Cancer Res Treat.  2013 Jun;45(2):79-85.

Treatment of Non-small Cell Lung Carcinoma after Failure of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor

• Lee JC
• Jang SH
• Lee KY
• Kim YC

Abstract

Since the first description of non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutation as a distinct clinical entity, studies have proved EGFR tyrosine kinase inhibitors (TKIs) as a first choice of treatment. The median response duration of TKIs as a first-line treatment for EGFR mutant tumors ranges from 11 to 14 months. However, acquired resistance to EGFR-TKIs is inevitable due to various mechanisms, such as T790M, c-Met amplification, activation of alternative pathways (IGF-1, HGF, PI3CA, AXL), transformation to mesenchymal cell or small cell features, and tumor heterogeneity. Until development of a successful treatment strategy to overcome such acquired resistance, few options are currently available. Here we provide a summary of the therapeutic options after failure of first line EGFR-TKI treatment for NSCLC.

Keyword

EGFR tyrosine kinase inhibitor; Non-small-cell lung carcinoma; Drug resistance; Neoplasms

MeSH Terms

Carcinoma, Non-Small-Cell Lung
Drug Resistance
Epidermal Growth Factor
Lung
Population Characteristics
Protein-Tyrosine Kinases
Receptor, Epidermal Growth Factor
Epidermal Growth Factor
Protein-Tyrosine Kinases
Receptor, Epidermal Growth Factor

Figure

• 

  Fig. 1 Schematic tumor volume-time curve according to on-and-off of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Tumor volume is the sum of EGFR-TKI sensitive clones and resistant clones regardless of their molecular mechanisms. The number of EGFR-TKI sensitive clones shows a rapid decrease after initiation of EGFR-TKI, however, that of EGFR-TKI resistant clones shows a steady increase despite EGFR-TKI treatment. Initially, tumor volume reaches partial response (PR) due to decrease of EGFR-TKI sensitive clones, but eventually shows progressive disease (PD) with the increase of EGFR-TKI resistant clones. If EGFR-TKI is discontinued at disease progression, explosive growth of EGFR-TKI sensitive clones can cause disease flare. If EGFR-TKI is reintroduced, EGFR-TKI sensitive clones show a decrease again, and tumor volume can be stabilized (decreasing stable disease [SD] or PR). However, because of increasing EGFR-TKI resistant clones, the duration of tumor volume stabilization would be shorter than that of initial treatment with EGFR-TKI.

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