First-Generation EGFR Tyrosine Kinase Inhibitors Associated With Poorer Progression-Free Survival vs Conventional Chemotherapy in EGFR Wild-Type NSCLC
Activating EGFR mutations are found in approximately 10% of Western patients and 50% of Asian patients with non–small cell lung cancer (NSCLC), and EGFR tyrosine kinase inhibitors are recommended for use in first-line treatment in this setting. Both tyrosine kinase inhibitors and cytotoxic chemotherapy are used in previously treated patients with wild-type EGFR, although it is unclear whether tyrosine kinase inhibitors provide any advantage over chemotherapy.
In a meta-analysis reported in JAMA, Lee et al found that use of first-generation tyrosine kinase inhibitors in patients with advanced wild-type EGFR NSCLC was associated with poorer progression-free survival compared with chemotherapy, although no difference in overall survival was observed.
Study Details
The meta-analysis incorporated 11 trials comparing first-generation tyrosine kinase inhibitors (erlotinib [Tarceva] or gefitinib [Iressa]) with conventional chemotherapy in advanced NSCLC, including 1,605 patients with wild-type EGFR (811 in the tyrosine kinase inhibitor group, 794 in the chemotherapy group). The primary outcome measure was progression-free survival.
All 11 trials were open-label. Four were performed in first-line settings, four in the second-line setting, and three in second- or later-line settings. All trials used tyrosine kinase inhibitors in their standard dosing and schedule. All trials except one used commonly recommended chemotherapy drugs as the control group (ie, doublet chemotherapy including cisplatin or carboplatin in first-line treatment, docetaxel or pemetrexed [Alimta] in second- or later-line treatment).
Seven trials used only direct sequencing for detecting EGFR mutations, with four using other platforms to increase sensitivity of the analysis. Six trials included mostly Asian patients, and five included mostly white patients.
Progression-Free and Overall Survival
Among patients with wild-type EGFR, tyrosine kinase inhibitor treatment was associated with significantly increased risk of progression or death vs chemotherapy (hazard ratio [HR] = 1.41, 95% confidence interval [CI] =1.10–1.81). Objective response rate was significantly higher with chemotherapy (16.8% vs 7.2%, relative risk of nonresponse for tyrosine kinase inhibitor = 1.11, 95% CI = 1.02–1.21). There was no difference in overall survival between the tyrosine kinase inhibitor and chemotherapy groups (HR = 1.08, 95% CI = 0.96–1.22).
Subgroup Analyses of Progression-Free Survival
Subgroup analyses of progression-free survival showed a nonsignificant advantage with chemotherapy vs tyrosine kinase inhibitor treatment in first-line treatment (HR = 1.53, 95% CI = 0.87–2.69) and a significant advantage in second- or later-line treatment (HR = 1.34, 95% CI = 1.09–1.65; P = .58 for subgroup difference), nonsignificant advantages when erlotinib (HR = 1.33, 95% CI = 0.97-1.81) or gefitinib (HR = 1.49, 95% CI = 0.96–2.33; P = .67 for difference) was the comparator tyrosine kinase inhibitor, a nonsignificant advantage in Asian-dominant study population (HR = 1.30, 95% CI = 0.82–2.06), and a significant advantage in white-dominant populations (HR = 1.47, 95% CI = 1.15–1.87; P = .78 for difference).
There was a nonsignificant advantage when EGFR mutation analysis was performed by direct sequencing only (HR = 1.12, 95% CI = 0.79–1.58), but a significant advantage when more sensitive methods were used (HR = 1.84, 95% CI = 1.35–2.52; P = .11 for difference).
The investigators concluded, “Among patients with advanced NSCLC harboring [wild-type] EGFR, conventional chemotherapy, compared with first-generation EGFR [tyrosine kinase inhibitors], was associated with improvement in [progression-free survival] but not overall survival.”
Dong-Wan Kim, MD, PhD, of Seoul National University Hospital, is the corresponding author for the JAMA article.
The study was supported in part by grants from the National Research Foundation of Korea. For full disclosures of the study authors, visit jama.jamanetwork.com.
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