Erlotinib and gefitinib for treating non-small cell lung cancer that has progressed following prior chemotherapy (review of NICE technology appraisals 162 and 175): a systematic review and economic evaluation.

BACKGROUND: Lung cancer is the second most diagnosed cancer in the UK. Over 70% of lung cancers are non-small cell lung cancers (NSCLCs). Patients with stage III or IV NSCLC may be offered treatment to improve survival, disease control and quality of life. One-third of these patients receive further treatment following disease progression; these treatments are the focus of this systematic review. OBJECTIVES: To appraise the clinical effectiveness and cost-effectiveness of erlotinib [Tarceva(®), Roche (UK) Ltd] and gefitinib (IRESSA(®), AstraZeneca) compared with each other, docetaxel or best supportive care (BSC) for the treatment of NSCLC after disease progression following prior chemotherapy. The effectiveness of treatment with gefitinib was considered only for patients with epidermal growth factor mutation-positive (EGFR M+) disease. DATA SOURCES: Four electronic databases (EMBASE, MEDLINE, The Cochrane Library, PubMed) were searched for randomised controlled trials (RCTs) and economic evaluations. Manufacturers' evidence submissions to the National Institute for Health and Care Excellence were also considered. REVIEW METHODS: Outcomes for three distinct patient groups based on EGFR mutation status [EGFR M+, epidermal growth factor mutation negative (EGFR M-) and epidermal growth factor mutation status unknown (EGFR unknown)] were considered. Heterogeneity of the data precluded statistical analysis. A de novo economic model was developed to compare treatments (incremental cost per quality-adjusted life-year gained). RESULTS: Twelve trials were included in the review. The use of gefitinib was compared with chemotherapy (n = 6) or BSC (n = 1), and the use of erlotinib was compared with chemotherapy (n = 3) or BSC (n = 1). One trial compared the use of gefitinib with the use of erlotinib. No trials included solely EGFR M+ patients; all data were derived from retrospective subgroup analyses from six RCTs [Kim ST, Uhm JE, Lee J, Sun JM, Sohn I, Kim SW, et al. Randomized phase II study of gefitinib versus erlotinib in patients with advanced non-small cell lung cancer who failed previous chemotherapy. Lung Cancer 2012;75:82-8, V-15-32, Tarceva In Treatment of Advanced NSCLC (TITAN), BR.21, IRESSA Survival Evaluation in Lung cancer (ISEL) and IRESSA NSCLC Trial Evaluating REsponse and Survival versus Taxotere (INTEREST)]. These limited data precluded conclusions regarding the clinical effectiveness of any treatment for EGFR M+ patients. For EGFR M- patients, data were derived from the TArceva Italian Lung Optimization tRial (TAILOR) trial and Docetaxel and Erlotinib Lung Cancer Trial (DELTA). Retrospective data were also derived from subgroup analyses of BR.21, Kim et al., TITAN, INTEREST and ISEL. The only statistically significant reported results were for progression-free survival (PFS) for TAILOR and DELTA, and favoured docetaxel over erlotinib [TAILOR hazard ratio (HR) 1.39, 95% confidence interval (CI) 1.06 to 1.82; DELTA HR 1.44, 95% CI 1.08 to 1.92]. In EGFR unknown patients, nine trials (INTEREST, IRESSA as Second-line Therapy in Advanced NSCLC - KoreA, Li, Second-line Indication of Gefitinib in NSCLC, V-15-32, ISEL, DELTA, TITAN and BR.21) reported overall survival data and only one (BR.21) reported a statistically significant result favouring the use of erlotinib over BSC (HR 0.7, 95% CI 0.58 to 0.85). For PFS, BR.21 favoured the use of erlotinib when compared with BSC (HR 0.61, 95% CI 0.51 to 0.74) and the use of gefitinib was favoured when compared with BSC (HR 0.82, 95% CI 0.73 to 0.92) in ISEL. Limitations in the clinical data precluded assessment of cost-effectiveness of treatments for an EGFR M+ population by the Assessment Group (AG). The AG's economic model suggested that for the EGFR M- population, the use of erlotinib was not cost-effective compared with the use of docetaxel and compared with BSC. For EGFR unknown patients, the use of erlotinib was not cost-effective when compared with BSC. CONCLUSIONS/FUTURE WORK: The lack of clinical data available for distinct patient populations limited the conclusions of the assessment. Future trials should distinguish between patients with EGFR M+ and EGFR M- disease. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Cetuximab for recurrent and/or metastatic squamous cell carcinoma of the head and neck: a NICE single technology appraisal.

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of cetuximab (Merck Serono) to submit evidence for the clinical and cost effectiveness of cetuximab in combination with platinum-based chemotherapy (CTX) for the treatment of patients with recurrent and/or metastatic squamous cell cancer of the head and neck (SCCHN) according to the Institute's Single Technology Appraisal (STA) process. The Liverpool Reviews and Implementation Group at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG). This article summarizes the ERG's review of the evidence submitted by the manufacturer. A summary of the Appraisal Committee (AC) decision is provided. The ERG reviewed the clinical evidence in accordance with the decision problem defined by NICE. The analysis of the submitted model assessed the appropriateness of the manufacturer's approach to modelling the decision problem, the reliability of model implementation and the extent of conformity to published standards and prevailing norms of practice within the health economics modelling community. Particular attention was paid to issues likely to impact substantially on the base-case cost-effectiveness results. Clinical-effectiveness evidence was derived from a single randomized controlled trial (RCT). Results presented for clinical outcomes were strongly supportive of benefits resulting from the use of cetuximab. Cetuximab + platinum-based CTX with 5 fluorouracil (5-FU) extended median overall survival (OS) from 7.4 months in the CTX group to 10.1 months in the cetuximab + CTX group. Median progression-free survival rose from 3.3 months to 5.6 months, best overall response to therapy increased from 19.5% to 35.6%, disease control rate rose from 60% to 81.1% and median time to treatment failure was 4.8 months compared with 3.0 months. Exploratory subgroup analyses indicated significant OS benefits in 11 of 16 pre-planned analyses. The ERG identified a number of issues relating to the clinical-effectiveness results: consideration was limited to first-line use of cetuximab; patients in the trial were younger and fitter than those presenting in UK clinical practice; there was no evidence of survival advantage for patients with metastatic disease; there was no evidence of effectiveness in patients not cetuximab-naive; and the quality-of-life data were poor. The submitted incremental cost-effectiveness ratio was considerably above the NICE threshold. The ERG questioned the submitted economic model on a number of grounds: the rationale for creating an economic model rather than direct analysis of trial data; the use of Weibull functions for survival models; inaccurate CTX costs; selection of health state utilities; inaccurate unit costs; and lack of mid-cycle correction. After amending the model, the ERG considered the use of cetuximab to be not cost effective for NICE at any price. The AC concluded that cetuximab in combination with platinum-based CTX should not be recommended for the treatment of patients with recurrent and/or metastatic SCCHN. Patients already receiving this treatment for this indication should have the option to continue treatment until they and their clinician consider it appropriate to stop. This was the first appraisal to consider the end-of-life medicines criteria introduced by NICE in January 2009.