomised trial. Docetaxel 75mg/m2 Every 3 weeks BSC 49 (75mg Doc) Thatcher 2005 ISEL International Phase III Gefitinib 250mg Daily 2.9 months randomised, Placebo 2.7 months. 563 double blind trial. Douillard 2007 (Conference presentation) INTEREST International Phase III randomised, openlabel trial. Gefitinib Docetaxel 250mg 75mg/m2 Daily Every 3 weeks. Mean time on treatment: 4.4 months. Mean time on treatment: 3.0 months Cufer 2006 SIGN International Phase II randomised, openlabel trial. Gefitinib 250mg Daily 3.0 months. 68 Docetaxel 75mg/m2 Every 3 weeks. 2.8 months. 73 CONFIDENTIAL: Evidence synthesis to support erlotinib in NSCLC 14
15 Table 2: Patient Characteristics for Included Trials Trial Median age Percentage female SIGN GFT: 63.0 GFT: 21 (31%) [range: 34- DOC: 22 (30%). 85], DOC: 59.5 [range: 29-83]. INTEREST <65: GFT: GFT: 36%, DOC: 61%, 33%. DOC: 67%. JMEI PEM: 59 PEM: 31.4%, [range: 22- DOC: 24.7% 81], DOC: 57 [range: 28-87] TAX317 DOC: 61 [range: 37-73], BSC: 61 [range: 28-77]. DOC: 20 (36.4%), BSC: 35 (35.0%). Disease Stage Performance Status Previous Chemotherapy IIB/IV ECOG 0: GFT 13 (19.1%), DOC:11 1 previous line CT. Metastatic disease: (15.1%) 1 previous line: GFT: 66 (97.1%), DOC: 72 (98.6%) GFT: 41 (60.3%), ECOG 1: GFT: 30 (44.1%), DOC: 41 Platinum-based: GFT: 62 (91.2%), DOC: 70 (95.9%). DOC: 41 (56.2%). (56.2%) ECOG 2: GFT: 25 (36.8%), DOC: 21 (28.8%) Locally advanced ECOG 0: GFT 30%, DOC:25% 1-2 previous lines CT (incl. 1 platinum based). or metastatic ECOG 1: GFT: 58%, DOC: 63% 1 previous line: GFT: 84%, DOC: 83%. NSCLC. ECOG 2: GFT: 12%, DOC: 12% III/IV ECOG 0/1: PEM: 88.6%, DOC: 87.6% 1+ lines of platinum/paclitaxel-based CT. Stage IV: PEM: ECOG 2: PEM: 11.4%, DOC: 12.4%. Paclitaxel-based: PEM: 25.8%, DOC: 27.8%. 74.9%, DOC: Platinum-based: PEM: 92.6%, DOC: 89.9%. 74.7% IIIB/IV ECOG 0: DOC: 13 (23.6%), BSC: 22 1 previous platinum-based CT. Stage IIIA/B: DOC: (22.0%) 1 previous line: DOC: 44 (80%), BSC: 76 (76.0%) 15 (27.3%), BSC: ECOG 1: DOC: 28 (50.9%), BSC: 53 2 previous lines: DOC: 7 (12.7%), BSC: 15 (15%) 19 (19.0%). (53.0%) 3 previous lines: DOC: 4 (7.3%), BSC: 9 (9%). Stage IV: 40 ECOG 2: DOC: 14 (25.5%), BSC: 25 (72.7%), 81 (25.0%) (81.0%) CONFIDENTIAL: Evidence synthesis to support erlotinib in NSCLC 15
16 BR21 ELT: 62 (range: 34-87), ELT: 35.5%, PLAC: 34.2%. IIIB/IV ECOG O: ELT: 13.1%, PLAC: 14% ECOG 1: ELT: 52.5%, PLAC: 54.3% ECOG 2: ELT: 25.8%, PLAC: 23% 1 previous line CT: ELT: 50.6%, PLAC: 50.2%. 2+ previous lines: ELT: 49.4%, PLAC: 49.8%. Platinum-based: ELT: 92%, PLAC: 91.8%. PLAC: 59 (range: 32-89). ECOG 3: ELT: 8.6%. PLAC: 8.6% ISEL GFT: 62 [range: 28-90], PLAC: 61 [range: 21-87]. GFT: 368 (33%), PLAC: 185 (33%). Locally advanced or metastatic NSCLC. ECOG 0: GFT 140 (12%), PLAC: 70 (12%) ECOG 1: GFT: 598 (53%), PLAC: 318 (56%) ECOG 2: GFT: 332 (29%), PLAC: 145 (26%) ECOG 3: GFT: 55 (5%), PLAC: 29 (5%) 1-2 previous lines CT. 1 previous line: GFT: 549 (49%), PLAC: 274 (49%) 2 previous lines: GFT: 566 (50%), PLAC: 281 (50%) 3 previous lines: GFT: 13 (1%), PLAC: 7 (1%). Platinum-based: GFT: 1085 (96%), PLAC: 538 (96%) Platinum and docetaxel-based: GFT: 304 (27%), PLAC: 158 (28%) BSC = Best supportive care, CT = chemotherapy, ECOG= Eastern Cooperative Oncology Group, ELT = Erlotinib, DOC = Docetaxel, GFT = Gefitinib, PEM = Pemetrexed, PLAC = Placebo CONFIDENTIAL: Evidence synthesis to support erlotinib in NSCLC 16
17 Table 3: Quality Assessment of Included Trials using Jadad scale (Appendix 2) Author & Date Randomisation - reported Randomisation - appropriate Double Blind - reported Double Blind - appropriate SIGN YES NOT STATED NO NOT APPLICABLE INTEREST YES NOT STATED NO NOT APPLICABLE Withdrawals accounted for Jadad score YES 2 NO 1 JMEI YES NOT STATED NO NOT YES 2 APPLICABLE TAX 317 YES NOT STATED NO NOT YES 2 APPLICABLE BR21 YES NOT STATED YES NOT STATED YES 3 ISEL YES NOT STATED YES YES YES 4 Table 4: Survival Data for Included Trials Author & Date Treatment HR 95% LCI 95% UCI p-value SIGN Gefitinib INTEREST Docetaxel Gefitinib JMEI Docetaxel Pemetrexed TAX 317 Docetaxel Docetaxel BR21 BSC Erlotinib < ISEL Placebo Gefitinib Placebo BSC = best supportive care, HR = hazard ratio, LCI = lower confidence interval, UCI = upper confidence interval CONFIDENTIAL: Evidence synthesis to support erlotinib in NSCLC 17
18 Table 5: Hazard ratios from individual studies Log Hazard Study Treatment Comparator Hazard Ratio Mean (95% CI) Ratio Mean (SE) BR21 Erlotinib Placebo 0.70 (0.58,0.85) (0.10) JMEI Pemetrexed Docetaxel 0.99 (0.82,1.2) (0.10) TAX 317 Docetaxel Placebo (p=0.039) (0.25) (p=0.004) (0.35) ISEL Gefitinib Placebo 0.89 (0.79,1.01) (0.06) INTEREST Gefitinib Docetaxel 1.02 (0.91,1.15) (0.06) SIGN Gefitinib Docetaxel 0.97 (0.61,1.52) (0.23) Table 6: Comparable hazard ratios estimates from network meta-analysis Treatment Hazard Ratio Placebo 1 Erlotinib 0.70 (0.58,0.85) Pemetrexed 0.85 (0.66,1.08) Docetaxel 0.85 (0.72,1.00) Gefitinib 0.88 (0.78,0.99) *P-value from Shepherd et al. (2000) taken as Table 7: Comparable hazard ratios estimates from network meta-analysis Treatment Hazard Ratio Placebo 1 Erlotinib 0.70 (0.58,0.85) Pemetrexed 0.82 (0.64,1.05) Docetaxel 0.83 (0.70,0.97) Gefitinib 0.87 (0.77,0.97) *P-value from Shepherd et al. (2000) taken as CONFIDENTIAL: Evidence synthesis to support erlotinib in NSCLC 18
19 Table 8: Comparable hazard ratios excluding the INTEREST trial Treatment Hazard Ratio Placebo 1 Erlotinib 0.70 (0.58,0.85) Pemetrexed 0.69 (0.45,1.00) Docetaxel 0.69 (0.48,0.96) Gefitinib 0.88 (0.78,0.99) *P-value from Shepherd et al. (2000) taken as CONFIDENTIAL: Evidence synthesis to support erlotinib in NSCLC 19
20 FIGURES Figure 1: Existing evidence network for second-line NSCLC Erlotinib Pemetrexed Shepherd et al 2005 Placebo Hanna et al, 2004 ISEL Shepherd et al, 2000 Gefitinib Interest, SIGN Docetaxel CONFIDENTIAL: Evidence synthesis to support erlotinib in NSCLC 20
21 Figure 2: Results of the network meta-analysis Gefetinib Docetaxel Pemetrexed Erlotinib Placebo Hazard Ratio CONFIDENTIAL: Evidence synthesis to support erlotinib in NSCLC 21
22 REFERENCES Cooper NJ, Sutton AJ, Guobing L, Khunti K. Mixed comparison of stroke prevention treatments in individuals with nonrheumatic atrial fibrillation. Archives of Internal Medicine 2006; 166: Cufer T, Vrdoljak E, Gaafar R, et al. Phase II, open-label, randomized study (SIGN) of single-agent gefitinib (IRESSA) or docetaxel as second-line therapy in patients with advanced (stage IIIb or IV) non-small-cell lung cancer. Anticancer Drugs. 2006; 17(4): Douillard JY, Kim ES, Hirsh V, et al. Gefitinib (IRESSA) versus docetaxel in patients with locally advanced or metastatic non-small cell lung cancer pre-treated with platinum-based chemotherapy: a randomized, open-label Phase III study (INTEREST). Presented at the World Conference of Lung Cancer Griffin S, Bojke L, Main C, Palmer S. Incorporating direct and indirect evidence using Bayesian methods: an applied case study in ovarian cancer. Value in Health 2006; 9: Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004; 22(9): Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17(1):1-12. Karrison TG, Maitland ML, Stadler WM, Ratain MJ. Design of phase II cancer trials using a continuous endpoint of change in tumor size: application to a study of sorafenib and erlotinib in non small-cell lung cancer. Journal of the National Cancer Institute 2007; 99(19): Lu G, Ades AE. Combination of direct and indirect evidence in mixed treatment comparisons. Statistics in Medicine 2004; 23(20): Moher D, Cook DJ, Jadad AR, et al. Assessing the quality of reports of randomised trials: implications for the conduct of meta-analyses. Health Technology Assessment 3(12) National Collaborating Centre for Acute Care. Diagnosis and treatment of lung cancer. London: National Collaborating Centre for Acute Care; 2005 Feb. Niho S, Ichinose Y, Tamura T, et al. Results of a randomized Phase III study to compare the overall survival of gefitinib (IRESSA) versus docetaxel in Japanese patients with non-small-cell lung cancer who failed one or two chemotherapy regimens. Presented at 2007 ASCO Annual Meeting Nixon RM, Bansback N, Brennan A. Using mixed treatment comparisons and metaregression to perform indirect comparisons to estimate the efficacy of biologic CONFIDENTIAL: Evidence synthesis to support erlotinib in NSCLC 22
23 treatments in rheumatoid arthritis. Statistics in Medicine 2007; 26: Scagliotti G. An evaluation of pemetrexed in second-line treatment of non-small cell lung cancer. Expert Opinion on Pharmacotherapy 2005; 6(16): Shepherd FA. Discussion. Presented at the 12 th World Conference on Lung Cancer Shepherd FA, Rodrigues Pereira J, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005; 353(2): Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000; 18(10): Song F, Altman DG, Glenny A-M, Deeks, JJ. Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analysis. BMJ 2003; 326: Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 2005; 366(9496): CONFIDENTIAL: Evidence synthesis to support erlotinib in NSCLC 23
24 APPENDICES Appendix 1: Search strategy Details of electronic databases searched, the full search syntax used in each and the resulting numbers of hits are provided below. EMBASE Search conducted 24th October 2007 in EMBASE (1988 to 2007 Week 42). # Search History Results 1 Lung non Small Cell Cancer/ nonsmall cell lung cancer$.ti,ab nonsmall cell pulmonary cancer$.ti,ab. 0 4 nonsmall cell lung carcinoma$.ti,ab nonsmall cell pulmonary carcinoma$.ti,ab. 0 6 nonsmall cell lung tum?r$.ti,ab. 2 7 nonsmall cell pulmonary tum?r$.ti,ab. 0 8 nonsmall cell lung neoplasm$.ti,ab. 0 9 nonsmall cell pulmonary neoplasm$.ti,ab non small cell lung cancer$.ti,ab non small cell pulmonary cancer$.ti,ab non small cell lung carcinoma$.ti,ab non small cell pulmonary carcinoma$.ti,ab non small cell lung tum?r$.ti,ab non small cell pulmonary tum?r$.ti,ab non small cell lung neoplasm$.ti,ab non small cell pulmonary neoplasm$.ti,ab nsclc.ti,ab nscpc.ti,ab ((large cell adj2 carcinoma) and (lung or pulmonary)).af or/ (Clinical trial/ or randomized controlled trial/ or randomization/ or single blind procedure/ or double blind procedure/ or crossover procedure/ or placebo/ or (randomi?ed controlled trial$ or rct or random allocation or randomly allocated or allocated randomly or (allocated adj2 random) or single blind or double blind or ((treble or triple) adj blind$) or placebo$).tw. or prospective study/) not (case study/ or case report.tw. or abstract report/ CONFIDENTIAL: Evidence synthesis to support erlotinib in NSCLC 24
25 or letter/) 23 (alimta or pemetrexed).mp (iressa or gefitinib).mp (tarceva or erlotinib).mp (taxotere or docetaxel).mp or/ and 22 and limit 28 to (humans and english language and yr=" ") limit 29 to "review" not This retrieved 1439 records. MEDLINE Search conducted 24th October 2007 in MEDLINE (1950 to October Week ). # Search History Results 1 Carcinoma, Non-Small-Cell Lung/ nonsmall cell lung cancer$.ti,ab nonsmall cell pulmonary cancer$.ti,ab. 1 4 nonsmall cell lung carcinoma$.ti,ab nonsmall cell pulmonary carcinoma$.ti,ab. 0 6 nonsmall cell lung tum?r$.ti,ab. 3 7 nonsmall cell pulmonary tum?r$.ti,ab. 0 8 nonsmall cell lung neoplasm$.ti,ab. 0 9 nonsmall cell pulmonary neoplasm$.ti,ab non small cell lung cancer$.ti,ab non small cell pulmonary cancer$.ti,ab non small cell lung carcinoma$.ti,ab non small cell pulmonary carcinoma$.ti,ab non small cell lung tum?r$.ti,ab non small cell pulmonary tum?r$.ti,ab non small cell lung neoplasm$.ti,ab non small cell pulmonary neoplasm$.ti,ab. 0 CONFIDENTIAL: Evidence synthesis to support erlotinib in NSCLC 25
26 18 nsclc.ti,ab nscpc.ti,ab ((large cell adj2 carcinoma) and (lung or pulmonary)).af or/ (randomized controlled trials/ or randomized controlled trial.pt. or random allocation/ or double blind method/ or single-blind method/ or clinical trial.pt. or exp clinical trials/ or (clinic$ adj trial$1).tw. or ((singl$ or doubl$ or treb$ or trip$) adj (blind$3 or mask$3)).tw. or placebos/ or placebo$.tw. or randomly allocated.tw. or (allocated adj2 random).tw.) not (case report.tw. or (letter or historical article or review of reported cases or review, multicase).pt.) (alimta or pemetrexed).mp (iressa or gefitinib).mp (tarceva or erlotinib).mp (taxotere or docetaxel).mp or/ and 22 and limit 28 to (humans and english language and yr=" ") limit 29 to "review" not This retrieved 502 records. MEDLINE in process Search conducted 24th October 2007 in MEDLINE (1950 to October Week ). # Search History Results 1 Carcinoma, Non-Small-Cell Lung/ 0 2 nonsmall cell lung cancer$.ti,ab nonsmall cell pulmonary cancer$.ti,ab. 0 4 nonsmall cell lung carcinoma$.ti,ab. 4 5 nonsmall cell pulmonary carcinoma$.ti,ab. 0 6 nonsmall cell lung tum?r$.ti,ab. 0 7 nonsmall cell pulmonary tum?r$.ti,ab. 0 8 nonsmall cell lung neoplasm$.ti,ab. 0 9 nonsmall cell pulmonary neoplasm$.ti,ab non small cell lung cancer$.ti,ab. 659 CONFIDENTIAL: Evidence synthesis to support erlotinib in NSCLC 26
27 11 non small cell pulmonary cancer$.ti,ab non small cell lung carcinoma$.ti,ab non small cell pulmonary carcinoma$.ti,ab non small cell lung tum?r$.ti,ab non small cell pulmonary tum?r$.ti,ab non small cell lung neoplasm$.ti,ab non small cell pulmonary neoplasm$.ti,ab nsclc.ti,ab nscpc.ti,ab ((large cell adj2 carcinoma) and (lung or pulmonary)).af or/ (randomized controlled trials/ or randomized controlled trial.pt. or random allocation/ or double blind method/ or single-blind method/ or clinical trial.pt. or exp clinical trials/ or (clinic$ adj trial$1).tw. or ((singl$ or doubl$ or treb$ or trip$) adj (blind$3 or mask$3)).tw. or placebos/ or placebo$.tw. or randomly allocated.tw. or (allocated adj2 random).tw.) not (case report.tw. or (letter or historical article or review of reported cases or review, multicase).pt.) (alimta or pemetrexed).mp (iressa or gefitinib).mp (tarceva or erlotinib).mp (taxotere or docetaxel).mp or/ and 22 and This retrieved 22 records. CONFIDENTIAL: Evidence synthesis to support erlotinib in NSCLC 27
28 Appendix 2: Jadad score The following description of the Jadad scale and scoring algorithm is adapted from Moher et al (1999). Jadad s scale Randomisation Trials that report using the following methods are to receive a point: reporting that the trial was randomised. Trials that describe an appropriate method of randomisation (e.g. table of random numbers, computer generated) receive an additional point. However, if the report described the trial as randomised and the randomisation method was inappropriate (e.g. date of birth, hospital numbers) a point is deducted. Double-blinding Trials that report using the following methods are to receive a point: reporting that a trial was double-blind. Trials that describe an appropriate method of double-blinding (e.g. identical placebo, active placebo) receive an additional point. However, if the report described the trial as double-blind and the blinding method was inappropriate CONFIDENTIAL: Evidence synthesis to support erlotinib in NSCLC 28
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