Comparison of T790M Acquisition After Treatment With First- and Second-Generation Tyrosine-Kinase Inhibitors: A Systematic Review and Network Meta-Analysis

Abstract

BackgroundLung adenocarcinoma is a common disease with a high mortality rate. Epidermal growth factor receptor (EGFR) mutations are found in adenocarcinomas, and oral EGFR-tyrosine kinase inhibitors (EGFR-TKIs) show good responses. EGFR-TKI therapy eventually results in resistance, with the most common being T790M. T790M is also a biomarker for predicting resistance to first- and second-generation EGFR-TKIs and is sensitive to osimertinib. The prognosis was better for patients with acquired T790M who were treated with osimertinib than for those treated with chemotherapy. Therefore, T790M mutation is important for deciding further treatment and prognosis. Previous studies based on small sample sizes have reported very different T790 mutation rates. We conducted a meta-analysis to evaluate the T790M mutation rate after EGFR-TKI treatment.MethodsWe systematic reviewed the electronic databases to evaluate the T790M mutation rate after treatment with first-generation (gefitinib, erlotinib, and icotinib) and second-generation (afatinib and dacomitinib) EGFR-TKIs. Random-effects network meta-analysis and single-arm meta-analysis were conducted to estimate the T790M mutation rate of the target EGFR-TKIs.ResultsA total of 518 studies were identified, of which 29 were included. Compared with afatinib, a higher odds ratio (OR) of the T790M mutation rate was observed after erlotinib [OR = 1.48; 95% confidence interval (CI):1.09–2.00] and gefitinib (OR = 1.45; 95% CI: 1.11–1.90) treatments. An even OR of the T790M mutation rate was noted after icotinib treatment (OR = 0.91, 95% CI: 0.46–1.79) compared with that after afatinib. The T790M mutation rate was significantly lower with afatinib (33%) than that with gefitinib (49%) and erlotinib treatments (47%) (p < 0.001). The acquired T790M mutation rate in all participants was slightly lower in Asians (43%) than that in Caucasians (47%).ConclusionsErlotinib and gefitinib had a higher OR for the T790M mutation than afatinib. The T790M mutation rate was significantly lower in afatinib than in gefitinib and erlotinib. T790M is of great significance because osimertinib shows a good prognosis in patients with T790M mutation.Systematic Review RegistrationPROSPERO, identifier CRD42021257824.

Sequential treatment in advanced epidermal growth factor receptor-mutated lung adenocarcinoma patients receiving first-line bevacizumab combined with 1st/2nd-generation EGFR-tyrosine kinase inhibitors

“…The results of our study indicated that bevacizumab in addition to 1st/2nd-generation EGFR-TKIs does not alter the mechanism of acquired resistance in advanced primary EGFR-mutated NSCLC. Some previous studies showed that prior afatinib therapy was associated with a lower secondary T790M mutation-positive rate when compared with first-generation EGFR-TKIs, and these results were similar to those in our study ( 23 , 24 ). Some previous studies showed that prior afatinib therapy was not associated with a lower secondary T790M mutation-positive rate and that this rate was even higher than that for first-generation EGFR-TKIs ( 25 , 26 ).…”

Anti-cancer effects of bis-oxidized thiopyran derivatives on non-small cell lung cancer: rational design, synthesis, and activity evaluation

“…However, 80% of patients with EGFR T790M positive mutations were found to get an exon 20 acquired resistance mutation C797S (nucleophilic CYS becomes hypersensitive SER) at the site of drug binding after about 12 months of treatment with Osimertinib, 33 which led to the resistance to Osimertinib. Therefore, it is necessary to develop new and more effective EGFR inhibitors.…”