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Meta-analysis of EGFR kinase inhibitors: not always greater than the sum of its parts.

In contrast with the quote attributed to Aristotle, “The whole is greater than the sum of its parts,” the meta-analysis of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) by Lee et al. (1) in this issue of the Journal adds incrementally to the existing scientific literature. The impact of EGFR TKIs vs chemotherapy as initial therapy for patients with sensitizing EGFR mutations has been consistent, and the important clinical issues have been covered extensively by both the original articles and two recent meta-analyses (2,3). Since the submission of the article, additional published information gives further insight into the use of EGFR TKIs as initial therapy in patients who have not been selected by genotype compared with those given initial chemotherapy (4). Lee and colleagues have otherwise provided additional information about the use of EGFR TKIs in patients treated in the second- or third-line setting and with maintenance therapy. In their meta-analysis, the authors address the impact of EGFR TKIs on progression-free survival (PFS) and overall survival (OS) in advanced non–small cell lung cancer (NSCLC) patients whose tumors do or do not harbor EGFR mutations in multiple clinical settings. They identified 23 randomized clinical trials (comprising 14 570 patients) of varying designs performed in the first-line (n = 13 trials), relapsed (n = 7 trials), and maintenance settings (n = 3 trials), expanding on two recently published meta-analyses, both of which were limited to studying the impact of upfront EGFR TKI therapy in patients bearing EGFR mutations (2,3). EGFR mutation status was determined in 4473 (31%) trial patients, including 1741 (12%) patients with EGFR mutations and 2732 (19%) with wild-type tumors. The results of the meta-analysis once again confirm the consistent superiority of EGFR TKIs in prolonging the PFS of patients with advanced NSCLC bearing EGFR mutations compared with wild-type EGFR, with hazard ratios (HRs) of 0.43 (95% confidence interval [CI] = 0.38 to 0.49), 0.34 (95% CI = 0.20 to 0.60), and 0.15 (95% CI = 0.08 to 0.27) in the upfront, relapsed, and maintenance settings, respectively. In contrast with the PFS results, once again there was no OS benefit from EGFR TKI therapy in the EGFR mutation–positive population in any of the three clinical settings, as has been shown in all of the individual trials, although survival information with 70% to 80% maturity is not yet available from several studies (5–8). One potential explanation for the lack of an OS advantage is the crossover rates of 59% to 98% from chemotherapy to EGFR TKI at disease progression reported in the trials (5–10). Given the magnitude of the PFS benefit and the superiority of EGFR TKIs in terms of tolerability and quality of life (11), current National Comprehensive Cancer Network (12), American Society of Clinical Oncology (13), and European Society for Medical Oncology (14) guidelines agree on the importance of early characterization of EGFR in the treatment algorithm for advanced NSCLC, and all patients with EGFR mutant advanced NSCLC should be offered treatment with an EGFR TKI during the course of their disease, preferably in the first-line setting. The meta-analysis by Lee et al. adds little to the existing, already convincing literature. Several issues with the results in the EGFR wild-type population raised by Lee and his colleagues deserve further consideration. Although the authors found no advantage to administering an EGFR TKI as initial therapy compared with chemotherapy, there was no shortening of the PFS (HR = 1.06, 95% CI = 0.94 to 1.19) or OS (HR = 1.00, 95% CI = 0.88 to 1.14). Four of the eight trials included in the first-line PFS analysis (at least 42% of the EGFR wild-type patients) compared EGFR TKI with chemotherapy vs chemotherapy alone, each showing no significant difference in PFS between the treatment arms in the subgroup of EGFR wild-type patients. Conversely, the Iressa Pan Asia Study (IPASS) convincingly demonstrated significantly shorter PFS with gefitinib compared with carboplatin plus paclitaxel (HR = 2.85, 95% CI = 2.05 to 3.98) in the first-line treatment of patients with EGFR wildtype NSCLC (10). Similarly, the recently published Tarceva or Chemotherapy trial (TORCH, not included in the Lee et al. metaanalysis) showed that a strategy of first-line erlotinib followed at progression by cisplatin plus gemcitabine resulted in shorter OS (HR = 1.24, 95% CI = 1.04 to 1.47) compared with initial chemotherapy followed by erlotinib in patients with advanced NSCLC who were not selected by genotype (4). In a retrospective subgroup analysis of EGFR wild-type patients, PFS was shorter with upfront erlotinib compared with initial chemotherapy (HR = 2.07, 95% CI = 1.58 to 2.71), similar to the findings in the IPASS trial. Thus far, in first-line therapy, platinum-based chemotherapy remains the treatment of choice in EGFR wild-type advanced NSCLC patients. In second- or third-line therapy, the authors report that EGFR TKIs are inferior to chemotherapy as assessed by PFS (HR = 1.23, 95% CI = 1.05 to 1.46), but not OS (HR = 0.93, 95% CI = 0.79 to 1.10) in patients with EGFR wild-type tumors. All five trials included in the PFS analysis compared EGFR TKIs with singleagent chemotherapy; four of the five trials enrolled NSCLC patients who were not selected by genotype. The largest of these four trials, the Iressa NSCLC Trial Evaluating Response and Survival against Taxotere (INTEREST) study, showed gefitinib to be noninferior