Scientific Advances in Thoracic Oncology 2016

Lung cancer care is rapidly changing with advances in genomic testing, the development of next-generation targeted kinase inhibitors, and the continued broad study of immunotherapy in new settings and potential combinations. The International Association for the Study of Lung Cancer and the Journal of Thoracic Oncology publish this annual update to help readers keep pace with these important developments. Experts in thoracic cancer and care provide focused updates across multiple areas, including prevention and early detection, molecular diagnostics, pathology and staging, surgery, adjuvant therapy, radiotherapy, molecular targeted therapy, and immunotherapy for NSCLC, SCLC, and mesothelioma. Quality and value of care and perspectives on the future of lung cancer research and treatment have also been included in this concise review.     

Update on International Cooperative Groups Studies in Thoracic Malignancies: The Emergence of Immunotherapy

Cancer cooperative groups have historically played a critical role in the advancement of non–small-cell lung cancer therapy. Representatives from cooperative groups worldwide convene at the International Lung Cancer Congress annually. The International Lung Cancer Congress had its 17th anniversary in the summer of 2016. The present review highlights the thoracic malignancy studies discussed by presenters. The included studies are merely a sample of the trials of thoracic malignancies ongoing globally.     

Serum levels of the angiogenic factor pleiotrophin in relation to disease stage in lung cancer patients.

Pleiotrophin is a heparin-binding growth factor involved in the differentiation and proliferation of neuronal tissue during embryogenesis, and also secreted by melanoma and breast carcinoma cells. Pleiotrophin exhibits mitogenic and angiogenic properties and has been shown to influence the vascular supply, expansion and metastasis of tumour cells. Our aim was to study the serum and plasma concentrations of pleiotrophin and the classical angiogenic growth factor vascular endothelial growth factor. Using a specific ELISA-test we studied patients with small cell lung cancer (n=63), and patients with non-small cell lung cancer (n=22) in comparison to healthy control subjects (n=41). In most of the lung cancer patients (81%), we found serum levels of pleiotrophin above those of control subjects (P<0.001). Of the 63 small cell lung cancer patients in the study pleiotrophin serum levels were elevated in 55 cases (87%) and in 14 cases (63%) of the 22 non-small cell lung cancer patients. Pleiotrophin mean serum concentrations were 10.8-fold higher in the tumour patient group as compared to the control group (P<0.001). Furthermore, pleiotrophin serum levels correlated positively with the stage of disease and inversely with the response to therapy. Plasma vascular endothelial growth factor concentrations were elevated in only in 28.6% of small cell lung cancer and 45.5% of non-small cell lung cancer patients by an average of 2.3-fold. Quite strikingly, there was no apparent correlation between the plasma vascular endothelial growth factor concentration and the stage of disease. Our study suggests that pleiotrophin may be an early indicator of lung cancer and might be of use in monitoring the efficacy of therapy, which needs to be confirmed by larger studies.     

Afatinib in NSCLC With HER2 Mutations: Results of the Prospective,Open-Label Phase II NICHE Trial of European Thoracic Oncology Platform (ETOP)

IntroductionMutations in erb-b2 receptor tyrosine kinase 2 (HER2) oncogene are observed in approximately 3% of lung adenocarcinomas or mixed tumors with adenocarcinoma component. Activity of various biologically distinct HER2 inhibitors, including the pan-HER inhibitor afatinib, has been reported in several retrospective trials or small series in advanced pretreated NSCLC with HER2 mutations. We report the first prospective evaluation of afatinib for the treatment of this molecularly defined entity.MethodsNICHE, a single-arm phase II trial using a two-stage Simon’s design, explored the potential of afatinib to control disease in pretreated patients with advanced NSCLC harboring HER2 exon 20 mutations. A total of 13 patients entered the trial and were treated with afatinib 40 mg/day until tumor progression or lack of tolerability.ResultsThe first-stage stopping boundary was crossed when five of nine patients did not achieve disease control at 12 weeks. The accrual into the trial was stopped with total 13 patients enrolled, with 7 (53.8%) achieving disease control at 12 weeks. Except for 1 patient with early death, progression was documented for all patients, with median progression-free survival of 15.9 weeks (95% confidence interval: 6.0–35.4), and median overall survival of 56.0 weeks (95% confidence interval: 16.3– upper limit not estimable). The toxicity profile was in the expected range.ConclusionsAfatinib did not show the expected potential for disease control in NSCLC. However, more than half of the patients in the full cohort achieved disease control at 12 weeks.     

Asian Thoracic Oncology Research Group Expert Consensus Statement on Optimal Management of Stage III NSCLC

Stage III NSCLC represents a heterogeneous disease for which optimal treatment continues to pose a clinical challenge. Recent changes in the American Joint Commission on Cancer staging to the eighth edition has led to a shift in TNM stage grouping and redefined the subcategories (IIIA–C) in stage III NSCLC for better prognostication. Although concurrent chemoradiotherapy has remained standard-of-care for stage III NSCLC for almost 2 decades, contemporary considerations include the impact of different molecular subsets of NSCLC, and the roles of tyrosine kinase inhibitors post-definitive therapy and of immune checkpoint inhibitors following chemoradiotherapy. With rapid evolution of diagnostic algorithms and expanding treatment options, the need for interdisciplinary input involving multiple specialists (medical oncologists, radiation oncologists, pulmonologists, radiologists, pathologists and thoracic surgeons) has become increasingly important. The unique demographics of Asian NSCLC pose further challenges when applying clinical trial data into clinical practice. This includes differences in smoking rates, prevalence of oncogenic driver mutations, and access to health care resources including molecular testing, prompting the need for critical review of existing data and identification of current gaps. In this expert consensus statement by the Asian Thoracic Oncology Research Group, an interdisciplinary group of experts representing Hong Kong, Korea, Japan, Taiwan, Singapore, Thailand, Malaysia, and Mainland China was convened. Standard clinical practices for stage III NSCLC across different Asian countries were discussed from initial diagnosis and staging through to multi-modality approaches including surgery, chemotherapy, radiation, targeted therapies, and immunotherapy.     

Progression-Free and Overall Survival for Concurrent Nivolumab With Standard Concurrent Chemoradiotherapy in Locally Advanced Stage IIIA-B NSCLC: Results From the European Thoracic Oncology Platform NICOLAS Phase II Trial (European Thoracic Oncology Platform 6-14)

IntroductionThe NICOLAS study is the first completed single-arm phase II trial in stage III NSCLC evaluating hierarchically first the safety and then the efficacy of adding nivolumab concurrently to standard definitive concurrent chemoradiotherapy. The safety end point was reported earlier; here, we present the efficacy results.MethodsStage IIIA-B unresectable treatment-naive patients with NSCLC received three cycles of platinum-based chemotherapy and concurrent radiotherapy (66 Gy, 33 fractions), along with nivolumab (360 mg, 3-weekly). Nivolumab was continued as monotherapy consolidation for a maximum of 1 year (480 mg, 4-weekly). The primary end point was 1-year progression-free survival (PFS), with a target improvement compared with historical data of at least 15%, from 45% to 60%. To test this efficacy hypothesis, a sample size of 74 assessable patients provided a power of 83% with a one-sided alpha of 5%.ResultsA total of 79 patients were enrolled with a median follow-up of 21.0 months (interquartile range: 15.8–25.8 mo) for the primary PFS analysis. A total of 35.4% of the patients had stage IIIA, and 63.3% had stage IIIB disease. The 1-year PFS was 53.7% (95% confidence interval [CI]: 42.0%–64.0%) and the median PFS was 12.7 months (95% CI: 10.1–22.8 mo). Because 37 PFS events occurred in the first year posttreatment among the first 74 assessable patients, a 1-year PFS rate of at least 45% could not be rejected (p = 0.23). At an extended follow-up (median 32.6 mo), 37 deaths have been recorded, with a median overall survival (OS) of 38.8 months (95% CI: 26.8 mo–not estimable) and a 2-year OS rate of 63.7% (95% CI: 51.9%–73.4%). The OS of patients with stage IIIA disease was found to be significantly higher than patients with stage IIIB disease, with a 2-year OS of 81% and 56%, respectively (p = 0.037).ConclusionsPFS and OS are arithmetically higher in studies involving the same population. However, on the basis of the formal hierarchical efficacy analysis, we could not reject that the 1-year PFS rate is at least 45%.     

Lack of any Association between Blood Groups and Lung Cancer,Independent of Histology

Introduction: Lung cancer, the leading cause of cancer deaths, is divided into 2 main classes based on itsbiology, therapy and prognosis: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Manycases are at an advanced stage at diagnosis, which is a major obstacle to improving outcomes. It is important todefine the high risk group patients for early diagnosis and chance of cure. Blood group antigens are chemicalcomponents on erythrocyte membranes but they are also expressed on a variety of epithelial cells. Links betweenABO blood groups with benign or malignant diseases, such as gastric and pancreas cancers, have been observedfor a long time. In this study, we aimed to investigate any possible relationship between lung cancer histologicalsubtypes and ABO-Rh blood groups. Materials and Methods: The files of 307 pathologically confirmed lungcancer patients were reviewed retrospectively. Cases with a serologically determined blood group and Rh factorwere included and those with a history of another primary cancer were excluded, leaving a total of 221. Thedistribution of blood groups of the lung cancer patients were compared with the distribution of blood groups ofhealthy donors admitted to the Turkish Red Crescent Blood Service in our city in the year 2012. Results: Therewas no significant difference between patients with lung cancer of either type and the control group in termsof distribution of ABO blood groups and Rh factor (p: 0.073). There was also no relationship with non smallcell cancer histological subtypes. Conclusions: In this study, we found no relationship between the ABO-Rhesusblood groups and NSCLC and SCLC groups. To our knowledge this is the first analysis of ABO blood groupsin SCLC patients.     

Geriatric Oncology Research in the Cooperative Groups: A Report of a SIOG Special Meeting

PURPOSE: The purpose of this meeting was to bring together geriatric oncology researchers in the cooperative groups to discuss the design of clinical trials to improve our knowledge of the efficacy and toxicity of cancer therapeutics in older adults with cancer. DESIGN: Meeting of cooperative group leaders in geriatric oncology research RESULTS: Several strategies were suggested to improve our knowledge of the efficacy and toxicity of cancer therapeutics in older adults. These include: 1) developing therapeutic studies for older adults who are not eligible for standard clinical trials (because of comorbidity or functional status), or for patients who are deemed to be at high risk for toxicity from standard therapy (frail or vulnerable); 2) identifying the age group of older adults who are underrepresented on clinical trials and developing trials specifically for these patients; 3) designing trials to include a certain proportion of older adults for subset analyses; and 4) including a geriatric assessment in therapeutic clinical trials in order to identify factors other than chronologic age that identify those older adults who are "vulnerable" (at risk for toxicity) and "fit" (able to tolerate cancer therapy without significant toxicity). CONCLUSIONS: To address knowledge gaps in geriatric oncology, national and international cooperative group leaders discussed strategies in clinical trial design to improve the evidence-based research and accrual of older adults. Linking the efforts among cooperative groups will expedite this progress, and this conference was a major first step toward this goal.     

Evaluating antiangiogenesis agents in the clinic: the Eastern Cooperative Oncology Group Portfolio of Clinical Trials.

Recent evidence indicates that treatment with a humanized monoclonal antibody (bevacizumab) directed at vascular endothelial growth factor improves response and survival in metastatic colorectal cancer when added to standard chemotherapy, validating angiogenesis as a therapeutic target. Investigators from the Eastern Cooperative Oncology Group (ECOG) have initiated a number of Phase III studies that will help further define the role of antiangiogenic agents for the treatment of breast, colon, lung, renal, and head and neck cancer, as well as melanoma and myeloma. The agents being evaluated target various biological functions involved in angiogenesis, including vascular endothelial growth factor (bevacizumab), endothelial cell proliferation (thalidomide, IFN-alpha), and matrix metalloproteinases (marimastat). These clinical trials include correlative laboratory studies aimed at elucidating how these agents may exert their clinical effects. The portfolio of Eastern Cooperative Oncology Group studies will serve to further define the role of this therapeutic strategy for patients with advanced cancer.     

Prognostic Impact of KRAS G12C Mutation in Patients With NSCLC: Results From the European Thoracic Oncology Platform Lungscape Project

IntroductionKRAS mutations, the most frequent gain-of-function alterations in NSCLC, are currently emerging as potential predictive therapeutic targets. The role of KRAS-G12C (Kr_G12C) is of special interest after the recent discovery and preclinical analyses of two different Kr_G12C covalent inhibitors (AMG-510, MRTX849).MethodsKRAS mutations were evaluated in formalin-fixed, paraffin-embedded tissue sections by a microfluidic-based multiplex polymerase chain reaction platform as a component of the previously published European Thoracic Oncology Platform Lungscape 003 Multiplex Mutation study, of clinically annotated, resected, stage I to III NSCLC. In this study, -Kr_G12C mutation prevalence and its association with clinicopathologic characteristics, molecular profiles, and postoperative patient outcome (overall survival, relapse-free survival, time-to-relapse) were explored.ResultsKRAS gene was tested in 2055 Lungscape cases (adenocarcinomas: 1014 [49%]) with I or II or III stage respective distribution of 53% or 24% or 22% and median follow-up of 57 months. KRAS mutation prevalence in the adenocarcinoma cohort was 38.0% (95% confidence interval (CI): 35.0% to 41.0%), with Kr_G12C mutation representing 17.0% (95% CI: 14.7% to 19.4%). In the "histologic-subtype" cohort, Kr_G12C prevalence was 10.5% (95% CI: 9.2% to 11.9%). When adjusting for clinicopathologic characteristics, a significant negative prognostic effect of Kr_G12C presence versus other KRAS mutations or nonexistence of KRAS mutation was identified in the adenocarcinoma cohort alone and in the "histologic-subtype" cohort. For overall survival in adenocarcinomas, hazard ratio (HR)_{G12C versus other KRAS} is equal to 1.39 (95% CI: 1.03 to 1.89, p = 0.031) and HR_{G12C versus no KRAS} is equal to 1.32 (95% CI: 1.03 to 1.69, p = 0.028) (both also significant in the "histologic-subtype" cohort). For time-to-relapse, HR_{G12C versus other KRAS} is equal to 1.41 (95% CI: 1.03 to 1.92, p = 0.030). In addition, among all patients, for relapse-free survival, HR_{G12C versus no KRAS} is equal to 1.27 (95% CI: 1.04 to 1.54, p = 0.017).ConclusionsIn this large, clinically annotated stage I to III NSCLC cohort, the specific Kr_G12C mutation is significantly associated with poorer prognosis (adjusting for clinicopathologic characteristics) among adenocarcinomas and in unselected NSCLCs.     

Incidence and Mortality of Lung Cancer Among Never Smokers in Relationship to Secondhand Smoking: Findings From the PLCO Trial

PurposeTo assess the impact of secondhand smoking on the incidence and mortality of lung cancer among never smokers enrolled onto the Prostate, Lung, Colorectal, and Ovary (PLCO) study.Patients and MethodsDeidentified data sets from the PLCO study were accessed and never smokers who completed the supplementary questionnaire’s questions related to history of exposure to secondhand smoking were included in the current study. Multivariate Cox regression analysis was conducted to evaluate the impact of adulthood and childhood secondhand smoking on lung cancer incidence and mortality.ResultsA total of 49,569 participants were included in the current analysis. Using multivariate Cox regression analysis, participants with secondhand smoking most of their work time had a higher risk of lung cancer diagnosis (hazard ratio, 2.038; 95% confidence interval, 1.313-3.164; P = .002). Likewise, participants with secondhand smoking most of their adult living time had a higher risk of lung cancer diagnosis (hazard ratio, 1.809; 95% confidence interval, 1.161-2.819; P = .009). Moreover, participants with secondhand smoking most of the adult time had a higher risk of death from lung cancer (hazard ratio, 1.925; 95% confidence interval, 1.035-3.575; P = .038). Participants with secondhand smoking most of the adult time were also more likely to have had hypertension (P < .001), diabetes mellitus (P < .001), heart attack (P < .001), stroke (P = .028), chronic bronchitis (P < .001), and emphysema (P < .001).ConclusionNever smokers with a history of adult secondhand smoking had a higher probability of a subsequent diagnosis of lung cancer. Likewise, never smokers with a history of adult secondhand smoking were more likely to die from lung cancer.     

Synchronous small cell carcinoma and adenocarcinoma of the lung representing different retinoblastoma tumor suppressor protein status

We report a case of synchronous primary lung cancers —small cell carcinoma and adenocarcinoma. We analyzed the expression of neuropeptides and tumor suppressor gene products in the two carcinomas, using immunohistochemistry. The small cell carcinoma showed absence of retinoblastoma (RB) tumor suppressor protein and the presence of neural differentiation-related protein, while the adenocarcinoma showed expression of RB protein with nuclear localization and the absence of neural protein. These results indicate that different carcinogenic steps may have been involved in the development of small cell carcinoma and adenocarcinoma in this patient.     

Dosing to rash: A phase II trial of the first-line erlotinib for patients with advanced non-small-cell lung cancer an Eastern Cooperative Oncology Group Study (E3503)

BackgroundThe development of a rash has been retrospectively associated with increased response and improved survival when treated with erlotinib at the standard dose of 150 mg per day. The objective of this trial was to evaluate the association of the activity of erlotinib in the first-line setting in patients with advanced non-small-cell lung cancer (NSCLC) with the development of a tolerable rash via dose escalation of erlotinib or tumour characteristics.MethodsPatients, with advanced NSCLC without prior systemic therapy, were treated with erlotinib 150 mg orally per day. The dose was increased by 25 mg every two weeks until the development of grade 2/tolerable rash or other dose limiting toxicity. Tumour biopsy specimens were required for inclusion.ResultsThe study enrolled 137 patients, 135 were evaluable for safety and 124 were eligible and evaluable for response. Only 73 tumour samples were available for analysis. Erlotinib dose escalation occurred in 69/124 patients. Erlotinib was well tolerated with 70% of patients developing a grade 1/2 rash and 10% developing grade 3 rash. Response rate and disease control rate were 6.5% and 41.1% respectively. Median overall survival was 7.7 months. Toxicity and tumour markers were not associated with response. Grade 2 or greater skin rash and low phosphorylated mitogen-activated protein kinase (pMAPK) were associated with improved survival.ConclusionsOverall survival was similar in this trial compared to first-line chemotherapy in this unselected patient population. Dose escalation to the development of grade 2 skin rash was associated with improved survival in this patient population.