Targeted therapy in non-small cell lung cancer: An update

Sheila Piva, Milena Vitali, Marina C. Garassino

Research output: Contribution to journalArticlepeer-review

Abstract

Until recently the treatment of non-small cell lung cancer was based on histology, the only criteria that could guide the physician in the choice of the best available chemotherapy. Subsequently, specific mutations such as K-ras were identified, creating different subgroups of non-small cell lung cancer patients. The first mutation to have a real impact on clinical practice was the epithelial growth factor receptor mutation. Some important studies showed that epithelial growth factor receptor-mutated patients had dramatic and long-lasting responses to treatment with tyrosine kinase inhibitors when compared to standard chemotherapy in first-line or advanced non-small cell lung cancer treatment, especially in adenocarcinoma histology. These mutations can be found most frequently in women, Asians, and non-smokers. About 50% of these patients eventually develop resistance to treatment with tyrosine kinase inhibitors, so an irreversible tyrosine kinase inhibitor called afatinib was developed and this has enabled these patients to overcome the resistance and obtain a good response to treatment. Another mechanism of resistance to tyrosine kinase inhibitors is the focal amplification of the MET proto-oncogene, and specific target therapies, which could restore sensitivity to tyrosine kinase inhibitors, are currently under development. A minority of patients also expresses the EML4-ALK fusion gene and this specific subgroup responds very well to treatment with the ALK inhibitor crizotinib. Not many targets have been developed so far for squamous cell carcinoma. The most promising is fibroblast growth factor receptor 1 and specific drugs are currently under investigation. K-ras is one of the most studied biomarkers in non-small cell lung cancer and patients with K-ras mutations tend to have a worse prognosis, but no specific target therapies have been developed yet. HER2 and B-RAF are also promising targets for which specific drugs are currently being investigated. Probably the most innovative trials in radically changing the approach to treatment of non-small cell lung cancer are the BATTLE 1 and 2 trials. They were designed with an adaptive randomization, in which patients were assigned to a treatment arm according to the results of biomarker analyses and treated with the corresponding specific target therapy. The results of the BATTLE 1 trial showed that patients whose treatment was selected according to their tumor biomarker expression had a greater benefit compared to patients who received standard treatment. These new discoveries will surely change the one-for-all approach previously used in the treatment of lung cancer. Patients should methodically undergo screening for driver mutations, which can guide us in the choice of the treatment. A rational approach to testing lung cancer patients could help us perform the tests in those patients that are likely to have the mutations, employing the new therapies only in a limited number of cases with a cost-effective strategy.

Original languageEnglish
Pages (from-to)128-134
Number of pages7
JournalCancer and Chemotherapy Reviews
Volume7
Issue number3
Publication statusPublished - 2012

Keywords

  • Epidermal growth factor receptor
  • K-ras
  • Molecularly targeted therapy
  • Non-small cell lung cancer

ASJC Scopus subject areas

  • Oncology
  • Pharmacology (medical)

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