Rational approach to the treatment of EGFR-positive lung cancer

Molecularly targeted therapy with tyrosine kinase inhibitors (TKI) has been recognized as the optimal treatment option for patients with EGFR-positive non-small-cell lung cancer (NSCLC). At present, 5 drugs of this group are available: first generation – erlotinib and gefitinib, second generation – afatinib and dacomitinib (not registered in Russia), and third generation – osimertinib. The drugs have some peculiarities, this refers to their antitumor activity, safety profile, and resistance mechanisms. Knowledge of these differences is necessary to determine a rational treatment plan. Gefitinib and erlotinib increase the time before progression compared to standard chemotherapy, but do not affect the overall survival rate. Afatinib significantly increases the time before progression, and in the cohort of patients with deletion in the 19th exon – the overall survival rate. Dacomitinib was more effective than gefitinib in terms of time before progression and total survival. On average, the disease progresses after a year and a half of successful treatment. The dominant mechanism of resistance development to TKI of the first and second generation consists in accumulation of mutation of the gatekeeper gene T790M. Most often it is determined in patients with deletion in the 19th exon (Del19). Osimertinib has proved to be effective against tumors not only with activating mutations, but also with T790M resistance mutation, and with minimal activity to EGFR «wild» type receptors. The first indication that it was registered was progression on targeted therapy with first and second generation drugs caused by the secondary mutation of T790M. Later, the advantage of osimertinib compared to gefitinib/erlotinib in untreated EGFR-positive patients was proved. Thus, there are at least two main options for treatment tactics: the consistent use of second and third generation drugs or prescription of osimertinib in the first line with subsequent chemotherapy. Evaluation and consideration of known prognostic factors will allow choosing the optimal tactics for a particular patient.

non-small-cell lung cancer, acquired resistance, EGFR mutations, EGFR tyrosine kinase inhibitors, T790M, Del19, L858R

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