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Second generation tyrosine kinase inhibitors for the treatment of metastatic non-small-cell lung cancer.

Stasi I, Cappuzzo F - Transl Respir Med (2014)

Bottom Line: However, after an initial response, all patients inevitably progress and several mechanisms including a secondary mutation in exon 20 of the EGFR gene (T790M) or MET or HER2 amplifications are responsible for acquired resistance (AR).In clinical practice few options are available for patients with AR, and several new agents or strategies are currently under investigation, including second generation TKIs.Aim of the present review is to present available data on new EGFR-TKIs and to discuss how these agents could overcome AR to erlotinib or gefitinib.

View Article: PubMed Central - PubMed

Affiliation: Medical Oncology Department, IstitutoToscanoTumori, OspedaleCivile, Livorno, Italy.

ABSTRACT

Backgruond: Since their first description, activating epidermal growth factor receptor (EGFR) mutations identify a distinct clinical entity of patients with non-small-cell lung cancer (NSCLC).

Findings: New targeted therapies for molecularly selected NSCLC are changing the natural history of the disease, with results superior to standard chemotherapy as demonstrated in large phase III studies with first generation EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. However, after an initial response, all patients inevitably progress and several mechanisms including a secondary mutation in exon 20 of the EGFR gene (T790M) or MET or HER2 amplifications are responsible for acquired resistance (AR). In clinical practice few options are available for patients with AR, and several new agents or strategies are currently under investigation, including second generation TKIs.

Conclusions: Aim of the present review is to present available data on new EGFR-TKIs and to discuss how these agents could overcome AR to erlotinib or gefitinib.

No MeSH data available.


Related in: MedlinePlus

Mechanisms responsible for acquired resistance (adapted fromhttp://cancerdiscovery.aacrjournals.org).
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Fig1: Mechanisms responsible for acquired resistance (adapted fromhttp://cancerdiscovery.aacrjournals.org).

Mentions: Unfortunately, after a median of 8–10 months, all responding patients develop acquired resistance (AR) to EGFR-TKI therapy, with the inevitable consequence of disease progression. Recent studies demonstrated that several mechanisms are responsible for AR (Figure 1), with approximately 30% of patients in which resistance factors are not yet identified [10]. The firstly described and the most common event responsible for resistance is the acquisition of the T790M missense mutation, which is found in ≈ 50% of patients progressing after an initial response to erlotinib or gefitinib [11, 12]. Other less frequent mechanisms include secondary mutations within EGFR[13, 14], MET amplification [15], HER2 amplification [16, 17], small cell histologic transformation [18]. Identification of mechanisms responsible for AR has therapeutic implications, and several agents are currently under investigation particularly for individuals with the secondary T790M mutation.Figure 1


Second generation tyrosine kinase inhibitors for the treatment of metastatic non-small-cell lung cancer.

Stasi I, Cappuzzo F - Transl Respir Med (2014)

Mechanisms responsible for acquired resistance (adapted fromhttp://cancerdiscovery.aacrjournals.org).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4215821&req=5

Fig1: Mechanisms responsible for acquired resistance (adapted fromhttp://cancerdiscovery.aacrjournals.org).
Mentions: Unfortunately, after a median of 8–10 months, all responding patients develop acquired resistance (AR) to EGFR-TKI therapy, with the inevitable consequence of disease progression. Recent studies demonstrated that several mechanisms are responsible for AR (Figure 1), with approximately 30% of patients in which resistance factors are not yet identified [10]. The firstly described and the most common event responsible for resistance is the acquisition of the T790M missense mutation, which is found in ≈ 50% of patients progressing after an initial response to erlotinib or gefitinib [11, 12]. Other less frequent mechanisms include secondary mutations within EGFR[13, 14], MET amplification [15], HER2 amplification [16, 17], small cell histologic transformation [18]. Identification of mechanisms responsible for AR has therapeutic implications, and several agents are currently under investigation particularly for individuals with the secondary T790M mutation.Figure 1

Bottom Line: However, after an initial response, all patients inevitably progress and several mechanisms including a secondary mutation in exon 20 of the EGFR gene (T790M) or MET or HER2 amplifications are responsible for acquired resistance (AR).In clinical practice few options are available for patients with AR, and several new agents or strategies are currently under investigation, including second generation TKIs.Aim of the present review is to present available data on new EGFR-TKIs and to discuss how these agents could overcome AR to erlotinib or gefitinib.

View Article: PubMed Central - PubMed

Affiliation: Medical Oncology Department, IstitutoToscanoTumori, OspedaleCivile, Livorno, Italy.

ABSTRACT

Backgruond: Since their first description, activating epidermal growth factor receptor (EGFR) mutations identify a distinct clinical entity of patients with non-small-cell lung cancer (NSCLC).

Findings: New targeted therapies for molecularly selected NSCLC are changing the natural history of the disease, with results superior to standard chemotherapy as demonstrated in large phase III studies with first generation EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. However, after an initial response, all patients inevitably progress and several mechanisms including a secondary mutation in exon 20 of the EGFR gene (T790M) or MET or HER2 amplifications are responsible for acquired resistance (AR). In clinical practice few options are available for patients with AR, and several new agents or strategies are currently under investigation, including second generation TKIs.

Conclusions: Aim of the present review is to present available data on new EGFR-TKIs and to discuss how these agents could overcome AR to erlotinib or gefitinib.

No MeSH data available.


Related in: MedlinePlus