1. Epidermal growth factor receptor-mutated lung carcinomas with insufficient response to epidermal growth factor receptor inhibitors.
- Author
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Moiseenko, Fedor, Kuligina, Ekaterina, Elsakova, Ekaterina, and Imyanitov, Evgeny
- Abstract
Administration of single-agent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is a standard treatment option for metastatic non–small cell lung carcinomas with EGFR exon 19 deletions (ex19del) and L858R substitutions. However, there is a significant interpatient heterogeneity with regard to the degree of the response and its duration. Patients with EGFR ex19del mutation, TP53 wild-type, good performance status, low tumor burden and no circulating tumor DNA (ctDNA) at baseline have the best chances to derive pronounced benefit from TKI therapy. In contrast, subjects with EGFR L858R substitution, mutated TP53, poor overall condition, high tumor volume and detectable ctDNA are generally poor responders to EGFR inhibitors. ctDNA dynamics in the first days or weeks of treatment allows reliable identification of patients, who are very unlikely to derive clinically meaningful benefit from single-agent TKIs. These patients are candidates for clinical trials, which may involve the addition of chemotherapy and antiangiogenic drugs to patients, who failed to achieve immediate benefit from TKI monotherapy. Article highlights Virtually all patients with epidermal growth factor receptor (EGFR) mutations demonstrate some benefit immediately after initiation of EGFR tyrosine kinase inhibitors (TKI) therapy; therefore, EGFR testing is the first and a critical step in treatment planning. However, there is significant interpatient heterogeneity in the degree of the response and its duration. Patients with the EGFR ex19del mutation are more likely to derive a marked benefit from TKI therapy. In contrast, those with the EGFR L858R substitution are generally poor responders. Poor performance status, high number of metastatic sites and the presence of extrathoracic tumor spread are also well-established negative prognostic factors. TP53 is strong negative predictor for response to EGFR TKIs. Genetic alterations in some other genes may affect the efficacy of EGFR TKIs, although none of the proposed predictors has the level of evidence comparable with that of TP53. The predictive value of the baseline ctDNA level may be attributed to its ability to identify particularly aggressive tumors. Measurement of ctDNA may outperform imaging tools for assessment of the tumor volume and spread of NSCLC. Clinical trials comparing the efficacy of combined administration of EGFR TKI and cytotoxic therapy with TKI alone demonstrated significant prolongation of progression-free survival. This outcome is expected, given that both TKIs and chemotherapy are efficacious against EGFR-mutated NSCLC. Synergy between antiangiogenic drugs and EGFR TKIs has been observed. Bevacizumab and ramucirumab seem particularly promising. Combining bevacizumab with TKIs and chemotherapy seems feasible and warrants further study. Patients with poor early response to single-agent EGFR TKIs, as assessed by ctDNA dynamics, are candidates for clinical trials combining EGFR TKIs with other drugs. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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