sSupplementary Legends for Figures 1-5 from Cetuximab Attenuates Metastasis and u-PAR Expression in Non–Small Cell Lung Cancer: u-PAR and E-Cadherin are Novel Biomarkers of Cetuximab Sensitivity

PurposeCisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non–small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting.Patients and MethodsThis noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m2on day 1 and gemcitabine 1,250 mg/m2on days 1 and 8 (n = 863) or cisplatin 75 mg/m2and pemetrexed 500 mg/m2on day 1 (n = 862) every 3 weeks for up to six cycles.ResultsOverall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P ≤ .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common.ConclusionIn advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type.

Purpose: Patients with malignant pleural mesothelioma, a rapidly progressing malignancy with a median survival time of 6 to 9 months, have previously responded poorly to chemotherapy. We conducted a phase III trial to determine whether treatment with pemetrexed and cisplatin results in survival time superior to that achieved with cisplatin alone. Patients and Methods: Chemotherapy-naive patients who were not eligible for curative surgery were randomly assigned to receive pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day 1, or cisplatin 75 mg/m2 on day 1. Both regimens were given intravenously every 21 days. Results: A total of 456 patients were assigned: 226 received pemetrexed and cisplatin, 222 received cisplatin alone, and eight never received therapy. Median survival time in the pemetrexed/cisplatin arm was 12.1 months versus 9.3 months in the control arm (P = .020, two-sided log-rank test). The hazard ratio for death of patients in the pemetrexed/cisplatin arm versus those in the control arm was 0.77. Median time to progression was significantly longer in the pemetrexed/cisplatin arm: 5.7 months versus 3.9 months (P = .001). Response rates were 41.3% in the pemetrexed/cisplatin arm versus 16.7% in the control arm (P < .0001). After 117 patients had enrolled, folic acid and vitamin B12 were added to reduce toxicity, resulting in a significant reduction in toxicities in the pemetrexed/cisplatin arm. Conclusion: Treatment with pemetrexed plus cisplatin and vitamin supplementation resulted in superior survival time, time to progression, and response rates compared with treatment with cisplatin alone in patients with malignant pleural mesothelioma. Addition of folic acid and vitamin B12 significantly reduced toxicity without adversely affecting survival time.

Epigenetic research has the potential to improve our understanding of the pathogenesis of cancer, specifically non-small-cell lung cancer, and support our efforts to personalize the management of the disease. Epigenetic alterations are expected to have relevance for early detection, diagnosis, outcome prediction, and tumor response to therapy. Additionally, epi-drugs as therapeutic modalities may lead to the recovery of genes delaying tumor growth, thus increasing survival rates, and may be effective against tumors without druggable mutations. Epigenetic changes involve DNA methylation, histone modifications, and the activity of non-coding RNAs, causing gene expression changes and their mutual interactions. This systematic review, based on 110 studies, gives a comprehensive overview of new perspectives on diagnostic (28 studies) and prognostic (25 studies) epigenetic biomarkers, as well as epigenetic treatment options (57 studies) for non-small-cell lung cancer. This paper outlines the crosstalk between epigenetic and genetic factors as well as elucidates clinical contexts including epigenetic treatments, such as dietary supplements and food additives, which serve as anti-carcinogenic compounds and regulators of cellular epigenetics and which are used to reduce toxicity. Furthermore, a future-oriented exploration of epigenetic studies in NSCLC is presented. The findings suggest that additional studies are necessary to comprehend the mechanisms of epigenetic changes and investigate biomarkers, response rates, and tailored combinations of treatments. In the future, epigenetics could have the potential to become an integral part of diagnostics, prognostics, and personalized treatment in NSCLC.

Background: Several strategies have been investigated to improve the 4% survival advantage of adjuvant chemotherapy in early-stage non-small-cell lung cancer (NSCLC). In this investigator-initiated study we aimed to evaluate the predictive utility of the messenger RNA (mRNA) expression levels of excision repair cross complementation group 1 (ERCC1) and thymidylate synthase (TS) as assessed in resected tumor. Patients and methods: Seven hundred and seventy-three completely resected stage II-III NSCLC patients were enrolled and randomly assigned in each of the four genomic subgroups to investigator's choice of platinum-based chemotherapy (C, n = 389) or tailored chemotherapy (T, n = 384). All anticancer drugs were administered according to standard doses and schedules. Stratification factors included stage and smoking status. The primary endpoint of the study was overall survival (OS). Results: Six hundred and ninety patients were included in the primary analysis. At a median follow-up of 45.9 months, 85 (24.6%) and 70 (20.3%) patients died in arms C and T, respectively. Five-year survival for patients in arms C and T was of 65.4% (95% CI (confidence interval): 58.5% to 71.4%) and 72.9% (95% CI: 66.5% to 78.3%), respectively. The estimated hazard ratio (HR) was 0.77 (95% CI: 0.56-1.06, P value: 0.109) for arm T versus arm C. HR for recurrence-free survival was 0.89 (95% CI: 0.69-1.14, P value: 0.341) for arm T versus arm C. Grade 3-5 toxicities were more frequently reported in arm C than in arm T. Conclusion: In completely resected stage II-III NSCLC tailoring adjuvant chemotherapy conferred a non-statistically significant trend for OS favoring the T arm. In terms of safety, the T arm was associated with better efficacy/toxicity ratio related to the different therapeutic choices in the experimental arm.

Neoadjuvant therapy can improve outcome by increasing the resection rate, down staging the primary tumor and improving postoperative survival. PD-1/PD-L1 inhibitors have been approved in the treatment of advanced lung cancer, breast cancer, melanoma and other common cancers, and its success has moved immunotherapy forward to the early stage setting. In this study, we summarized the ongoing clinical trials which focus on neoadjuvant immunotherapy in solid cancers, and discussed their treatment strategy, efficacy and adverse events.

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.

A substantial proportion of patients with nononcogene-addicted non-small-cell lung cancer (NSCLC) has 'aggressive disease', as reflected in short time to progression or lack of disease control with initial platinum-based chemotherapy. Recently, clinical correlates of aggressive disease behavior during first-line therapy have been shown to predict greater benefit from addition of nintedanib to second-line docetaxel in adenocarcinoma NSCLC. Positive predictive effects of aggressive disease have since been reported with other anti-angiogenic agents (ramucirumab and bevacizumab), while such features may negatively impact on outcomes with nivolumab in nonsquamous NSCLC with low PD-L1 expression. Based on a review of the clinical data, we recommend aggressive nonsquamous NSCLC should be defined by progression within <6-9 months of first-line treatment initiation. Lay abstract: Chemotherapy with platinum-containing drugs was for many years the standard initial treatment for advanced NSCLC. Today's treatment options also include drugs that help the immune system to attack the cancer ('immunotherapies'). These drugs may be used with or without chemotherapy, depending on the molecular profile of the tumor. However, many patients have a fast-growing ('aggressive') form of NSCLC and so gain little benefit from initial chemotherapy. This patient subgroup has often been overlooked in clinical research to date. In this article, we discuss how 'aggressive NSCLC' can be defined and consider how many patients are affected. We also look at the impact of aggressive disease on the effectiveness of other treatments used after initial chemotherapy. Based on a thorough review of the evidence, we recommend that patients who need to change treatment within 6-9 months of starting initial therapy should be defined as having aggressive NSCLC. We hope this definition can help doctors to recognize aggressive tumors and adapt treatment accordingly to improve patients' outcome.

This article is the result of a round table discussion held at the European Lung Cancer Conference (ELCC) in Geneva in May 2017. Its purpose is to explore and discuss the advances in the knowledge about the biology and treatment of brain metastases originating from non-small cell lung cancer. The authors propose a series of recommendations for research and treatment within the discussed context.

Objectives: To investigate whether low-dose computed tomography (LDCT) screening is capable of enhancing the detection rate of early-stage lung cancer in high-risk population of China with both smoking and non-smoking related factors. Methods: From 2013-2014, eligible participants with high-risk factors of lung cancer were randomly assigned to a screening group or a control group with questionnaire inquiries. Any non-calcified nodules or masses with longest diameters of >= 4 mm identified on LDCT images were considered a; positive. Results: A total of 6717 eligible participants were randomly enrolled to a study group (3550 to LDCT screening and 3167 to standard care). 3512 participants (98.9%) underwent LDCT screening, and 3145 participants (99.3%) received questionnaire inquiries. A positive screening result was observed in 804 participants (22.9%). In the two-year follow-up period, lung cancer was detected in 51 participants (1.5%) in the LDCT group versus 10 (0.3%) in the control group (stage I: 48 vs 2; stage II to IV or limited stage: 3 vs 8), respectively. Early-stage lung cancer was found in 94.1% vs 20%, respectively. Conclusions: Compared to usual care, LDCT led to a 74.1% increase in detecting early-stage lung cancer. This study provides insights about the non-smoking related risk factors of lung cancer in the Chinese population.

Over the past few years, there have been considerable advances in the treatments available to patients with metastatic or locally advanced NSCLC, particularly those who have progressed during first-line treatment. Some of the treatment options available to patients are discussed here, with a focus on checkpoint inhibitor immunotherapies (nivolumab and pembrolizumab) and antiangiogenic agents (bevacizumab, ramucirumab, and nintedanib). It is hypothesized that combining immunotherapy with antiangiogenic treatment may have a synergistic effect and enhance the efficacy of both treatments. In this review, we explore the theory and potential of this novel treatment option for patients with advanced NSCLC. We discuss the growing body of evidence that proangiogenic factors can modulate the immune response (both by reducing T-cell infiltration into the tumor microenvironment and through systemic effects on immune-regulatory cell function), and we examine the preclinical evidence for combining these treatments. Potential challenges are also considered, and we review the preliminary evidence of clinical efficacy and safety with this novel combination in a variety of solid tumor types.

Medical therapy in advanced NSCLC in 2016 is characterized by personalization, individualization, and therapy precision. Not only clinical factors are used for treatment differentiation but also the histological type (squamous versus non-squamous) and the molecular profile (mutant versus wild type). In addition, the complexity of the treatment algorithm has gradually increased over time by the incorporation of a number of approved molecules for 1st, 2nd -, subsequent line therapy (Peters, 2012; Masters, 2015; NCCN, 2016). NSCLC – 1st-line-therapy – wild-type: For patients with wild-type non-squamous NSCLC it is generally accepted that upfront platinum based doublet chemotherapy (DCT) remains the backbone for individuals with good performance and that this approach should be modified according to feasibility and tolerability, co-morbidity, and age over 70 years. Progress has been made through pemetrexed, which is recommended as the favorite partner of platinum-based components (Scagliotti; 2008/2011). In addition, it has lately been demonstrated that the extension of induction chemotherapy by single agent pemetrexed until progression – in case of non-progression under four cycles of DCT not containing pemetrexed (switch maintenance) (Ciuleanu, 2009) or containing pemetrexed (continuation maintenance) (Paz-Ares, 2012/2013) – prolongs survival. In this case survival may also be prolonged by erlotinib, when used in the switch maintenance setting, but erlotinib's benefit seem to be restricted to patients, which have experienced disease stabilization to induction chemotherapy (Cappuzzo, 2010; Coudert, 2012). Bevacizumab, when added to platinum-based to DCT, significantly improves response rate, progression free survival, as well as overall survival in eligible patients (Sandler, 2006/2010; Reck, 2009/2010). In wild-type squamous NSCLC platinum based DCT (no pemetrexed, no bevacizumab) remains standard. Nonetheless, necitumumab has recently shown to improve survival when combined with cisplatin/gemcitabine (Thatcher, 2015). Maintenance therapy in squamous tumors with docetaxel or erlotinib (switch) or gemcitabine (continuation) may be justified in some patients even so study evidence is weaker than for non-squamous tumors (Fidas, 2009; Perol, 2012). NSCLC – 1st-line-therapy - mutant: For patients with advanced NSCLC expressing specific molecular features – mainly non-squamous tumors – 1st-line treatment with targeted agents has been established. In tumors with EGFR mutations gefitinib, erlotinib, and afatinib have shown to prolong progression free survival over standard chemotherapy (Mok, 2009; Rosell, 2012; Sequist, 2013). In tumors bearing ALK-/ROS1-gene-rearrangements crizotinib has also shown to prolong progression free survival when compared to platinum/pemetrexed. (Solomon, 2014). Therefore, erlotinib, gefitinib or afatinib should be prescribed for patients with tumors bearing EGFR-mutations. For patients with tumors bearing ALK-/ROS1 crizotinib should be prescribed. However, for these patients molecular testing is critical and should be used to select patients for EGFR/ALK/ROS1 targeted therapy. Patients with lung adenocarcinoma should not be excluded from testing on the basis of clinical characteristics (ethnicity, gender, smoking status) (Lindeman, 2013). NSCLC - 2nd /subsequent-line therapy - wild-type: In patients with disease progression during or after completion of 1st -line chemotherapy, 2nd-, subsequent-line therapy is indicated when the patient remains in good clinical condition. Approved older treatment options include docetaxel, pemetrexed and erlotinib. Two anti-angiogenic agents and two immune-checkpoint inhibitors have recently been added. These include nintedanib and ramucirumab (Reck, 2014; Thatcher, 2015), as well as nivolumab and pembrolizumab (Brahmer, 2015; Borghaei, 2015; Herbst, 2016). Nintedanib/docetaxel increases significantly survival in patients with adenocarcinoma who specifically progressed within 9 months after the start of 1st-line therapy, who have experienced disease progression as best response to 1st-line therapy and decreases tumor burden and decelerates tumor growth. Nintedanib/docetaxel has been approved in the EU for the treatment of patients with adenocarcinoma. Ramucirumab/docetaxel has also been approved in the US and EU for patients with disease progression on or after DCT for wild-type non-squamous and squamous NSCLC. This approval has been based on phase III study evidence indicating survival advantage in non-squamous NSCLC (statistically significant) and squamous NSCLC (numerically longer). Comparing head-to head nivolumab and docetaxel in patients with squamous and non-squamous NSCLC after failure of DCT has demonstrated superior overall survival in patients receiving nivolumab. Nivolumab has received US and EU approval for advanced NSCLC with progression on or after DCT. Nivolumab appears to be most effective in patients with more than 6 months from completion of the latest treatment regimen to randomization in comparison to patients with less than 3 months to randomization. Pembrolizumab has received approval in the US and EU for patients with advanced NSCLC who's tumors expressed PD-L1 and who have disease progression on or after chemotherapy. Approval has been based on head-to-head comparison of pembrolizumab and docetaxel in patients with previously treated PD-L1 positive squamous and non-squamous NSCLC, which has demonstrated a significant survival benefit for pembrolizumab. NSCLC-2nd/subsequent-line therapy - mutant: Resistance to first and second generation EGFR-TKIs is a multifactorial process with a variety of clinically patterns. Its management requires different, case adapted approaches. Several strategies are currently under investigation, but some have already find its way into todays practice although study evidence is still rather weak. In case of oligoprogression the EGFR-TKI therapy may continue but local therapies (radiation, surgery) should be added. In case of diffuse progression EGFR-TKI therapy may continue, but in combination with chemotherapy; EGFR-TKI therapy may be switched to chemotherapy, but at the moment of chemotherapy resistance patients may be re-exposed to EGFR-TKI therapy; admission to clinical trials offering investigational agents may be a valid option for some patient. Osimertinib has just been approved and is recommended for tumors expressing P790M (Jänne, 2015). In tumors bearing ALK-/ROS-gene-rearrangements ceritinib is approved and recommended in case of crizotinib resistance (Shaw, 2014). During the past ten years the complexity of the treatment algorithm of advanced NSCLC has gradually increased by the incorporation of several approved molecules. Novel immunotherapies have recently changed the management of advanced wild-type NSCLC. Treatment by histo-type and geno-type has been established and it can be assumed by the given speed of growth of molecular information that the process of treatment differentiation will fast continue. Identification of new prognostic and predictive factors undoubtedly will accelerate this process.

Despite fast growing information of tumor molecular biology, the increase in the therapeutic portfolio, and a significant improvement in diagnostic radiology, treatment of advanced NSCLC in 2017 remains palliative with still no curative perspective for the vast majority of patients. Therefore, the main treatment goals include the change from an acute into a chronic disease, extending survival times as well as improving or just maintaining quality of life. In order to assure an optimal palliation the majority of patients with advanced NSCLC – considering the high age and concomitant comorbidities - frequently may require modifications of the treatment standard. Furthermore, it can also not be ignored that recently approved novel agents and innovative diagnostic technology represent a growing burden of financial toxicity leading to regional differences in the availability of modern therapy and in the access to molecular testing and modern imaging. Nonetheless, treatment algorithms for advanced NSCLC have over the last decade gradually gained in complexity by incorporating a number of diagnostic and therapeutic achievements allowing personalization, individualization, and precision of therapy. Not only patient factors such as performance status (PS), comorbidity, and patients' treatment expectation must lead to treatment differentiation and modification but also disease characteristics such as tumor stage, tumor load, histological type (squamous vs non–squamous) and the molecular profile of the tumor (mutant vs wild type) influence the process in reaching the goal of optimal sustainable palliation. Other critical elements in realizing personalized therapy and precision medicine within the process of optimal palliation consist in a rational selection of anti-cancer agents (predictive factors, mode of action, toxicity profile) and their appropriate application (single agent, concomitant combinations, drug sequencing) as well as other novel therapeutic actions such as interventional radiology, modern radio therapy, and minimal surgery. Optimal therapeutic management for sustainable palliation should definitely be based on clinically reliable evidence presented by frequently updated treatment recommendations: Today's treatment algorithm for advanced NSCLC is challenged by a number of newer agents, such as tyrosine kinase inhibitors, monoclonal antibodies, checkpoint inhibitors (Table 1), and the incorporation of new treatment strategies such as continuation or switch maintenance therapy (Fig 1). For advanced NSCLC (Fig 2) it is generally accepted that platinum based doubled chemotherapy remains the backbone for the majority of our patients with good PS and this combination therapy should be modified according to feasibility and tolerability, comorbidity, patients' age over 70 years, PS. For wild type non-squamous NSCLC there is pemetrexed which has been shown to be favorable over older cytotoxic agents if combined with platinum based components. In addition, pemetrexed has also sufficiently demonstrated that if it is continued in case non-progression under four cycles of standard platinum based doublet chemotherapy not containing pemetrexed (switch maintenance) or containing pemetrexed (continuation maintenance) prolongs survival. Another agent, the small molecule and EGFR-tyrosine kinase inhibitor erlotinib also prolongs survival if used in the switch maintenance setting but its benefit depends on the quality of response to the chemotherapy and is restricted to patients which have experienced disease stabilization only. The VEGFR-targeting antibody, bevacizumab, if added to platinum based doublet therapy, specifically to carboplatin/paclitaxel significantly improves response rate, duration of response, progression free survival, as well as overall survival in eligible patients. Human immune checkpoint inhibitor-antibodies inhibiting the PD-1 receptor or PD-1 ligand have recently been integrated into the treatment algorithms of wild type NSCLC. Pembrolizumab is currently the only checkpoint inhibitor approved and recommended for first line therapy in patients with a PD-L1 expression level ≥ 50 % and with negative or unknown EGFR/ALC/ROS1 testing. In wild type squamous NSCLC the given treatment options are still limited and platinum based therapy (no pemetrexed, no bevacizumab) remains the recommended treatment standard. Nonetheless, just recently the EGFR-targeting monoclonal antibody necitumumab has shown to significantly improve survival if combined with the standard doublet regimen cisplatin/gemcitabine in comparison to cisplatin/gemcitabine only and therefore, has just recently approved. Maintenance therapy in squamous tumors with docetaxel or erlotinib (switch) or gemcitabine (continuation) may be justified in some patients even here the statistical evidence is weak. For about 10-30% of NSCLC (in Europe < 15%) non-squamous tumors expressing specific molecular features first-line treatment by genotype has been established. Tumors with sensitizing EGFR mutations have been exposed by gefitinib, erlotinib, and afatinib and have shown to prolong progression free survival over standard platinum based doublet standard therapy. In tumors bearing ALK-/ROS1-gene-rearrangements crizotinib and ceritinib have also shown to prolong progression free survival if compared to platinum based / pemetrexed doublet chemotherapy. Therefore, EGFR-TKI therapy (erlotinib, gefitinib, afatinib) should be prescribed for patient with tumors bearing sensitizing EGFR-mutations and for patients with tumors bearing ALK-/ROS1-gene-rearrangements ALK-/ROS1-targeted therapy (crizotinib, ceritinib) should be prescribed. However, for these patients molecular testing is critical and should be used to select patients for EGFR/ALK/ROS1 targeted therapy. Patients with lung adenocarcinoma should not be excluded from testing on the basis of clinical characteristics (ethnicity, gender, smoking status). Last but not least, second-/subsequent-line therapy is another strong element contributing to sustainable palliation in patients with advanced NSCLC. For tumor without driver mutations agents available before 2014 include docetaxel, pemetrexed (for non-squamous cell tumors only) and erlotinib. In recent years the two antiangiogenic agents nintetanib and ramucirumab (both in combination with docetaxel) and three immune checkpoint inhibitors (nivolumab, pembrolizumab, azetolizumab) have been added to the armentarium to treat patients with advanced non-mutated NSCLC who have progressed on or after first-line therapy (Fig 2). In mutated NSCLC several therapeutic options for second-/subsequent line-therapies are recommended depending on the type of progression and the molecular profile of the tumor. Osimertinib has been just recently approved for EGFRm/790M expressing tumors. For ALK-positive tumors ceritinib, alectinib, and crizotinib can be prescribed. In general, selection of agents for second-/subsequent-line therapies is based on whether the drugs have been used earlier, or toxicity or patients view. References are available by the author.

BACKGROUND:Pre-planned futility analyses are commonly used in oncology studies. The LUME-Lung 2 study (NCT00806819; 1199.14) was stopped early based on a pre-planned, non-binding futility analysis of investigator-assessed progression-free survival (PFS), although subsequent analysis showed that the primary endpoint of improvement in centrally reviewed PFS was met. Retrospective analyses were conducted to understand the discrepancy between interim futility and final analyses.MATERIALS AND METHODS:LUME-Lung 2 investigated nintedanib in combination with pemetrexed versus placebo‒pemetrexed for the treatment of patients with advanced or recurrent non-squamous non-small cell lung cancer who had relapsed or failed one prior line of chemotherapy. Pre-planned futility analysis was carried out by the Data Monitoring Committee (DMC) after 50% of the events for the primary PFS analysis (713 events) had occurred; the threshold for futility was a conditional power of < 20%. Conditional/predictive powers and hazard ratios were calculated retrospectively after varying percentages of events had occurred for both investigator- and centrally reviewed PFS.RESULTS:At the time of the pre-planned futility analysis, the conditional power was 10.3% and the predictive power was 18.5%; no safety issues were identified. Retrospective analysis showed that the conditional and predictive powers fluctuated considerably over time for both investigator- and centrally reviewed PFS and that the power only dropped by a notable amount, and below the futility threshold, at the time of the futility analysis.CONCLUSIONS:Retrospective investigations suggest that, had the DMC analysis been carried out at another time point, or had centrally reviewed PFS data been used, the futility outcome may have been different and the trial may have been continued. The design of futility analyses requires careful consideration and confirming negative futility outcomes by second analysis may be appropriate.TRIAL NUMBER:NCT00806819.

Although the effectiveness of screening for lung cancer remains controversial, it is a fact that most lung cancers are diagnosed at an advanced stage outside of lung cancer screening programs. In 2013, the U.S. Preventive Services Task Force revised its lung cancer screening recommendation, now supporting lung cancer screening by low-dose computed tomography in patients at high risk. This is also endorsed by many major medical societies and advocacy group stakeholders, albeit with different eligibility criteria. In Europe, population-based lung cancer screening has so far not been recommended or implemented, as some important issues remain unresolved. Among them is the open question of how enlarging pulmonary nodules detected in lung cancer screening should be managed. This article comprises two parts: a review of the current lung cancer screening approaches and the potential therapeutic options for enlarging pulmonary nodules, followed by a meeting report including consensus statements of an interdisciplinary expert panel that discussed the potential of the different therapeutic options.

Personalized and precision medicine is gaining recognition due to the limitations by standard diagnosis and treatment; many areas of medicine, from cancer to psychiatry, are moving towards tailored and individualized treatment for patients based on their clinical characteristics and genetic signatures as well as novel imaging techniques. Advances in whole genome sequencing have led to identification of genes involved in a variety of diseases. Moreover, biomarkers indicating severity of disease or susceptibility to treatment are increasingly being characterized. The continued identification of new genes and biomarkers specific to disease subtypes and individual patients is essential and inevitable for translation into personalized medicine, in estimating both, disease risk and response to therapy. Taking into consideration the mostly unsolved necessity of tailored therapy in oncology the innovative project MOBIT (molecular biomarkers for individualized therapy) was designed. The aims of the project are: (i) establishing integrative management of precise tumor diagnosis and therapy including systematic biobanking, novel imaging techniques, and advanced molecular analysis by collecting comprehensive tumor tissues, liquid biopsies (whole blood, serum, plasma), and urine specimens (supernatant; sediment) as well as (ii) developing personalized lung cancer diagnostics based on tumor heterogeneity and integrated genomics, transcriptomics, metabolomics, and radiomics PET/MRI analysis. It will consist of 5 work packages. In this paper the rationale of the Polish MOBIT project as well as its design is presented. (iii) The project is to draw interest in and to invite national and international, private and public, preclinical and clinical initiatives to establish individualized and precise procedures for integrating novel targeted therapies and advanced imaging techniques.

C. Gridelli, T. Ciuleanu, M. Domine Gomez, A. Szczesna, I. Bover, M. Cobo Dols, N. Kentepozidis, S. Viteri, C. Manegold, D. Khayat, J-Y. Douillard, K. Kosmatopoulos, V. Georgoulias Oncology, S.G. Moscati Hospital, Avellino, Italy, Medical Oncology, The Oncology Institute Prof. Dr. Ion Chiricuta, Cluj-Napoca, Romania, Oncology, Fundaci on Jiménez D ıaz, Madrid, Spain, Medical Oncology, Mazowieckie Centrum, Otwock, Poland, Medical Oncology, Grupo Espa~ nol de Investigaci on en C ancer de Ovario (GEICO) and Hospital Son Ll atzer, Palma de Mallorca, Spain, Medical Oncology, Hospital Regional Universitario de Malaga, Malaga, Spain, Medical Oncology, 251 Hellenic Airforce General Hospital, Athens, Greece, Oncology Department, Dexeus University HospitalQuironSalud Group, Dr Rosell Oncology Institute, Barcelona, Spain, Chirurgische Klinik, Universit€atsklinikum Mannheim, Mannheim, Germany, Medical Oncology, Groupe Hospitalier Pitié Salpetriere, Paris, France, Department of Medical Oncology, Institut de Cancérologie de l’Ouest (ICO) René Gauducheau, Nantes, France, Vaxon Biotech, Vaxon Biotech, Paris, France, Medical Oncology, University Hospital of Heraklion, Heraklion, Greece

Background: Vx-001 is a a therapeutic cancer vaccine with TERT (telomerase reverse transcriptase) antigen as target. Methods: We tested the Vx-001 vaccine as maintenance therapy in a randomized double blind phase IIb trial in advanced NSCLC patients who did not progress after first line platinum based chemotherapy. Enrolled patients should be HLA-A 0201 positive and their tumor should express TERT. Overall survival (OS) was the primary endpoint of the study. Results: 1407 patients were screened and 221 were randomized. 190 patients (101 placebo and 89 Vx-001 treated) were analysed with no statistically significant in terms of OS beetwen arms. Interestingly there was a strong correlation between vaccine induced immune response and clinical outcome. OS was much longer in the 29% of patients who developed a Vx-001 specific immune response (21.3 months for immune responders vs 13.4 months for non-immune responders p = 0.004). 27% of enrolled patients had a natural immunity against several universal tumor antigens detected at baseline before vaccination suggesting that these patients should have strongly immunogenic tumors. Analysis of OS in this patient population with immunogenic tumors did not show any benefit in Vx-001 treated patients. Similar analysis of patients without natural immunity showed in Vx-001 arm a not statistically significant increase in OS (8.6 months vs 13.2 months, p = 0.27) suggesting that Vx-001 might be efficient in patients with non-immunogenic tumors. Since tumor immunogenicity is known to be associated to patients smoking status, a further analysis was focused according smoking habits. Very interestingly never smokers patients without natural immunity had a much longer OS when their were treated with Vx-001 as compared to placebo (8.6 vs 16.2 months HR = 0.20, p = 0.0008). This effects remained strong if we focused never smokers and former smokers who smoked for a short periode (less than 25 years). In this population OS in the Vx-001 arm was 20.7 months while in the placebo arm was 7.9 months (HR = 0.29, p = 0.0007). Conclusions: These results suggest that Vx-001 might be efficient in patients without natural immunity and particularly in never smokers. Clinical trial identification: NCT01935154, 26/08/2013 Legal entity responsible for the study: Vaxon Biotech Funding: Vaxon Biotech Disclosure: C. Gridelli: Honoraria as advisory board member for Vaxon Biotech. S. Viteri: Consulting (Boehringer Ingelheim, Clovis Oncology, Idea Pharma, Novartis, Promega Biotech Ibérica, Roche, Targovax). Research funding (AbbVie, Ariad, Astex, AstraZeneca/MedImmune, Boehringer Ingelheim, Clovis Oncology, CytRx, Daiichi Sankyo, GSK, Hanmi, Incyte, Merck KGaA, Novartis, Pfizer, Puma, Roche, Servier, Vaxon). C. Manegold: Travel support from Vaxon. D. Khayat: Consultant or advisory relationship to disclosure: Genomic Health France, Atlantic Sante, Celtic Biotech, Tolabo Radiochir. Stock or other ownership interest: Agenus Inc. J-Y. Douillard: Honoraria as advisory board member for Vaxon Biothec. All other authors have declared no conflicts of interest.

Despite the efficacy of a number of first-line treatments, most patients with advanced-stage non-small cell lung cancer (NSCLC) experience disease progression that warrants further treatment. In this review, we examine the role of novel active agents for patients who progress after first-line therapy and who are not candidates for targeted therapies. More therapeutic options are needed for the management of patients with NSCLC after failure of first-line chemotherapy. A PubMed search was performed for articles from January 2012 to May 2015 using the keywords NSCLC, antiangiogenic, immunotherapy, second-line, novel therapies and English language articles only. Relevant papers were reviewed; papers outside that period were considered on a case-by-case basis. A search of oncology congresses was performed to identify relevant abstracts over this period. In recent years, antiangiogenic agents and immune checkpoint inhibitors have been added to our armamentarium to treat patients with advanced NSCLC who have progressed on first-line chemotherapy. These include nintedanib, a triple angiokinase inhibitor; ramucirumab, a vascular endothelial growth factor receptor-2 antibody; and nivolumab, pembrolizumab and atezolizumab, just three of a growing list of antibodies targeting the programmed death receptor-1 (PD-1)/PD ligand-1 pathway. Predictive and prognostic factors in NSCLC treatment will help to optimise treatment with these novel agents. The approval of new treatments for patients with NSCLC after the failure of first-line chemotherapy has increased options after a decade of few advances, and holds promise for future evolution of the management of NSCLC.