Lung Cancer: Targets and Therapy最新文献

The discovery of epidermal growth factor receptor (EGFR) mutations and subsequent demonstration of the efficacy of genotype-directed therapies with EGFR tyrosine kinase inhibitors (TKIs) marked the advent of the era of precision medicine for non-small-cell lung cancer (NSCLC). First- and second-generation EGFR TKIs, including erlotinib, gefitinib and afatinib, have consistently shown superior efficacy and better toxicity compared with first-line platinum-based chemotherapy and currently represent the standard of care for EGFR-mutated advanced NSCLC patients. However, tumors invariably develop acquired resistance to EGFR TKIs, thereby limiting the long-term efficacy of these agents. The T790M mutation in exon 20 of the EGFR gene has been identified as the most common mechanism of acquired resistance. Osimertinib is a third-generation TKI designed to target both EGFR TKI-sensitizing mutations and T790M, while sparing wild-type EGFR. Based on its pronounced clinical activity and good safety profile demonstrated in early Phase I and II trials, osimertinib received first approval in 2015 by the US FDA and in early 2016 by European Medicines Agency for the treatment of EGFR T790M mutation-positive NSCLC patients in progression after EGFR TKI therapy. Recent results from the Phase III AURA3 trial demonstrated the superiority of osimertinib over standard platinum-based doublet chemotherapy for treatment of patients with advanced EGFR T790M mutation-positive NSCLC with disease progression following first-line EGFR TKI therapy, thus definitively establishing this third-generation TKI as the standard of care in this setting. Herein, we review preclinical findings and clinical data from Phase I-III trials of osimertinib, including its efficacy in patients with central nervous system metastases. We further discuss currently available methods used to analyze T790M mutation status and the main mechanisms of resistance to osimertinib. Finally, we provide an outlook on ongoing trials with osimertinib and novel therapeutic combinations that might continue to improve the clinical outcome of EGFR-mutated NSCLC patients.

Chronic obstructive pulmonary disease (COPD) and lung cancer share a common etiological factor (cigarette smoking) and usually coexist in everyday clinical practice. The prevalence of COPD among newly diagnosed patients with lung cancer sometimes exceeds 50%. COPD is an independent risk factor (2-4 times higher than non-COPD subjects) for lung cancer development. The presence of emphysema in addition to other factors (e.g., smoking history, age) could be incorporated into risk scores in order to define the most appropriate target group for lung cancer screening using low-dose computed tomography. Clinical management of patients with coexistence of COPD and lung cancer requires a multidisciplinary oncology board that includes a pulmonologist. Detailed evaluation (lung function tests, cardiopulmonary exercise test) and management (inhaled drugs, smoking cessation, pulmonary rehabilitation) of COPD should be taken into account for lung cancer treatment (surgical approach, radiotherapy).

As compared to other cancers, lung malignancies are associated with high symptom burden, poorer prognosis, and stigmatization. Such factors increase psychological distress and negatively impact quality of life. Research has documented the efficacy of psychosocial interventions to alleviate psychological distress and promote well-being among patients with cancer. This article summarizes the current literature on psychosocial interventions in lung cancer. Major types of psychosocial interventions in lung cancer include cognitive-behavioral therapies, psycho-education, mind-body, exercise, and supportive or palliative care strategies. Discussion relative to the purpose, sample, research design, outcomes, and quality of the studies is presented. Findings may be useful in clinical environments as a resource to help health providers better understand mental health treatment options and care for patients facing lung cancer. The need to direct future research toward the advancement of science and improve well-being and quality of life outcomes for patients with advanced lung cancer and their family members is discussed.

The era of immunotherapy has changed the face of how we approach treatment for many oncologic and hematologic malignancies. Lung cancer has been in the forefront of checkpoint inhibition for the past 2 years and has paved the path for other subspecialties. While PD-1 inhibitors nivolumab and pembrolizumab have been approved for non-small cell lung cancer (NSCLC), this review focuses on atezolizumab, its landmark studies, and ongoing trials. Atezolizumab is the first programmed death ligand 1 (PD-L1) inhibitor to receive US Food and Drug Administration (FDA) approval for metastatic NSCLC patients who have progressed on frontline chemotherapy. This approval was based on two open-label Phase II multicenter trials, POPLAR (NCT01903993) and BIRCH (NCT02031458). Both studies revealed a benefit in overall survival (OS), progression-free survival, and response rate in the atezolizumab arm when compared to single-agent docetaxol. There were also fewest Grade 3-5 treatment-related adverse events (TRAEs) in the atezolizumab cohort. The open-label randomized Phase III OAK trial (NCT02008227) further established the role of atezolizumab in previously treated NSCLC. This study compared atezolizumab with docetaxel in patients with advanced NSCLC (squamous or nonsquamous histologies) who had progressed on one to two prior chemotherapy regimens. OS in the PD-L1-enriched population was superior in the atezolizumab arm (n=241) at 15.7 months compared with docetaxel (n=222) at 10.3 months (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.58-0.93; p=0.0102). Patients lacking PD-L1 also had survival benefit with atezolizumab with a median OS (mOS) of 12.6 months versus 8.9 months with chemotherapy (HR 0.75, 95% CI 0.59-0.96). Benefit was noted in both squamous and nonsquamous NSCLC subsets and regardless of PD-L1 expressivity. As seen in the POPLAR and BIRCH studies, the toxicity profile was significantly better with immunotherapy. The future is unfolding rapidly as new checkpoint inhibitors are gaining FDA approval. It is still not known if these agents will be used in combination with chemotherapy, with other immune-modulating agents, radiation therapy, or all of the above. The results of these studies investigating their use in combination with chemotherapy agents, with other immunotherapy agents such as CTLA-4 inhibitors, and with radiation therapy, are eagerly awaited.

The vascular endothelial growth factor (VEGF) and receptor is a therapeutic target because of the importance of this pathway in carcinogenesis. This pathway regulates and promotes angiogenesis as well as increases endothelial cell proliferation, permeability, and cancer survival. Ramucirumab is a new fully human monoclonal antibody that targets the VEGF receptor-2, an important key receptor implicated in angiogenesis. Ramucirumab has been approved for the treatment of second-line advanced or metastatic non-small cell lung cancer (NSCLC) in combination with the chemotherapy agent docetaxel. This was based on the result of the randomized trial REVEL of 1,253 patients with metastatic NSCLC previously treated with a platinum-based combination therapy. The authors observed a significant improvement in overall survival (OS) with an acceptable toxicities profile. In this study, patients were randomized to receive ramucirumab plus docetaxel or placebo with docetaxel. The combination of docetaxel and ramucirumab showed an improved OS (hazard ratio [HR]: 0.86; 95% CI: 0.75, 0.98). Median OS was 10.5 months in the ramucirumab arm versus 9.1 months in the placebo arm. Regarding side effects, the toxicity described on the ramucirumab arm were principally diarrhea, fatigue, and neutropenia. The most common (5%) adverse reactions of grade 3 and 4 in the ramucirumab arm were fatigue, neutropenia, febrile neutropenia, leukopenia, and hypertension. Adding ramucirumab to docetaxel improves QoL of patients, and does not impair symptoms or functioning. There are currently several trials in progress evaluating the effects of ramucirumab in combination with other drugs in patients with advanced NSCLC.

In lung cancer, the prognosis and treatment options depend directly on tumor size and its spread at the time of diagnosis. There is therefore a constant search for methods that will allow early detection of cancerous lung nodules. With advancing imaging technology and implantation of screening routines in high-risk populations by low-dose computerized tomography, a significant increase in the number of diagnosed small peripheral lesions can be expected. While early detection of small cancerous lesions carries the benefit of wider treatment options and better prognosis, the process of obtaining a biopsy to confirm a cancerous tissue is not free of complications and bears inconveniences and stress to the patient. This review discusses the potential use of exhaled breath analysis as a simple, noninvasive tool for early detection of lung cancer and characterization of suspicious lung nodules.

Background: Pulmonary adenocarcinoma, recently benefited by new cytotoxic and molecularly targeted drugs, has been classified by driver mutations, such as EGFR mutations. The aim of this study was to research the proportions of patients treated with first- to third-line chemotherapy and to find influential factors for the introduction of chemotherapy and survival benefit from chemotherapy.

Materials and methods: Data were collected retrospectively on patients who met the following criteria: adenocarcinoma, diagnosed between June 2007 and March 2015 at our hospital, stage IIIB or IV, and EGFR wild type. A nonchemotherapy group of patients who did not receive chemotherapy was compared with a chemotherapy group of patients who received it. The patients who had received first- to third-line chemotherapy between June 2007 and November 2015 at our hospital were also analyzed.

Results: During the study period, 46 patients did not receive chemotherapy, while 148, 89, and 48 received first-, second- and third-line chemotherapy, respectively. As predictive factors for unlikely chemotherapy, multivariate logistic analysis detected Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥2, hemoglobin <13.2 g/dL, creatinine clearance (Ccr) <50.4 mL/min, and CRP ≥0.53 mg/dL. As factors predicting shorter survival after chemotherapy, multivariate Cox proportional-hazard analyses detected age ≥75 years, ECOG PS ≥2, lower lymphocyte counts, and higher CRP for the first line; female, higher neutrophil counts, lower lymphocyte counts, reduced Ccr, hyponatremia, and shorter interval between first- and second-line chemotherapy for the second line; and age ≥75 years, body mass index <18.5 kg/m², higher neutrophil counts, lower lymphocyte counts, hyponatremia, higher lactate dehydrogenase, and higher CRP for the third line.

Conclusion: Approximately 76% of patients were treated with first-line chemotherapy. Of those patients, 61% and 34% proceeded to second- and third-line chemotherapy, respectively. For patients with poor PS, anemia, reduced Ccr, and higher CRP, it is difficult to introduce chemotherapy.

The treatment options for metastatic non-small-cell lung cancer (NSCLC) have expanded dramatically in the last 10 years with the discovery of newer drugs and targeted therapy. Epidermal growth factor receptor (EGFR), when aberrantly activated, promotes cell growth and contributes in various ways to the malignant process. EGFR has become an important therapeutic target in a variety of malignancies. Small-molecule tyrosine kinase inhibitors (TKIs) of EGFR are being used to treat advanced NSCLC and are particularly effective in the presence of EGFR mutations. Monoclonal antibodies have also been developed that block the EGFR at the cell surface and work in conjunction with chemotherapy. Necitumumab is a second-generation fully human IgG1 monoclonal antibody that has shown promise in metastatic NSCLC. The benefit has mostly been restricted to squamous cell lung cancer in the frontline setting. Considering that the survival advantage for these patients was modest, there is a need to discover biomarkers that will predict which patients will likely have the best outcomes. This review focuses on the development and clinical trial experience with necitumumab in NSCLC.

Lung cancer is the leading killer of both men and women in the US, and the 5-year survival remains poor. However, the approval of checkpoint blockade immunotherapy has shifted the treatment paradigm and provides hope for improved survival. The ability of non-small-cell lung cancer (NSCLC) to evade the host immune system can be overcome by agents such as pembrolizumab (MK-3475/lambrolizumab), which is a monoclonal antibody targeting the programmed death 1 (PD-1) receptor. In early studies, treatment with pembrolizumab led to dramatic and durable responses in select patients (PD-L1+ tumors). This remarkable efficacy lead to approval of pembrolizumab in the second-line setting as response rates were almost doubled compared to standard of care (SOC) chemotherapy. Most recently, data in the first-line setting from the KEYNOTE-024 study have redefined the SOC therapy for a selected subset of patients. In patients with ≥50% PD-L1+ tumors, pembrolizumab had a clear progression-free survival and overall survival benefit. Toxicity was mostly immune related and similar to checkpoint blockade toxicities observed in previous studies. The initial approval and subsequent studies of pembrolizumab required and utilized a companion diagnostic test, Dako's IHC 22C3, to assess PD-L1 status of patients. The evaluation and scoring system of this assay has been used by other companies as a reference to develop their own assays, which may complicate selection of patients. Finally, the impact of pembrolizumab in NSCLC is growing as evidenced by the numerous, ongoing trials open for combinations with chemotherapy, chemoradiation, other immunotherapeutics, immunomodulators, tyrosine kinase inhibitors, PI3K inhibitors, MEK inhibitors, hypomethylating agents, and histone deacetylase inhibitors. Further studies are also evaluating pembrolizumab in small-cell lung cancer and malignant pleural mesothelioma. This explosion of studies truly conveys the lack of therapeutic answers for lung cancer patients and the promise of pembrolizumab.