Targeted Therapy for Non-Small Cell Lung Cancer
Targeted Therapy for Non-Small Cell Lung Cancer
In recent years, there has been a major paradigm shift in the management of non-small cell lung cancer (NSCLC). NSCLC should now be further sub-classified by histology and driver mutation if one is known or present. Translational research advances now allow such mutations to be inhibited by either receptor monoclonal antibodies (mAb) or small molecule tyrosine kinase inhibitors (TKI). Whilst empirical chemotherapy with a platinum-doublet remains the gold standard for advanced NSCLC without a known driver mutation, targeted therapy is pushing the boundary to significantly improve patient outcomes and quality of life. In this review, we will examine the major subtypes of oncogenic drivers behind NSCLC as well as the development of targeted agents available to treat them both now and in the foreseeable future.
Lung cancer remains by far the single most common cause of cancer-related mortality with nearly 1.6 million deaths worldwide in 2012 or nearly 20% of cancer mortality as a whole. Over the last decade, molecular translational research advances have heralded major breakthroughs in the understanding, diagnosis and management of lung cancer, particularly for the more common (~80%) non-small cell lung cancer (NSCLC). Conversely, treatment for small cell lung cancer remains chemotherapy-based and whilst there are promising results with novel cytotoxics, its platinum-etoposide backbone holds strong.
The term 'Theranostics' whereby therapeutics and diagnostics have been meaningfully combined to achieve personalised pharmacotherapy has now become commonplace in oncology. Sequencing of the human genome has permitted more efficient identification of epigenetic mutations, tumour-suppressor-gene inactivation as well as oncogene driver mutations that are potential targets for therapy. Such examples include trastuzumab for HER-2 over-expressing breast cancer and vemurafenib for BRAF-mutant melanoma.
It is now accepted that NSCLC is not a singular entity but is in fact multiple pathologies with unique molecular signatures that we are only beginning to unravel and understand. Broadly speaking, the main subtypes are pulmonary adenocarcinoma, squamous cell carcinoma (SCC) and large cell carcinoma. This distinction alone allows for a more tailored selection of cytotoxic chemotherapy in advanced NSCLC without a driver mutation, as seen with enhanced efficacy with pemetrexed in adenocarcinoma or the toxicity concerns of bevacizumab in patients with squamous histology.
Optimal management of NSCLC now requires that tumours be screened for a range of predictive and prognostic biomarkers that help to predict sensitivity to targeted therapy and estimate prognosis respectively. For NSCLC, much of the work in the last decade has been focussed on mutations of the epidermal growth factor receptor (EGFR) and on the abnormal fusion of the anaplastic lymphoma kinase (ALK) being inhibited successfully with EGFR tyrosine kinase inhibitors (TKI) and crizotinib respectively. Targeted agents are now being rationally designed to inhibit particular mutations leading to a more streamlined clinical trial process. In this review, we will examine the major subtypes of driver mutations that have been identified in NSCLC and relevant targeted therapies available both now, and in the foreseeable future.
Abstract and Introduction
Abstract
In recent years, there has been a major paradigm shift in the management of non-small cell lung cancer (NSCLC). NSCLC should now be further sub-classified by histology and driver mutation if one is known or present. Translational research advances now allow such mutations to be inhibited by either receptor monoclonal antibodies (mAb) or small molecule tyrosine kinase inhibitors (TKI). Whilst empirical chemotherapy with a platinum-doublet remains the gold standard for advanced NSCLC without a known driver mutation, targeted therapy is pushing the boundary to significantly improve patient outcomes and quality of life. In this review, we will examine the major subtypes of oncogenic drivers behind NSCLC as well as the development of targeted agents available to treat them both now and in the foreseeable future.
Introduction
Lung cancer remains by far the single most common cause of cancer-related mortality with nearly 1.6 million deaths worldwide in 2012 or nearly 20% of cancer mortality as a whole. Over the last decade, molecular translational research advances have heralded major breakthroughs in the understanding, diagnosis and management of lung cancer, particularly for the more common (~80%) non-small cell lung cancer (NSCLC). Conversely, treatment for small cell lung cancer remains chemotherapy-based and whilst there are promising results with novel cytotoxics, its platinum-etoposide backbone holds strong.
The term 'Theranostics' whereby therapeutics and diagnostics have been meaningfully combined to achieve personalised pharmacotherapy has now become commonplace in oncology. Sequencing of the human genome has permitted more efficient identification of epigenetic mutations, tumour-suppressor-gene inactivation as well as oncogene driver mutations that are potential targets for therapy. Such examples include trastuzumab for HER-2 over-expressing breast cancer and vemurafenib for BRAF-mutant melanoma.
It is now accepted that NSCLC is not a singular entity but is in fact multiple pathologies with unique molecular signatures that we are only beginning to unravel and understand. Broadly speaking, the main subtypes are pulmonary adenocarcinoma, squamous cell carcinoma (SCC) and large cell carcinoma. This distinction alone allows for a more tailored selection of cytotoxic chemotherapy in advanced NSCLC without a driver mutation, as seen with enhanced efficacy with pemetrexed in adenocarcinoma or the toxicity concerns of bevacizumab in patients with squamous histology.
Optimal management of NSCLC now requires that tumours be screened for a range of predictive and prognostic biomarkers that help to predict sensitivity to targeted therapy and estimate prognosis respectively. For NSCLC, much of the work in the last decade has been focussed on mutations of the epidermal growth factor receptor (EGFR) and on the abnormal fusion of the anaplastic lymphoma kinase (ALK) being inhibited successfully with EGFR tyrosine kinase inhibitors (TKI) and crizotinib respectively. Targeted agents are now being rationally designed to inhibit particular mutations leading to a more streamlined clinical trial process. In this review, we will examine the major subtypes of driver mutations that have been identified in NSCLC and relevant targeted therapies available both now, and in the foreseeable future.
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