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

Abstract

BackgroundLung 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.ObjectivesTo 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 sourcesFour 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 methodsOutcomes 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).ResultsTwelve 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 Cancer2012;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, Kimet 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 workThe 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.FundingThe National Institute for Health Research Health Technology Assessment programme.

A Cost-Effectiveness Analysis of Nivolumab versus Docetaxel for Advanced Nonsquamous NSCLC Including PD-L1 Testing

“…In a UK study, docetaxel was cost-effective compared to best supportive care 8 and pemetrexed, mainly studied as first-line treatment 9 , was not cost-effective as maintenance in our previous Swiss study 10 . With respect to erlotinib and other epidermal growth factor receptor (EGFR) inhibitors, patient selection by EGFR mutation status is recommended [11][12][13] .…”

Mutation Profiling of Lung Cancers with Long-Term Response to Gefitinib Therapy

“…EGFR TKIs are well established in the treatment of patients with advanced NSCLC and EGFR mutations, but their role in patients with EGFR wild type has recently been questioned [22,23]. In vitro, many cell lines with EGFR wild type were resistant to a TKI [35].…”

“…Further trials confirmed that gefitinib, erlotinib, and afatinib have superior activity compared with chemotherapy in patients with EGFR exon 19 deletion or L858R [18,19,20,21]. In patients with wild type EGFR (or unknown EGFR mutation status), the role of EGFR TKIs is currently debated [22,23]. In Switzerland, erlotinib is the only EGFR TKI approved independently of EGFR mutation status, based on the results of the BR.21 and SATURN trials [24,25].…”

PHD3 Controls Lung Cancer Metastasis and Resistance to EGFR Inhibitors through TGFα

“…6B). Erlotinib has been used for the treatment of lung cancer patients both with wild-type EGFR and with activating EGFR mutations, but it is most effective in the latter group (39). Therefore, we next examined if PHD3 also controls the erlotinib sensitivity of lung cancer cell lines carrying activating EGFR mutations, such as HCC827 (with EGFR E746-A750 deletion) and HCC4006 (with EGFR L747 -E749 deletion and A750P substitution (40)).…”