Protein kinase inhibitors to treat non-small-cell lung cancer

Introduction: Activating mutations of the EGFR and rearrangement of anaplastic lymphoma kinase (ALK) best illustrate the therapeutic relevance of molecular characterization in NSCLC patients.

Areas covered: For this review article, all published data on the most relevant Phase III trials with tyrosine kinase inhibitors (TKIs) for the treatment of NSCLC were collected and analyzed.

Expert opinion: Eight Phase III trials clearly established EGFR TKIs as the best therapeutic option for front-line therapy in EGFR-mutated patients. In pretreated NSCLC, EGFR TKIs are considered more effective than standard monotherapy with cytotoxics in presence of classical EGFR mutations, whereas in the EGFR wild-type population, a similar efficacy to docetaxel or pemetrexed in term of survival has been demonstrated. In ALK-translocated NSCLC, a Phase III trial demonstrated the superiority of a multi-target TKI, including ALK, in terms of progression-free survival, response rate and toxicity profile when compared to standard second-line chemotherapy. New agents targeting EGFR or ALK are under evaluation particularly in individuals with acquired resistance to EGFR TKIs or crizotinib.     

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.     

Targeting epidermal growth factor receptor in the treatment of non-small-cell lung cancer

Importance of the field: The management of non-small-cell lung cancer (NSCLC) has undergone a paradigm shift in the last decade, with the survival advantage demonstrated by the incorporation of anti-epidermal growth factor receptor (EGFR) agents to the standard treatment of advanced/metastatic NSCLC.

Areas covered in this review: We review the existing data regarding the distinct anti-EGFR agents in the NSCLC treatment and the potential role of the investigated biomarkers in the clinical outcome.

What the reader will gain: Tyrosine kinase inhibitors have been used in first-line, second-line and more settings with extremely good results in a subgroup of patients. Cetuximab remains the only anti-EGFR monoclonal antibody to show survival benefit when combined with a cytotoxic agent in the front-line setting. Anti-EGFR treatment is associated with a dramatic clinical benefit in a subgroup of patients, emphasizing the importance of customizing treatment. Several biomarkers have been investigated for their predictive or prognostic value. Validation of identification of biomarkers remains a focus of intense research that may ultimately guide therapeutic decision making, as none of these is considered ideal to discriminate responding from non-responding patients. However, the current evidence of the EGFR mutation analysis from a recent randomised trial suggests that EGFR mutation analysis is quite a good predictive marker for responsiveness to anti-EGFR TKIs. Moreover, the identification of surrogate markers to indicate optimal activity of the anti-EGFR agent is also needed. This review article provides data from large clinical trials using anti-EGFR agents and correlates these results with the tested biomarkers.

Take home message: EGFR inhibition has shown very encouraging results and has improved the outcome of the NSCLC treatment. However, a plateau of significant clinical benefit seems to have been reached and we believe that the time to move away from the traditional treatment approach to more individualizing therapies has come.     

Vandetanib for the treatment of non-small-cell lung cancer

Introduction: The use of targeted therapies in the treatment of advanced non-small-cell lung cancer (NSCLC) is increasing, especially as conventional chemotherapy affords relatively small benefits at a cost of increased toxicity. Two of the more established therapeutic targets in NSCLC are the vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR). Vandetanib is an orally available inhibitor of VEGFR and EGFR signalling and is an attractive therapeutic agent owing to the simultaneous inhibition of both pathways.

Areas covered: This review encompasses the clinical efficacy, safety and tolerability of vandetanib in advanced NSCLC. Of particular interest are the randomized Phase III clinical trials, which did not show clinically significant overall survival benefit for vandetanib monotherapy or in combination with standard chemotherapy regimens.

Expert opinion: Vandetanib has anti-tumour activity in NSCLC, with improved objective responses and disease control. However, significant survival benefits were not demonstrated in Phase III clinical trials and at present vandetanib is not in further development for use in NSCLC.     

Personalized treatment of EGFR mutant and ALK-positive patients in NSCLC

Introduction: The epidermal growth factor receptor (EGFR) is mutated in 15% of adenocarcinomas of the lung. In addition, the anaplastic lymphoma kinase (ALK) is altered in 8% of adenocarcinomas of the lung. Treatment of EGFR mutant and ALK translocation-positive tumors in NSCLC with tyrosine kinase inhibitors (TKI) results in a dramatic therapeutic response and has revolutionized therapy. Unfortunately, resistance to TKIs invariably develops. Many promising new therapies are under investigation to overcome the resistance.

Areas covered: We analyzed the current primary literature and recent national meetings to evaluate the clinical characteristics and therapeutic implications of relevant treatments for EGFR mutant and ALK-positive NSCLC in the first-line, acquired resistance, and adjuvant settings.

Expert opinion: Treatment with EGFR TKIs in the first-line setting of EGFR mutant NSCLC results in a significant clinical benefit. Several promising third generation EGFR TKIs are being evaluated in Phase II and III trials in the acquired resistance setting. Crizotinib is superior to chemotherapy in the first-line setting for ALK-positive NSCLC. Ceritinib is effective and approved for ALK-positive NSCLC in the acquired resistance setting. Continued investigation is needed to develop novel therapies to overcome acquired resistance to TKIs.     

Epidermal growth factor receptor tyrosine kinase inhibitors in previously treated advanced non-small-cell lung cancer with wild-type EGFR

Introduction: While epidermal growth factor receptor (EGFR) – tyrosine kinase inhibitors (TKIs) lead to longer progression-free survival (PFS) when compared with conventional chemotherapy in non-small-cell lung cancer (NSCLC) harboring activating EGFR mutations, the role of EGFR-TKI remains unclear in EGFR-wild-type (WT) NSCLC.

Areas covered: This article reviews selected data from randomized trials regarding the use of TKIs in EGFR-WT NSCLC. Nine randomized phase III trials have compared EGFR-TKI with chemotherapy in NSCLC patients in a second or later line setting. Two of these trials, TAILOR and DELTA, which were designed to investigate treatment benefits according to EGFR genotype, demonstrated that docetaxel chemotherapy displayed significantly better in progression-free survival (PFS) when compared with the EGFR-TKI erlotinib. Biomarkers to predict clinical benefits of the drug against EGFR WT tumor, and the efficacy of combination regimens using erlotinib or single-use afatinib against tumors are also covered in this article.

Expert opinion: Considering the modest benefits of erlotinib for EGFR-WT tumors, future studies are warranted, including the exploration of useful biomarkers and new treatment strategies for EGFT-TKI use, as well as the development of more sensitive EGFR mutation tests.     

Osimertinib for EGFR T790M mutation-positive non-small cell lung cancer

Introduction: Significant advances have been made since the development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) targeting EGFR mutations in non-small-cell lung cancer (NSCLC), however, lung cancer cells eventually acquire resistance to those agents. Osimertinib (AZD9291) has been developed as 3^rd generation EGFR-TKI with activities against sensitizing mutations and T790 M resistance mutation, which account for about 50% of the mechanisms of acquired resistance to 1^st or 2^nd generation EGFR-TKIs. A recent phase I/II clinical trial with osimertinib for advanced NSCLC patients with known sensitizing EGFR mutations and documented disease progression on prior EGFR-TKIs revealed promising effect with acceptable toxicities.

Areas covered: This article summarizes current understanding and available preclinical and clinical data on osimertinib and also discusses future directions. The literature search included PubMed and the latest articles from international conferences.

Expert commentary: The development of osimertinib has provided new therapeutic options for NSCLC patients harboring T790 M. Compared with other EGFR-TKIs including rociletinib, osimertinib seems to possess an advantage with respect to the effect and safety profile among existing EGFR-TKIs. However, tumor progression still occurs even when treating with osimertinib. A further understanding of the mechanisms of resistance is eagerly anticipated in order to develop next generation EGFR-TKIs.     

Recent understanding of the molecular mechanisms for the efficacy and resistance of EGF receptor-specific tyrosine kinase inhibitors in non-small cell lung cancer

Introduction: The epidermal growth factor receptor (EGFR) and its family members are involved in many aspects of tumor biological processes. Aberrant activation of the EGFR tyrosine kinase by mutations or protein overexpression is observed in various types of human cancer, including lung cancer. EGFR tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, are highly effective in lung cancer patients who harbor active mutations in the EGFR gene. However, patients who are initially sensitive to EGFR-TKIs eventually relapse within few years.

Areas covered: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and is associated with a high frequency of EGFR mutations. This review describes the EGFR mutations that determine the sensitivity to EGFR-TKIs and the current understanding of the molecular mechanisms of acquired resistance to EGFR-TKIs in NSCLC. Furthermore, the authors describe recent strategies developed to overcome acquired resistance using second-generation EGFR-TKIs and combination therapies with several molecular-targeting drugs.

Expert opinion: Although recent findings have contributed to our understanding of the mechanism of acquired resistance and helped the development of novel strategies to overcome such resistance, the underlying mechanisms are complex and additional research is necessary to develop effective therapeutic strategies for individual patients with lung cancer.     

Emerging drugs for EGFR-mutated non-small cell lung cancer

Introduction: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent the standard of care for patients with metastatic non-small-cell lung cancer (NSCLC) harboring sensitizing EGFR mutations. However, these agents are associated with inevitable treatment resistance. Newer generations of TKIs are under development that may prevent or overcome resistance and enhance intracranial activity.

Areas covered: In this review, we will discuss newer generations of EGFR TKIs for EGFR-mutated NSCLC. We will also address resistance mutations and escape pathways associated with these agents such as secondary mutations, downstream signaling, bypass pathways, phenotypic transformation, anti-apoptotic signaling, immune evasion, and angiogenesis. Furthermore, this article encompasses emerging data from combination trials with next-generation TKIs that are being pursued to delay or prevent the occurrence of resistance.

Expert opinion: The promise and challenge of precision oncology is encapsulated in the treatment of EGFR-mutated NSCLC with TKIs. Third generation TKIs have shown superior efficacy in the front-line setting and have become standard of care. A better understanding of mechanisms of treatment failure and disease relapse will be required to develop novel therapeutic strategies to further improve patient outcomes in the future.     

Meta-analysis of the incidence and risk of arterial and venous thromboembolic events associated with anti-EGFR agents in non-small-cell lung cancer patients

Background: To determine the risk of arterial and venous thromboembolic events (ATEs and VETs) associated with anti-epidermal growth factor receptor (EGFR) agents in non-small-cell lung cancer (NSCLC) patients.

Methods: Prospective randomized trials evaluating therapy with or without anti-EGFR agents in NSCLC patients. Data on VTEs and ATEs were extracted.

Results: A total of 8,410 patients from 12 trials were included for analysis. Anti-EGFR agents significantly increased the risk of all-grade and high-grade VTEs (Peto OR 1.50, 95%CI 1.16–1.95, P = 0.002; Peto OR 1.73, 95%CI: 1.32–2.26, p < 0.001, respectively), but not for all-grade and high-grade ATEs.

Conclusion: The use of anti-EGFR agents significantly increased the risk of all-grade and high-grade VTEs but not for ATEs in NSCLC patients.     

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.     

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.     

Targeting epidermal growth factor receptor: Central signaling kinase in lung cancer

Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. Platinum-based doublets remain the current standard therapy for advanced NSCLC. However, overall survival (OS) has reached a plateau, even with the improvement in these regimens. Advances in the knowledge of molecular mechanisms of carcinogenesis have prompted the development of many novel molecular-targeted agents including the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Results of the recent phase III IPASS trial showed that the EGFR-TKI gefitinib has a superior progression-free survival (PFS) to the most commonly used platinum-based doublet carboplatin-paclitaxel as the first-line chemotherapy for pulmonary lung adenocarcinoma among nonsmokers in East Asia. This trial also demonstrated that the presence of EGFR mutation is the best predictor of gefitinib treatment compared with the other biomarkers including EGFR gene copy number. Despite the therapeutic benefit of EGFR-TKIs in NSCLC, most patients eventually develop resistance to these drugs. A secondary mutation of EGFR (T790M) and amplification of MET account for 70% of all cases of acquired resistance to EGFR-TKIs. This review summarizes the significance of EGFR mutations and the mechanisms of resistance to EGFR-TKIs in NSCLC, both of which are critical for patient selection to extend survival as well as to overcome resistance in NSCLC patients treated with EGFR-TKIs.     

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.     

Pharmacokinetic drug evaluation of osimertinib for the treatment of non-small cell lung cancer

Introduction: First- and second-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, erlotinib, icotinib, and afatinib are the standard-of-care for first-line therapy of non-small-cell lung cancer (NSCLC) harboring activating EGFR mutations. Unfortunately, after initial activity of an average 9–13 months, disease progression has been reported in the majority of patients. In about 50% of cases the progression is due to the onset of the T790M mutation in exon 20 of the EGFR gene. Third-generation EGFR-TKIs targeting this mutation were investigated, with osimertinib the only reaching clinical practice.

Areas covered: A structured search of bibliographic databases for peer-reviewed research literature and of main meetings using a focused review question addressing osimertinib, was undertaken.

Expert opinion: Osimertinib is the standard-of-care for EGFR-mutated patients progressing to first-line EGFR-TKIs due to the acquired EGFR T790M mutation. Results from the head-to-head first-line trial comparing osimertinib versus gefitinib or erlotinib in activating EGFR mutations might change the front-line approach. Osimertinib in combination regimens, such as immunotherapy, and in adjuvant setting are ongoing. Thus, the strategic approach for the management of EGFR-mutated NSCLC patients will change further in the next few years.     

Afatinib for the first-line treatment of patients with metastatic EGFR-positive NSCLC: a look at the data

Introduction: Epidermal growth factor receptor (EGFR) mutations are detected in about 10–15% of Caucasian and 30–40% of Asian patients with advanced or metastatic non-small-cell lung cancer (NSCLC). In patients harbouring EGFR mutations, the treatment with different available EGFR tyrosine kinase inhibitors (TKIs) showed to be more effective and safe than platinum-based chemotherapy regimens.

Areas covered: The current evidences about the role of afatinib for patients with EGFR-positive NSCLC are reviewed and discussed. We report a review based on a MEDLINE/PubMed, searched for randomized phase II or III trials evaluating afatinib in EGFR-positive NSCLC.

Expert commentary: Afatinib is the third EGFR TKI approved for the treatment of NSCLC harbouring EGFR mutations, showing high efficacy in this setting of patients.     

Erlotinib for the treatment of brain metastases in non-small cell lung cancer

Introduction: Brain metastases (BM) are a common and lethal complication of non-small cell lung cancer (NSCLC) with up to 40% experiencing this complication. The use of erlotinib, a small molecule epidermal growth factor receptor (EGFR) inhibitor, holds promise in this somewhat refractory cohort of patients, and has become the subject of active clinical investigation.

Areas covered: This review covers the preclinical and clinical studies of erlotonib as it relates to its use in the treatment of NSCLC patients with BM. A literature search in part utilized the PubMed database up through Dec 2015.

Expert opinion: Preclinical and retrospective data for erlotinib provide evidence of CNS penetration, and objective responses in the setting of BM from EGFR mutated NSCLC. Phase I and II data have demonstrated the feasibility of concomitant delivery of erlotinib and WBRT in the treatment of BM from NSCLC. Phase II/III data however, from non-EGFR mutation enriched populations, have demonstrated no benefit in progression free or overall survival with the addition of erlotinib to metastasis directed radiotherapy. Currently the utilization of erlotinib with WBRT or SRS is therefore investigational and may be a reasonable option in erlotinib naïve, EGFR mutated patients with refractory BM.     

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.     

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.     

First-line gefitinib for elderly patients with advanced NSCLC harboring EGFR mutations. A combined analysis of North-East Japan Study Group studies

Objective: To assess outcomes of elderly patients with advanced NSCLC harboring an EGFR mutation treated with gefitinib, as well as safety and impact on quality of life (QoL).

Methods: We performed a retrospective analysis of pooled data from one Phase III and two Phase II studies of 71 patients aged ≥ 70 years with a performance status of 0 – 2. The main outcome measures were progression-free survival (PFS), overall survival (OS) and response rate (RR), as well as incidence of adverse events and time to 9.1% deterioration in QoL.

Results: Median PFS (14.3 vs 5.7 months, p < 0.001) and overall RR (73.2 vs 26.5%, p < 0.001) in the gefitinib group were superior to those in the standard chemotherapy group, whereas median OS was not significantly different (30.8 vs 26.4 months, p = 0.42). Elevation of aspartate transaminase and/or alanine transaminase (18.3%) was the most common adverse event, and one treatment-related death (pneumonitis) occurred. Time to 9.1% deterioration in the QoL domains of pain and dyspnea, anxiety, and daily functioning was similar between the two age groups.

Conclusion: First-line gefitinib is efficacious with acceptable toxicity in relatively fit elderly patients with advanced NSCLC harboring an EGFR mutation.