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BACKGROUND: Patients with non-small cell lung cancer (NSCLC) and stable disease (SD) have an unmet clinical need to help guide early treatment adjustments. OBJECTIVE: To evaluate the potential of tumor biomarkers to inform on survival outcomes in NSCLC SD patients. METHODS: This post hoc analysis included 480 patients from the IMpower150 study with metastatic NSCLC, treated with chemotherapy, atezolizumab and bevacizumab combinations, who had SD at first CT scan (post-treatment initiation). Patients were stratified into high- and low-risk groups (overall survival [OS] and progression-free survival [PFS] outcomes) based on serum tumor biomarker levels. RESULTS: The CYFRA 21-1 and CA 125 biomarker combination predicted OS and PFS in patients with SD. Risk of death was ~4-fold higher for the biomarker-stratified high-risk versus low-risk SD patients (hazard ratio [HR] 3.80; 95% confidence interval [CI] 3.02–4.78; p < 0.0001). OS in patients with the low- and high-risk SD was comparable to that in patients with the CT-defined partial response (PR; HR 1.10; 95% CI 0.898–1.34) and progressive disease (PD) (HR 1.05; 95% CI 0.621–1.77), respectively. The findings were similar with PFS, and consistent across treatment arms. CONCLUSIONS: Biomarker testing shows potential for providing prognostic information to help direct treatment in NSCLC patients with SD. Prospective clinical studies are warranted. ClinicalTrials.gov: NCT02366143 [ABSTRACT FROM AUTHOR]

Background: Lung cancer (LC) causes more deaths worldwide than any other cancer type. Despite advances in therapeutic strategies, the fatality rate of LC cases remains high (95%) since the majority of patients are diagnosed at late stages when patient prognosis is poor. Analysis of the International Association for the Study of Lung Cancer (IASLC) database indicates that early diagnosis is significantly associated with favorable outcome. However, since symptoms of LC at early stages are unspecific and resemble those of benign pathologies, current diagnostic approaches are mostly initiated at advanced LC stages. Methods: We developed a LC diagnosis test based on the analysis of distinct RNA isoforms expressed from the GATA6 and NKX2-1 gene loci, which are detected in exhaled breath condensates (EBCs). Levels of these transcript isoforms in EBCs were combined to calculate a diagnostic score (the LC score). In the present study, we aimed to confirm the applicability of the LC score for the diagnosis of early stage LC under clinical settings. Thus, we evaluated EBCs from patients with early stage, resectable non-small cell lung cancer (NSCLC), who were prospectively enrolled in the EMoLung study at three sites in Germany. Results: LC score-based classification of EBCs confirmed its performance under clinical conditions, achieving a sensitivity of 95.7%, 91.3% and 84.6% for LC detection at stages I, II and III, respectively. Conclusions: The LC score is an accurate and non-invasive option for early LC diagnosis and a valuable complement to LC screening procedures based on computed tomography. [ABSTRACT FROM AUTHOR]

Small cell lung cancer (SCLC), which accounts for 10%-15% of lung cancer cases, is an aggressive disease characterized by rapid growth and early widespread metastasis. Although up to 80% of patients respond to first-line chemotherapy, most eventually relapse, and there are no approved agents beyond the second line. Despite the high incidence of mutations in SCLC, to date no targeted therapy has shown a benefit for this patient population, and systemic treatment has not changed significantly during the past 3 decades. Given that extensive-stage SCLC has a 5-year survival rate of only 1%-2%, novel therapies are desperately needed. Recent evidence shows that the immune system is capable of generating antitumor responses against various tumors, including lung cancer, suggesting that immunotherapy may be a viable therapeutic approach to the treatment of patients with SCLC. Of the immunotherapies being investigated for patients with SCLC, antibodies that target the programmed cell death protein-1 (nivolumab and pembrolizumab) and cytotoxic T-lymphocyte antigen-4 (ipilimumab) immune checkpoint pathways are perhaps the most promising. Because these immune checkpoint pathways, which under normal circumstances function to protect healthy tissues from damage during inflammatory responses and maintain self-tolerance, can help tumor cells evade elimination by the immune system, they represent potential therapeutic targets. This review discusses the rationale for immunotherapy and the early clinical results of immunotherapeutic agents being investigated in SCLC. [ABSTRACT FROM AUTHOR]

Objectives ABIGAIL, a phase II, randomized, open-label, multicenter study evaluated the correlation between biomarkers and best overall response (BOR) to bevacizumab with chemotherapy in patients with advanced or recurrent non-small-cell lung cancer (NSCLC). Exploratory analyses of vascular endothelial growth factor (VEGF) clinical genotyping data are presented. Materials and methods A total of 303 patients with NSCLC were randomized to receive bevacizumab 7.5 mg/kg or 15 mg/kg until progression or unacceptable toxicity (plus six cycles of chemotherapy). Patients provided blood samples for biomarker analysis. Exploratory analyses were conducted to assess whether genetic variants in VEGF-A or VEGFR-1/-2 act as efficacy or safety biomarkers. Single nucleotide polymorphisms (SNPs) were determined using individual genotyping assays. DNA analysis for 12 SNPs across three genes is reported: VEGF-A (five SNPs), VEGFR-1 (three SNPs), and VEGFR-2 (four SNPs). Results VEGF-A: c.+405/c.−634 (CG), VEGF-A: c.−460 >C; c−1498 >C (CT), and VEGF-A: c.−2578 C>A were associated with >50% higher odds of responding to treatment. VEGFR-1: rs9554316 (GT) was associated with >30% higher risk of progression and >40% higher risk of death. VEGF-A: c.+936 C>T was associated with higher incidence of hypertension. Conclusions Four genetic variants of VEGF-A and VEGFR-1 were associated with bevacizumab treatment outcome. Three variants in VEGF-A were associated with increased BOR, one variant in VEGFR-1 was associated with worse progression-free survival/overall survival. These associations were not statistically significant after correction for multiple testing. No genetic variant was associated with significantly higher risk of hypertension. Replication in additional studies may provide insight into the use of these variants to predict response to bevacizumab. [ABSTRACT FROM AUTHOR]

An unmet need remains for effective, well-tolerated treatment options in advanced non-small-cell lung cancer that can alleviate the disease burden for a broad selection of patients. Nintedanib (Vargatef) is a potent, oral, triple angiokinase inhibitor of three distinct pro-angiogenic pathways. A recent Phase III trial of second-line nintedanib plus docetaxel met the primary end point of progression-free survival and demonstrated significant benefit in the key secondary end point of overall survival, with median overall survival greater than 1 year for patients with adenocarcinoma histology. This article summarizes preclinical and clinical experience with nintedanib in non-small-cell lung cancer to date and discusses how it may be used in the future, including prospects for individualizing treatment by tumor proliferation dynamics and molecular biomarkers of response. [ABSTRACT FROM AUTHOR]

We investigated the relationship between plasma protein biomarker concentrations and clinical outcomes in 52 patients with relapsed/refractory advanced non-small cell lung cancer (NSCLC) treated with 400~mg bid sorafenib in a phase II trial. Blood samples were collected at baseline, on day 15 of cycle 1 (C1D15), and on day 1 of cycle 3 (C3D1), and plasma concentrations of total VEGF, VEGF-165, soluble (s) VEGFR-2, PDGF-BB, sPDGFR-β, sEGFR, sHER-2, uPA, PAI-1, uPAR, TIMP-1, and circulating Ras p21 were assayed by ELISA. Elevated baseline VEGF, VEGF-165, PDGF-BB, Ras p21, and TIMP-1 concentrations were associated with poorer patient outcomes (shorter overall survival [OS] and/or progression-free survival [PFS]). During treatment, the mean concentrations of sVEGFR-2, PDGF-BB, sPDGFR-β, TIMP-1, uPAR, and PAI-1 decreased, while the mean sEGFR concentration increased. Increases in VEGF, VEGF-165, PDGF-BB, and TIMP-1 during treatment were associated with better outcomes (longer OS and/or PFS), whereas increases in plasma Ras p21 during treatment were associated with shorter PFS. The associations between baseline concentrations and/or pharmacodynamic changes in plasma proteins and clinical outcomes in NSCLC patients treated with sorafenib suggest that these biomarkers may have a prognostic role and/or predict the efficacy of sorafenib in patients with NSCLC. [ABSTRACT FROM AUTHOR]

Abstract: Lung cancer continues to present an enormous global burden of morbidity and mortality, despite an increasing therapeutic armamentarium of chemotherapy and targeted agents. Recent research efforts have been directed towards identifying predictors of response to treatment, in order to facilitate the selection of patients likely to obtain the greatest benefit from specific therapeutic interventions, with the ultimate goal of providing customized therapy. A strong scientific basis exists for the use of markers to identify patients who are most likely to respond to biological and targeted therapies, based on characteristics such as tumour genotype and histology. Biomarkers have the potential to aid in patient stratification (risk assessment), treatment-response identification (surrogate markers), or differential diagnosis (identifying individuals who are likely to respond well to specific therapies). Numerous trials have demonstrated correlations between molecular biomarkers and the outcome of treatment with targeted therapies such as epidermal growth factor inhibitor tyrosine-kinase inhibitors in patients with non-small-cell lung cancer (NSCLC). The recently completed MarkER Identification Trial (MERIT) found some evidence of a link between the molecular profile of a tumour and the clinical response to erlotinib in patients with relapsed NSCLC. However, MERIT also highlighted the difficulties in obtaining adequate samples for the various procedures involved in genetic analyses in clinical trials. Routine clinical practice brings its own challenges relating to biopsy techniques and tissue availability and this has implications for the application of molecular analyses in treatment decision-making. Applying the lessons learned from tissue sampling and molecular testing in MERIT and other major NSCLC trials will be essential in paving the way for the routine use of biomarker analyses in clinical practice. [Copyright &y& Elsevier]

Summary Background Necitumumab is a second-generation recombinant human immunoglobulin G1 EGFR monoclonal antibody that competitively inhibits ligand binding. We aimed to compare necitumumab plus pemetrexed and cisplatin with pemetrexed and cisplatin alone in patients with previously untreated, stage IV, non-squamous non-small-cell lung cancer (NSCLC). Methods We did this randomised, open-label, controlled phase 3 study at 103 sites in 20 countries. Patients aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and adequate organ function, were randomly assigned 1:1 to treatment with a block randomisation scheme (block size of four) via a telephone-based interactive voice-response system or interactive web-response system. Patients received either cisplatin 75 mg/m 2 and pemetrexed 500 mg/m 2 on day 1 of a 3-week cycle for a maximum of six cycles alone, or with necitumumab 800 mg on days 1 and 8. Necitumumab was continued after the end of chemotherapy until disease progression or unacceptable toxic effects. Randomisation was stratified by smoking history, ECOG performance status, disease histology, and geographical region. Patients and study investigators were not masked to group assignment. The primary endpoint was overall survival. Efficacy analyses were by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00982111 . Findings Between Nov 11, 2009, and Feb 2, 2011, we randomly assigned 633 patients to receive either necitumumab plus pemetrexed and cisplatin (n=315) or pemetrexed and cisplatin alone (n=318). Enrolment was stopped on Feb 2, 2011, after a recommendation from the independent data monitoring committee. There was no significant difference in overall survival between treatment groups, with a median overall survival of 11·3 months (95% CI 9·5–13·4) in the necitumumab plus pemetrexed and cisplatin group versus 11·5 months (10·1–13·1) in the pemetrexed and cisplatin group (hazard ratio 1·01 [95% CI 0·84–1·21]; p=0·96). The incidence of grade 3 or worse adverse events, including deaths, was higher in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group; in particular, deaths regarded as related to study drug were reported in 15 (5%) of 304 patients in the necitumumab group versus nine (3%) of 312 patients in the pemetrexed and cisplatin group. Serious adverse events were likewise more frequent in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group (155 [51%] of 304 vs 127 [41%] of 312 patients). Patients in the necitumumab plus pemetrexed and cisplatin group had more grade 3–4 rash (45 [15%] of 304 vs one [<1%] of 312 patients in the pemetrexed and cisplatin alone group), hypomagnesaemia (23 [8%] vs seven [2%] patients), and grade 3 or higher venous thromboembolic events (23 [8%] vs 11 [4%] patients) than did those in the pemetrexed and cisplatin alone group. Interpretation Our findings show no evidence to suggest that the addition of necitumumab to pemetrexed and cisplatin increases survival of previously untreated patients with stage IV non-squamous NSCLC. Unless future studies identify potentially useful predictive biomarkers, necitumumab is unlikely to provide benefit in this patient population when combined with pemetrexed and cisplatin. Funding Eli Lilly and Company. [ABSTRACT FROM AUTHOR]