Class act: safety comparison of approved tyrosine kinase inhibitors for non-small-cell lung carcinoma

Introduction: The past decade has seen the development and widespread use of tyrosine kinase inhibitors (TKIs) targeting a mutated EGFR (mEGFR) for the treatment of metastatic NSCLC. We discuss the main properties of the TKIs currently recommended for the treatment of mEGFR NSCLC: gefitinib, erlotinib and afatinib.

Areas covered: The mechanism of action, pharmacodynamics and pharmacokinetics of these drugs, with emphasis on the historical context of their preclinical and clinical development, will be covered, including potential resistance mechanisms to these first-generation TKIs that has driven the trial design for second and third generations of EGFR inhibitors. Six Phase III clinical trials comparing these three TKIs with cisplatin-based chemotherapy upfront for mEGFR NSCLC provide the basis for the comparative safety and toxicity analysis between these agents. Class-related toxicity of these EGFR inhibitors, including life-threatening effects, will be discussed.

Expert opinion: Toxicity and safety analysis from the Phase III trials of these agents in mEGFR populations suggests that afatinib has more frequent and severe side effects. Given that an efficacy advantage has not yet been demonstrated for afatinib over erlotinib and gefitinib, the consistent class toxicity profile of these agents means that gefitinib and erlotinib are a safer first-line treatment recommendation.     

EGFR-TKIs治疗非小细胞肺癌进展

目前,肺癌依然是导致人类恶性肿瘤死亡的首位疾病。在过去10年中,EGFR-TKI药物的出现,显著改善了患者的生存,从而改变了肺癌的标准治疗模式。作为一线、二线或其他治疗,EGFR-TKI药物,包括吉非替尼和厄洛替尼,在特定人群中(腺癌、女性、非吸烟、亚裔患者)疗效显著。除上述两种药物,由浙江贝达药业有限公司研发的EGFR-TKIs埃克替尼也已经完成了其III期临床试验(ICOGEN),并取得可喜的结果。本文将对以上3种EGFR-TKI药物治疗非小细胞肺癌进展进行综述。     

Small-molecule EGFR tyrosine kinase inhibitors for the treatment of cancer

Introduction: EGFR has been implicated in various malignancies such as NSCLC, breast, head and neck, and pancreatic cancer. Numerous drugs have been developed in order to target the tyrosine domain of EGFR as an approach in cancer treatment.

Areas covered: This article focuses on the different generations of EGFR tyrosine kinase inhibitors (TKIs). This spans from the emergence of the first-generation EGFR-TKIs to overcoming drug resistance using second-generation EGFR-TKIs and to reducing adverse effect (AE) using mutant-selective third-generation EGFR-TKIs.

Expert opinion: Current TKI treatment is frequently accompanied by drug resistance and/or serious AEs. There has been the promise of advancements in second-generation EGFR-TKIs that could overcome drug resistance, acting as second- or third-line salvage treatment, but this promise has yet to be met. That being said, both issues are currently being addressed with mutant-selective EGFR-TKIs with the expectation of bringing more EGFR-targeted therapy into the next phase of cancer therapy in the future.     

Advances in chemotherapy in advanced non-small-cell lung cancer

Importance of the field: Lung cancer is the most common cancer in the world today, in terms of both incidence and mortality. Non-small-cell lung cancer (NSCLC) accounts for about 85% of all lung cancers diagnosis, and the majority of people diagnosed with NSCLC have advanced disease.

Areas covered in this review: In this review the main advances achieved in the medical treatment of advanced NSCLC are discussed, regarding both targeted therapies and chemotherapy. Among targeted therapies, recent data on the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab and the epidermal growth factor receptor tyrosyne kinase inhibitors (EGFR-TKIs) gefitinib and erlotinib are described. Among chemotherapeutic agents, the role of pemetrexed is discussed.

What the reader will gain: The reader will gain up-to-date information on the main advances, achieved in the last 3 years in the medical treatment of advanced NSCLC.

Take home message: Some recent advances have changed the face of the first-line chemotherapy of advanced NSCLC, giving physicians more options to tailor choice in this challenging setting.     

Erlotinib in non-small-cell lung cancer

Epidermal growth factor receptor (EGFR) plays an essential role in normal cell growth and differentiation, and is involved in tumour proliferation and survival. EGFR overexpression is a common feature in solid malignancies, including non-small-cell lung cancer (NSCLC), and is associated with poor clinical prognosis. Erlotinib is a small-molecule inhibitor of EGFR tyrosine kinase, showing a significant improvement in median survival, quality of life and related symptoms in an unselected population of advanced NSCLC patients in the second- or third-line setting. Erlotinib is well tolerated (with common toxicities including rash and diarrhoea) when administered at a standard oral daily dose of 150 mg. Further investigations are ongoing to contribute to our understanding of the role of erlotinib in NSCLC treatment.     

Safety profiles of first-line therapies for metastatic non-squamous non-small-cell lung cancer

ABSTRACT

Introduction: Lung cancer still represents the leading cause of death for cancer. About the 70% of diagnosis are in advanced-stage. Non-small-cell lung cancer (NSCLC) represents the 85% of all diagnosed lung cancers and non-squamous histology represents the 40% of all NSCLC. First-line therapies increase survival, control symptoms and improve quality of life, compared with best supportive care. It is crucial to choose a treatment with a low impact on patient’s life considering the related toxicities.

Areas covered: Adverse events (AEs) of first-line therapies for non-squamous NSCLC are here reviewed and discussed, from evidences in clinical trials conducting to drugs approval.

Expert opinion: For advanced disease, palliation and preserving patients QoL are still the primary goal of treatment. Therefore, differing toxicity profiles are often a deciding factor in first-line and also maintenance setting for non-squamous NSCLC.

Special attention is necessary to renal function and drugs’ nephrotoxicity. Moreover, it is to consider the specific AEs of drugs classes: hypertension, bleeding, and proteinuria, for anti-VEGF therapy; skin toxicity, diarrhea, interstitial lung disease for TKIs; vision disorders, and hepatotoxicity for ALK-inhibitor. It is important to select patients for a treatment on the basis of their comorbidities and the presence of risk factors.     

Epidermal growth factor receptor inhibitors in non-small-cell lung cancer

The epidermal growth factor receptor (EGFR) is a cell membrane receptor that plays a key role in cancer development and in the progression of many human malignancies, including non-small-cell lung cancer (NSCLC). EGFR-dependent signaling is involved in cancer cell proliferation, apoptosis, angiogenesis, invasion and metastasis. Targeting the EGFR is a valuable molecular approach in cancer therapy. This receptor is overexpressed in up to 80% of NSCLC cases. Thus, several molecules inhibiting this critical biologic pathway have been synthesized and tested as a single agent or in combination with other anticancer modalities in a wide of clinical trials, including reversible and irreversible small tyrosine kinase inhibitors, such as gefitinib and erlotinib, dual vascular endothelial growth factor receptor EGFR tyrosine kinase inhibitors, such as vandetanib (ZD-6474), and monoclonal antibodies, such as cetuximab, which have shown promising activity in patients with NSCLC. This review focuses on the preclinical and clinical results available with EGFR inhibitors in the treatment of NSCLC patients.     

Alectinib for ALK-positive non-small-cell lung cancer

Introduction: Anaplastic lymphoma kinase (ALK) rearrangements are present in about 5% of advanced non-small-cell lung cancer (NSCLC) patients. Despite the initial response, after a median of 1-2 years, ALK-positive patients developed an acquired resistance to the ALK-inhibitor crizotinib. Among the most promising second-generation ALK-inhibitors, alectinib is being investigated in crizotinib-naïve and -resistant ALK-positive NSCLC patients.

Areas covered: The current state-of-the-art of ALK-inhibitors treatment, and in particular the role of alectinib in this setting, is reviewed and discussed. A structured search of bibliographic databases for peer-reviewed research literature and of main meetings using a focused review question was undertaken.

Expert commentary: Alectinib reports promising results with a good safety profile, becoming a potentially very important option for ALK-translocated NSCLC patients. The preliminary results from the J-ALEX phase III randomized trial performed in ALK-rearranged NSCLC Japanese patients showed a better activity and tolerability of alectinib versus crizotinib.     

Optimization of genetics to create therapies for metastatic (stage IV) non-small-cell lung cancer

Importance of the field: Non-small-cell lung cancer (NSCLC) is a disseminated disease in 50% of cases, with a gloomy prognosis and median survivals of < 1 year.

Areas covered in this review: Based on substantial advances, cancer biology insights and novel biotechnology tools, customized treatment provides hints that cisplatin-based treatment can be optimized in favorable subgroups of patients according to gene expression DNA repair profiles. In 2004, it was discovered that 10 – 15% of NSCLC can harbor a new class of EGFR mutation conferring specific sensitivity to EGFR tyrosine kinase inhibitors.

What the reader will gain: The homologous recombination pathway provides information for customizing cisplatin-based chemotherapy. BRCA1 plays a central role in this pathway that can be used in tailoring chemotherapy. Patient subgroups can obtain significant increases in progression-free survival. For EGFR lung-addicted cancers, treatment with EGFR tyrosine kinase inhibitors like erlotinib provide impressive improvement in progression-free survival – up to 14 months with significant enhanced survival.

Take home message: Customized chemotherapy based on BRCA1 models can contribute to demonstrating this approach's clinical relevance, and the implementation of EGFR mutation assessment is warranted to identify EGFR-addicted lung cancers with a different prognosis that could benefit from a specifically targeted therapy approach.     

EGFR-directed therapies to treat non-small-cell lung cancer

Lung cancer is the leading cause of cancer death in men and women. In 2008, in the US > 200,000 patients were diagnosed with lung cancer and > 160,000 died from their disease. Over 80% of lung cancers are of the non-small cell type, for which chemotherapy has demonstrated modest survival benefits at all stages of disease. Agents that alter critical molecular cell growth pathways are a growing area of research and development including targeted therapies directed at the EGFR. Downstream effects of EGFR dimerization and activation include cell proliferation, differentiation and angiogenesis, key events in the malignant process. Two main classes of drugs have been developed, small molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies directed against the extracellular domain of the receptor. This review discusses clinical studies with several new therapies and the plans for drug development.     

Anaplastic lymphoma kinase inhibitors in phase I and phase II clinical trials for non-small cell lung cancer

Introduction: Crizotinib is a first-in-class ALK tyrosine kinase inhibitor (TKI), which has proven its superiority over standard platinum-based chemotherapy for the first-line therapy of ALK-rearranged non-small cell lung cancer (NSCLC) patients. The development of acquired resistance to crizotinib represents an ongoing challenge with the central nervous system being one of the most common sites of relapse. Ceritinib and alectinib are approved second-generation ALK TKIs. Several novel ALK inhibitors, more potent and with different selectivity compared to crizotinib, are currently in development.

Areas covered: This review will focus on new ALK inhibitors, currently in phase 1 or 2 clinical studies. We will also comment on the mechanisms of resistance to ALK inhibition and the strategies to delay or overcome resistance.

Expert opinion: The therapeutic management of ALK-rearranged NSCLC has been greatly improved. Next-generation ALK inhibitors have shown differential potency against ALK rearrangements and ALK resistance mutations. The molecular profile of the tumor at the time of disease progression to crizotinib is crucial for the sequencing of novel ALK TKIs. Ongoing clinical studies will address key issues, including the optimal therapeutic algorithm and whether combinational approaches are more effective than single ALK inhibition for the outcome of ALK-rearranged NSCLC patients.     

Strategies to overcome resistance to tyrosine kinase inhibitors in non-small-cell lung cancer

The use of molecularly targeted agents has dramatically improved the prognosis of defined subsets of patients with non-small-cell lung cancer harboring somatically activated oncogenes, such as mutant EGFR or rearranged ALK. However, after initial marked responses to EGFR or ALK tyrosine kinase inhibitors (TKIs), almost all patients inevitably progress due to development of acquired resistance. Multiple molecular mechanisms of resistance have been identified; the best characterized are secondary mutations in the tyrosine kinase domain of the oncogene, such as T790M in EGFR and L1196M in ALK, which prevent target inhibition by the corresponding TKI. Other mechanisms include copy number gain of the ALK fusion gene and the activation of bypass signaling pathways that can maintain downstream proliferation and survival signals despite inhibition of the original drug target. Here, the authors provide an overview of the known mechanisms of resistance to TKIs and outline the therapeutic strategies, including new investigational agents and targeted therapies combinations, that have been developed to overcome resistance.     

Ceritinib for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer

Non-small cell lung cancer (NSCLC) represents the paradigm of personalized treatment of human cancer. Several oncogenic druggable alterations have been so far identified, with anaplastic lymphoma kinase (ALK) gene rearrangements representing one of the newest and most appealing. Crizotinib is now recognized as the standard of care in ALK-positive NSCLC due to the positive results of recently published trials. Unfortunately, resistance inevitably occurs within the first year of treatment. Overcoming resistance is the major challenge in clinical oncology, and novel potent ALK inhibitors are currently under evaluation, including ceritinib. Ceritinib is an oral, potent, second-generation ALK inhibitor demonstrating activity in patients who develop resistance to crizotinib. Recent data also suggested efficacy in ALK-inhibitor-naive population, thus supporting investigation of the drug in front-line setting.     

Gefitinib for non-small-cell lung cancer treatment

Introduction: Gefitinib is an EGFR tyrosine kinase inhibitor (EGFR-TKI) that demonstrated efficacy in patients with advanced non-small cell lung cancer (NSCLC) across therapy lines. In the first-line setting, recent randomized Phase III trials comparing EGFR-TKIs versus platinum-based doublets demonstrated that in patients harboring an activating EGFR mutation, gefitinib is superior to chemotherapy in terms of response rate, progression-free survival, toxicity profile and quality of life, with a marginal positive effect on survival. In order to choose the best treatment, a molecular characterization is now mandatory, as part of baseline diagnostic procedures.

Areas covered: All published data on gefitinib in lung cancer were analyzed using PubMed. The aim of this review is to summarize activity and safety data from major clinical trials of gefitinib in patients with advanced NSCLC.

Expert opinion: EGFR-TKIs including gefitinib are the best option we can offer today in patients with EGFR mutation, regardless of treatment line. Administration of gefitinib to patients with advanced NSCLC is usually well-tolerated and it also appears to be feasible in special populations characterized by a significantly poorer risk:benefit ratio with standard chemotherapy, like elderly patients and patients with poor performance status.     

Epidermal growth factor receptor inhibitors in the treatment of non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in both men and women. Despite the introduction of the newer cytotoxic agents in NSCLC treatment during the last decade the survival rates of patients have reached a plateau. New strategies are clearly needed to improve treatment outcomes. Epidermal growth factor receptor (EGFR) has a key role in cancer development and progression and has been recognised as a target of increasing importance in NSCLC. Gefitinib, erlotinib and cetuximab are EGFR-targeting agents that are being extensively evaluated in NSCLC. EGFR inhibitors demonstrate significant clinical activity in ~ 10 – 20% of pretreated NSCLC patients. Somatic mutations in the kinase domain of the receptor have been shown to be associated with enhanced sensitivity to EGFR inhibitors. However, four large Phase III randomised, placebo-controlled trials of gefitinib and erlotinib in combination with standard platinum-based first-line chemotherapy failed to show any survival benefit in patients receiving the study drugs. Possible reasons include patient selection, drug scheduling, trial design or other factors. Active research is ongoing to improve the efficacy of EGFR inhibitors as monotherapy or in combination with other treatment modalities.     

Reviewing the safety of erlotinib in non-small cell lung cancer

Importance of the field: Erlotinib, a potent inhibitor of EGFR activity, is approved as a monotherapy for the treatment of advanced NSCLC and in combination with gemcitabine for advanced pancreatic cancer. The oral administration and manageable toxicity of erlotinib, along with its similar efficacy to chemotherapy, make it an important option as either maintenance therapy or in second-/third-line for patients with NSCLC who have previously received first-line chemotherapy. It is also an emerging option in other treatment settings in NSCLC.

Areas covered in this review: This review summarizes safety data from major clinical trials of erlotinib in patients with advanced NSCLC, as well as post-marketing data obtained in the 5 years since this drug was first approved.

What the reader will gain: An understanding of the common toxicities expected with erlotinib in patients with advanced NSCLC.

Take home message: Erlotinib is a well-tolerated treatment option for patients with advanced NSCLC. The main adverse events of rash and diarrhea are typically mild or moderate in severity, and rarely lead to treatment withdrawal. When necessary, rash and diarrhea can be easily managed prophylactically, by active intervention or through dose reduction.     

Emerging drugs for non-small-cell lung cancer

Non-small-cell lung cancer (NSCLC) accounts for 80% of all lung cancer cases and is the leading cause of cancer mortality. Despite the optimization of chemotherapy regimens, treatment outcomes for advanced disease are still disappointing. The EGFR tyrosine kinase inhibitor, erlotinib, and the recombinant monoclonal antibody against the VEGF, bevacizumab, have proven active in NSCLC. In the BR.21 trial, a 2-month benefit in overall survival was observed for previously treated NSCLC patients who received erlotinib versus placebo. The combination of chemotherapy plus bevacizumab yielded superior overall survival or progression-free survival in one randomized trial in advanced non-squamous NSCLC patients. However, despite the introduction of more effective agents, new treatment strategies are clearly needed in lung cancer management.

The review focuses on a number of new targeted agents/chemotherapy drugs now in clinical trials directed at improving NSCLC management. Mature results regarding their activity and usefulness can be expected in the near future.     

Afatinib and Erlotinib in the treatment of squamous-cell lung cancer

ABSTRACT

Introduction

Squamous-cell carcinoma (SCC) of the lung represents around 20% of non-small cell lung cancers. Although activating mutations of EGFR are rare in this subtype, its overexpression occurs in more than half the cases. Consequently, many epidermal growth factor receptor (EGFR)-targeted agents have been investigated in patients with SCC.     

Second-generation epidermal growth factor tyrosine kinase inhibitors in non-small cell lung cancer

Inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) has an established role in the treatment of advanced non-small cell lung cancer. The first-generation EGFR inhibitors erlotinib and gefitinib have been approved for treatment in the second- and third-line setting. Second-generation EGFR tyrosine kinase inhibitors are now in development aiming to improve efficacy and overcome primary and secondary resistance to the first-generation drugs. The two most common strategies being used to achieve these aims are irreversible binding of drug to target and kinase multi-targeting. This is an overview of the early clinical development of selected second-generation tyrosine kinase inhibitors focusing on the treatment of non-small cell lung cancer.     

PROFILing non-small-cell lung cancer patients for treatment with crizotinib according to anaplastic lymphoma kinase abnormalities: translating science into medicine

Introduction: In the recent years, the growing attention to the molecular background of non-small-cell lung cancer (NSCLC) led to the identification of different molecular subtypes according to genetic abnormalities driving the disease development and progression. Whereas the addicted pathways were successfully inhibited (such as the mutant epidermal growth factor receptor), clinicians have witnessed a dramatic survival improvement. In this regard, the molecular portrait of adenocarcinoma was recently enriched by the identification of a specific patients' subgroup characterized by abnormalities in the anaplastic lymphoma kinase (ALK), with unclear prognostic features but impressive response to specific inhibitors.

Areas covered: In this article, updated data derived from the development and the use of crizotinib (the most advanced in development among tyrosine kinase ALK inhibitors) in comparison with standard second-line chemotherapy for patients affected by ALK-altered NSCLC are reviewed.

Expert opinion: Taking into account the available data, pretreated NSCLC patients carrying the ALK-translocation require a selected targeted therapy which significantly improves activity, efficacy and symptoms control versus chemotherapy. In this context, the identification of this disease entity and the availability of such impressive therapeutic targeting represent a further step toward the understanding of the molecular complexity behind the adenocarcinoma of the lung.