Tyrosine Kinase Inhibitors for the Treatment of EGFR Mutation-Positive Non–Small-Cell Lung Cancer: A Clash of the Generations

Abstract

The availability of 3 generations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with different pharmacologic characteristics and clinical profiles has provided oncologists with a potentially confusing choice for the treatment of EGFR mutation-positive nonesmall-cell lung cancer. Although recent head-to-head clinical trials have demonstrated improved efficacy with second-generation (ie, afatinib, dacomitinib) and third-generation (ie, osimertinib) TKIs compared with the first-generation TKIs (eg, erlotinib, gefitinib), acquired resistance has been inevitable, regardless of which agent has been chosen as first-line therapy. Thus, the potential availability of subsequent treatment options is an important consideration. Recent data have demonstrated that osimertinib confers an overall survival benefit compared with first-generation EGFR TKIs, and dacomitinib has shown an overall survival benefit compared with gefitinib in an exploratory analysis. However, the relative benefits of different sequential EGFR-TKI regimens, especially those involving second-and third-generation agents, have remained uncertain and require prospective evaluation. Few such data currently exist to inform treatment choices. In the present review, we examined the pharmacologic characteristics and current clinical data for EGFR TKIs, including emerging information on the molecular mechanisms of resistance across the different generations of TKIs. Given the uncertainties regarding the optimal treatment choice, we have focused on the factors that might help determine the treatment decisions, such as efficacy and safety in patient subgroups. We also discussed the emerging real-world data, which have provided some insights into the benefits of sequential regimens in everyday clinical practice.

c-Src and EGFR Inhibition in Molecular Cancer Therapy: What Else Can We Improve?

“…The development and the use of three generations of EGFR inhibitors in the clinical setting significantly improved the prognosis of NSCLC cancer patients, in particular in ~10% to 15% of cases of white patients and even 50% of cases of Asian NSCLC patient, harboring activating EGFR mutations [ 104 ]. Unfortunately, the presence of innate or the onset of acquired resistance to EGFR inhibitors remains the most common cause for cancer relapse and mortality, highlighting the importance to investigate the complex network of cancer resistance mechanisms.…”

Real-world clinical outcomes of first-generation and second-generation epidermal growth factor receptor tyrosine kinase inhibitors in a large cohort of European non-small-cell lung cancer patients

“… 23 24 However, the benefits of different sequential EGFR TKI regimens, especially those involving second-generation and third-generation agents, have remained uncertain. 25 The impact of subsequent or first-line treatment with osimertinib was not analysed in this study, because osimertinib was not routinely available at the study cut-off date. Osimertinib has become routinely available in Poland only for second line treatment starting from November 2017.…”

Xanthohumol targets the ERK1/2‑Fra1 signaling axis to reduce cyclin D1 expression and inhibit non‑small cell lung cancer

“…Targeting therapies towards such driving mutations have emerged as first-line therapeutic strategies for advanced NSCLC. However, most patients who initially respond to targeted therapies eventually develop acquired resistance ( 5 , 6 ). Further elucidation of the underlying mechanisms of resistance and identification of novel anti-tumor agents for NSCLC treatment is necessary.…”