Clinical insights into small cell lung cancer: Tumor heterogeneity, diagnosis, therapy, and future directions.

Small cell lung cancer (SCLC) is characterized by rapid growth and high metastatic capacity. It has strong epidemiologic and biologic links to tobacco carcinogens. Although the majority of SCLCs exhibit neuroendocrine features, an important subset of tumors lacks these properties. Genomic profiling of SCLC reveals genetic instability, almost universal inactivation of the tumor suppressor genes TP53 and RB1, and a high mutation burden. Because of early metastasis, only a small fraction of patients are amenable to curative-intent lung resection, and these individuals require adjuvant platinum-etoposide chemotherapy. Therefore, the vast majority of patients are currently being treated with chemoradiation with or without immunotherapy. In patients with disease confined to the chest, standard therapy includes thoracic radiotherapy and concurrent platinum-etoposide chemotherapy. Patients with metastatic (extensive-stage) disease are treated with a combination of platinum-etoposide chemotherapy plus immunotherapy with an anti-programmed death-ligand 1 monoclonal antibody. Although SCLC is initially very responsive to platinum-based chemotherapy, these responses are transient because of the development of drug resistance. In recent years, the authors have witnessed an accelerating pace of biologic insights into the disease, leading to the redefinition of the SCLC classification scheme. This emerging knowledge of SCLC molecular subtypes has the potential to define unique therapeutic vulnerabilities. Synthesizing these new discoveries with the current knowledge of SCLC biology and clinical management may lead to unprecedented advances in SCLC patient care. Here, the authors present an overview of multimodal clinical approaches in SCLC, with a special focus on illuminating how recent advancements in SCLC research could accelerate clinical development.

Immune checkpoint inhibitors as adjuvant therapy in patients with completely resected nonsmall cell lung cancer.

PURPOSE OF REVIEW: The purpose of the review is to summarize the current status of immune checkpoint inhibitors as adjuvant therapy in patients with resected nonsmall cell lung cancer (NSCLC). RECENT FINDINGS: The IMpower010 phase 3 trial demonstrated improved disease-free survival and, in case of PD-L1 at least 50%, also improved overall survival for atezolizumab compared to best supportive care among patients with completely resected stage II-IIIA NSCLC. The PEARLS/KEYNOTE-091 trial showed increased disease-free survival for pembrolizumab among patients with stage IB-IIIA NSCLC. Trials with nivolumab and durvalumab are ongoing. SUMMARY: Atezolizumab or pembrolizumab have become options for adjuvant therapy in patients with completely resected NSCLC.

Immunotherapy combinations in advanced nonsmall cell lung cancer.

PURPOSE OF REVIEW: The purpose of the review is to summarize immunotherapy combinations in advanced nonsmall cell lung cancer (NSCLC). RECENT FINDINGS: First-line platinum-based chemotherapy plus an immune checkpoint inhibitor has improved progression-free and overall survival compared to chemotherapy alone in patients with advanced NSCLC. Although the benefits appear to increase with higher programmed death ligand 1 (PD-L1) expression, patients with low PD-L1 also benefit. Nivolumab plus ipilimumab has also been established as a treatment option. Combinations of immune checkpoint inhibitors with olaparib or lenvatinib are studied within phase 3 trials. SUMMARY: Platinum-based doublets combined with an immune checkpoint inhibitor have become standard first-line therapy. Other combinations are under clinical development.

Chemotherapy remains a cornerstone in the treatment of nonsmall cell lung cancer.

PURPOSE OF REVIEW: The purpose of the review is to summarize the current and future role of chemotherapy in the treatment of patients with nonsmall cell lung cancer (NSCLC). RECENT FINDINGS: Chemotherapy has been established in early-stage, locally advanced and metastatic NSCLC. Patients with driver mutation-positive NSCLC receive tyrosine kinase inhibitors as first-line therapy and chemotherapy later during the course of their disease. Immune checkpoint inhibitors have entered clinical practice as single agents or in combination with chemotherapy. These novel treatments will supplement chemotherapy in all tumor stages of NSCLC. SUMMARY: Targeted drugs and immune checkpoint inhibitors are gaining increasing importance in the treatment of NSCLC. They will supplement but not replace chemotherapy in the future.

Beyond tissue biopsy: a diagnostic framework to address tumor heterogeneity in lung cancer.

PURPOSE OF REVIEW: The objective of this review is to discuss the strength and limitations of tissue and liquid biopsy and functional imaging to capture spatial and temporal tumor heterogeneity either alone or as part of a diagnostic framework in non-small cell lung cancer (NSCLC). RECENT FINDINGS: NSCLC displays genetic and phenotypic heterogeneity - a detailed knowledge of which is crucial to personalize treatment. Tissue biopsy often lacks spatial and temporal resolution. Thus, NSCLC needs to be characterized by complementary diagnostic methods to resolve heterogeneity. Liquid biopsy offers detection of tumor biomarkers and for example, the classification and monitoring of EGFR mutations in NSCLC. It allows repeated sampling, and therefore, appears promising to address temporal aspects of tumor heterogeneity. Functional imaging methods and emerging image analytic tools, such as radiomics capture temporal and spatial heterogeneity. Further standardization of radiomics is required to allow introduction into clinical routine. SUMMARY: To augment the potential of precision therapy, improved diagnostic characterization of tumors is pivotal. We suggest a comprehensive diagnostic framework combining tissue and liquid biopsy and functional imaging to address the known aspects of spatial and temporal tumor heterogeneity on the example of NSCLC. We envision how this framework might be implemented in clinical practice.

Expenditures on Oncology Drugs and Cancer Mortality-to-Incidence Ratio in Central and Eastern Europe.

BACKGROUND: There is a steady decline in cancer mortality in Western Europe (WE), but this trend is not so obvious in Central and Eastern Europe (CEE). One of the largest discrepancies between WE and CEE is the level of investment in cancer care. The objective of our analysis was to examine the correlation between mortality-to-incidence (M/I) ratio and expenditures on oncology drugs in CEE and WE. MATERIALS AND METHODS: This cross-sectional analysis was done on publicly available data. Data on expenditures for oncology drugs were obtained from QuintilesIMS, and data on M/I ratio from Globocan. The main outcome was mortality-to-incidence ratio, and the primary analysis was performed by Spearman's rank correlation. RESULTS: There is a large discrepancy in expenditure on oncology drugs per cancer case between WE and CEE, and within CEE. Average expenditure on oncology drugs per capita as well as per new cancer case was 2.5 times higher in WE than in CEE. Availability of oncology drugs was highest in Germany (100%), relatively similar in WE (average of 91%), but in CEE it ranged from 37% to 86%, with an average of 70%. Annual expenditures on all oncology drugs per new cancer case was significantly negatively correlated with the M/I ratio (Spearman's ρ = -0.90, p < .001). CONCLUSION: There is a financial threshold for oncology drugs per cancer case needed to increase survival. Based on significantly lower expenditures for oncology drugs in CEE in comparison with WE, more investment for drugs as well as better, more organized, value- oriented consumption is needed. IMPLICATIONS FOR PRACTICE: Cancer is not treated equally successfully in Western Europe (WE) and in Central and Eastern Europe (CEE). This study showed that success in treatment of cancer is associated with the amount of money invested in oncology drugs. CEE countries spend on average 2.5 times less than WE countries for oncology drugs per new cancer case. These findings should be used by health care providers and oncologists struggling for more resources and better, more organized, evidence-based allocation of these resources as well as better oncology outcomes.

Biomarkers for immune checkpoint inhibitors in advanced nonsmall cell lung cancer.

PURPOSE OF REVIEW: Immune checkpoint inhibitors have been established as a new class of anticancer drugs for patients with advanced nonsmall cell lung cancer. Predictive biomarkers might help to select those patients who will derive the greatest benefit from these expensive drugs. This review summarizes the current status of predictive biomarkers for immune checkpoint inhibitors in advanced nonsmall cell lung cancer. RECENT FINDING: Programmed death ligand 1 (PD-L1) staining on tumor cells and immune cells has been studied as a predictive biomarker for immune checkpoint inhibitors. Higher PD-L1 levels appeared to be associated with greater benefit from these drugs in many studies, although such an association was absent in some studies. Tumor mutational load was associated with benefit from the combination of nivolumab plus ipilimumab. Immune checkpoint inhibitors combined with first-line chemotherapy improved survival compared to chemotherapy alone. These improvements were clinically relevant also in patients with PD-L1 expression in less than 1% of tumor cells. SUMMARY: PD-L1 expression on tumor and immune cells and tumor mutational load allow better selection of patients for treatment with immune checkpoint inhibitors as single agents. The role of PD-L1 for the selection of patients for chemoimmuntherapy remains to be seen.

Frequency, risk factors, and impact on mortality of arterial thromboembolism in patients with cancer.

In contrast to venous thromboembolism, little is known about arterial thromboembolism in patients with cancer. The aim of this study was to quantify the risk and explore clinical risk factors of arterial thromboembolism in patients with cancer, and investigate its potential impact on mortality. Patients with newly-diagnosed cancer or progression of disease after remission were included in a prospective observational cohort study and followed for two years. Between October 2003 and October 2013, 1880 patients (54.3% male; median age 61 years) were included. During a median follow up of 723 days, 48 (2.6%) patients developed arterial thromboembolism [20 (41.7%) myocardial infarction, 16 (33.3%) stroke and 12 (25.0%) peripheral arterial events], 157 (8.4%) developed venous thromboembolism, and 754 (40.1%) patients died. The cumulative 3-, 6-, 12-, and 24-month risks of arterial thromboembolism were 0.9%, 1.1%, 1.7%, and 2.6%, respectively. Male sex (subdistribution hazard ratio=2.9, 95%CI: 1.5-5.6; P=0.002), age (subdistribution hazard ratio per 10 year increase=1.5, 1.2-1.7; P<0.001), hypertension (3.1, 1.7-5.5; P<0.001), smoking (2.0, 1.1-3.7; P=0.022), lung cancer (2.3, 1.2-4.2; P=0.009), and kidney cancer (3.8, 1.4-10.5; P=0.012) were associated with a higher arterial thromboembolism risk. Furthermore, the occurrence of arterial thromboembolism was associated with a 3.2-fold increased risk of all-cause mortality (hazard ratio=3.2, 95%CI: 2.2-4.8; P<0.001). Arterial thromboembolism is a less common complication in patients with cancer than venous thromboembolism. The risk of arterial thromboembolism is high in patients with lung and kidney cancer. Patients with cancer who develop arterial thromboembolism are at a 3-fold increased risk of mortality.

Personalized treatment of advanced non-small-cell lung cancer in routine clinical practice.

Personalized treatment of patients with advanced non-small-cell lung cancer based on clinical and molecular tumor features has entered clinical routine practice. The 2015 pathological classification of lung cancer mandates immunohistochemical and molecular analysis. Therapeutic strategies focused on inhibition of angiogenesis and growth factor receptor signaling. Inhibitors of angiogenesis and monoclonal antibodies directed against the epidermal growth factor receptor have shown efficacy in combination with chemotherapy. Mutations in the epidermal growth factor receptor and anaplastic lymphoma kinase have become clinically relevant therapeutic targets. Immune checkpoint inhibitors are also entering routine clinical practice. Identification of predictive biomarkers is essential and faces several challenges including tumor heterogeneity and dynamic changes of tumor features over time. Liquid biopsies may overcome some of these challenges in the future.

Trimodality therapy for Pancoast tumors: T4 is not a contraindication to radical surgery.

OBJECTIVE: This study aims to evaluate the impact of T stage and extended surgery on the outcome of patients with Pancoast tumors after induction chemoradiation therapy. METHODS: Forty-six consecutive patients who underwent chemoradiation therapy (platin-based, 45-66 Gy) followed by surgery between 1998 and 2013 were retrospectively reviewed and analyzed. RESULTS: In 28 (61%) patients with T4 tumors, extended procedures (more than rib resection) were performed. There were 37 (80%) lobectomies, 6 (13%) pneumonectomies, and 3 (7%) sublobar resections. A total of 44 (96%) patients had R0 resection. About 30-day mortality was 0%, major surgical complications occurred in 9 (19.6%) patients. Overall survival (OS) at 5-years was 63%. Disease-free survival (DFS) at 5-years was 45%. At multivariate cox regression analysis adjusted for clinical factors, T factor (T3/T4) and extended surgical procedures did not impact survival. However, pathological positive N stage had a negative impact on OS and lack of pathological response negatively impacted both OS and DFS. CONCLUSION: Trimodality treatment including radical resection for Pancoast tumors provides good surgical outcome and favorable long-term results. Survival of patients with T4 tumors and extended surgical procedures comparable to that of patients with T3 tumors undergoing rib resection only.

Cancer Control in Central and Eastern Europe: Current Situation and Recommendations for Improvement.

: The incidence of many cancers is higher in Western European (WE) countries, but mortality is frequently higher in Central and Eastern European (CEE) countries. A panel of oncology leaders from CEE countries participating in the South Eastern European Research Oncology Group (SEEROG) was formed in 2015, aiming to analyze the current status and trends of oncology care in CEE and to propose recommendations leading to improved care and outcomes. The SEEROG panel, meeting during the 11th Central European Oncology Congress, proposed the following: (a) national cancer control plans (NCCPs) required in all CEE countries, defining priorities in cancer care, including finance allocation considering limited health care budgets; (b) national cancer registries, describing in detail epidemiological trends; (c) efforts to strengthen comprehensive cancer centers; (d) that multidisciplinary care should be mandated by the NCCPs; (e) that smaller hospitals should be connected to multidisciplinary tumor boards via the Internet, providing access to specialized expertise; (f) nationwide primary prevention programs targeting smoking, obesity, and alcohol consumption and centrally evaluated secondary prevention programs for cervical, colorectal, and breast cancers; (g) prioritize education for all involved in cancer care, including oncology nurses, general practitioners, and palliative care providers; (h) establish outpatient care in day hospitals to reduce costs associated with the current inpatient model of care in CEE countries and to improve patients' quality of life; (i) long-term pharmacoeconomic evaluations of new therapies in CEE countries; (j) increase national oncology budgets in view of the higher mortality rates in CEE compared with WE countries; and (k) CEE countries urgently need help from the European Union to increase and monitor overall investment in cancer care. IMPLICATIONS FOR PRACTICE: Significant differences in cancer incidence and mortality have been observed between European countries. While the incidence of many cancer types is higher in Western European (WE) countries, the mortality is generally higher in Central and Eastern Europe (CEE). The primary purpose of this review was to describe the current status and trends of oncology care in the CEE region, to raise awareness among physicians, regulators, and payers, and to propose the most needed changes in order to make the oncology care in CEE closer to the WE standards.

ERCC1 isoform expression and DNA repair in non-small-cell lung cancer.

BACKGROUND: The excision repair cross-complementation group 1 (ERCC1) protein is a potential prognostic biomarker of the efficacy of cisplatin-based chemotherapy in non-small-cell lung cancer (NSCLC). Although several ongoing trials are evaluating the level of expression of ERCC1, no consensus has been reached regarding a method for evaluation. METHODS: We used the 8F1 antibody to measure the level of expression of ERCC1 protein by means of immunohistochemical analysis in a validation set of samples obtained from 494 patients in two independent phase 3 trials (the National Cancer Institute of Canada Clinical Trials Group JBR.10 and the Cancer and Leukemia Group B 9633 trial from the Lung Adjuvant Cisplatin Evaluation Biology project). We compared the results of repeated staining of the entire original set of samples obtained from 589 patients in the International Adjuvant Lung Cancer Trial Biology study, which had led to the initial correlation between the absence of ERCC1 expression and platinum response, with our previous results in the same tumors. We mapped the epitope recognized by 16 commercially available ERCC1 antibodies and investigated the capacity of the different ERCC1 isoforms to repair platinum-induced DNA damage. RESULTS: We were unable to validate the predictive effect of immunostaining for ERCC1 protein. The discordance in the results of staining for ERCC1 suggested a change in the performance of the 8F1 antibody since 2006. We found that none of the 16 antibodies could distinguish among the four ERCC1 protein isoforms, whereas only one isoform produced a protein that had full capacities for nucleotide excision repair and cisplatin resistance. CONCLUSIONS: Immunohistochemical analysis with the use of currently available ERCC1 antibodies did not specifically detect the unique functional ERCC1 isoform. As a result, its usefulness in guiding therapeutic decision making is limited. (Funded by Eli Lilly and others.).

Third-generation epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer.

PURPOSE OF REVIEW: Patients with epidermal growth factor receptor (EGFR) mutation-positive nonsmall cell lung cancer (NSCLC) develop resistance during therapy with EGFR tyrosine kinase inhibitors (TKIs). In about half of the patients, this resistance is because of the emergence of the T790M mutation. Third-generation TKIs are active against EGFR-activating mutations and the T790M resistance mutation and have only limited efficacy against wild-type EGFR. Here we review the current status of the clinical development of these novel TKIs. RECENT FINDINGS: Third-generation TKIs in clinical development include osimertinib, rociletinib, and HM61713. Osimertinib and rociletinib have shown clinical efficacy in phase I/II trials in patients who had acquired resistance to first- or second-generation TKIs. Both TKIs are currently further evaluated in phase III trials as first-line or second-line therapy in patients with advanced EGFR mutation-positive NSCLC. HM61713 is in early clinical development. SUMMARY: Third-generation EGFR TKIs have shown activity in patients with acquired resistance to first- and second-generation EGFR TKIs and may further improve clinical outcome in patients with advanced EGFR mutation-positive NSCLC.

Epidermal growth factor receptor-directed monoclonal antibodies in nonsmall cell lung cancer: an update.

PURPOSE OF REVIEW: The epidermal growth factor receptor (EGFR) is overexpressed in many nonsmall cell lung cancers (NSCLCs). Blockade of EGFR by monoclonal antibodies has been studied as a strategy to improve the outcome of first-line chemotherapy in patients with NSCLC. The present review updates the findings from phase III trials. RECENT FINDINGS: Cetuximab improved survival when combined with first-line chemotherapy and this benefit was limited to patients with high EGFR expression in their tumors. A Southwest Oncology Group study currently prospectively evaluates the predictive biomarkers for cetuximab. In the SQUIRE phase III trial, necitumumab added to cisplatin and gemcitabine increased the survival in patients with advanced squamous cell NSCLC. The INSPIRE trial studied chemotherapy with and without necitumumab in patients with nonsquamous NSCLC but was prematurely halted because of increased thromboembolic events with chemotherapy and necitumumab. SUMMARY: EGFR monoclonal antibodies improved the outcome including survival in selected patients with advanced NSCLC. Prospective validation of predictive biomarkers is ongoing.

What is the best strategy for targeting EGF receptors in non-small-cell lung cancer?

EGF receptors (EGFRs) are often overexpressed or constitutively activated in non-small-cell lung cancer, and are an important therapeutic target. EGFR signaling can be blocked with tyrosine kinase inhibitors (TKIs) and anti-EGFR antibodies. Three EGFR-TKIs are approved as initial monotherapies in patients with EGFR-activating mutations, and erlotinib has a role as maintenance and second-line therapy. Investigational anti-EGFR monoclonal antibodies plus standard first-line therapy improve survival in patients with advanced non-small-cell lung cancer, especially in tumors with high EGFR expression. Anti-EGFR antibodies inhibit EGFR signaling and have the potential to stimulate antibody-dependent cell-mediated cytotoxicity. Multikinase TKIs are investigational as first- and second-line therapies, as monotherapies and in combination with chemotherapy. This article summarizes the available clinical data for EGFR-targeted therapies.

Novel drugs against non-small-cell lung cancer.

PURPOSE OF REVIEW: Important therapeutic advances for patients with advanced non-small-cell lung cancer (NSCLC) with focus on individualized therapy have recently occurred and are summarized in this review. RECENT FINDINGS: Cetuximab added to first-line chemotherapy has been shown to improve survival in patients with high epidermal growth factor receptor (EGFR) expression in their tumors. Afatinib has shown improved progression-free survival and better quality of life compared to chemotherapy in patients with EGFR-mutation-positive adenocarcinomas. Several other EGFR-directed agents are in clinical development. Crizotinib improved progression-free survival compared to second-line chemotherapy with docetaxel or pemetrexed in patients with advanced anaplastic lymphoma kinase-positive NSCLC. Selumetinib added to docetaxel has improved outcome compared with docetaxel in a randomized phase II trial in patients with advanced KRAS-mutant NSCLC and this combination is currently studied in a phase III trial. Nintedanib added to docetaxel improved progression-free survival in the second-line therapy of patients with advanced NSCLC but many other angiogenesis inhibitors failed to improve clinical outcome in phase III trials. Several other targeted therapies are currently evaluated in phase III trials in patients with advanced NSCLC. SUMMARY: Recent trials have led to the approval of afatinib and crizotinib for subsets of patients with advanced NSCLC.