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Abstract Background Bevacizumab, a humanized antibody to vascular endothelial growth factor (VEGF), shows clinical activity against human cancer, with its addition to standard chemotherapy having been found to improve outcome in patients with advanced nonsquamous non–small cell lung cancer (NSCLC). However, there have been no evidence-based studies to support the continued use of bevacizumab beyond disease progression in such patients treated with the drug in first-line therapy. We have now designed a randomized phase II trial to examine the clinical benefit and safety of continued bevacizumab treatment in patients with advanced nonsquamous NSCLC whose disease has progressed after first-line treatment with bevacizumab plus a platinum-based doublet. Methods/Design WJOG 5910L was designed as a multicenter, open-label, randomized, phase II trial by the West Japan Oncology Group of docetaxel (arm A) versus docetaxel plus bevacizumab (arm B) in patients with recurrent or metatstatic nonsquamous NSCLC whose disease has progressed after first-line treatment with bevacizumab plus a platinum-based doublet. Patients in arm A will receive docetaxel at 60 mg/m2 and those in arm B will receive docetaxel at 60 mg/m2 plus bevacizumab at 15 mg/kg, with each drug administered on day 1 every 21 days until progression or unacceptable toxicity. The primary endpoint of the study is progression-free survival, with secondary endpoints including response rate, overall survival, and safety, for patients treated in either arm. Trial registration UMIN (University Hospital Medical Information Network in Japan) 000004715

Background: Bevacizumab combined with platinum-based chemotherapy has been established as a standard treatment option in the first-line setting for advanced nonsquamous non-small cell lung cancer (NSCLC). However, there has been no evidence to support the use of bevacizumab beyond disease progression in such patients.Methods: West Japan Oncology Group 5910L was designed as a multicenter, open-label, randomized, phase 2 trial of docetaxel versus docetaxel plus bevacizumab every 3 weeks for patients with recurrent or metastatic nonsquamous NSCLC whose disease had progressed after first-line treatment with bevacizumab plus a platinum-based doublet. The primary endpoint was progression-free survival (PFS).Results: One hundred patients were randomly assigned to receive docetaxel (n = 50) or docetaxel plus bevacizumab (n = 50), and this yielded median PFS times of 3.4 and 4.4 months, respectively, with a hazard ratio (HR) of 0.71 and a stratified log-rank P value of .058, which met the predefined criterion for statistical significance (P < .2). The median overall survival also tended to be longer in the docetaxel plus bevacizumab group (13.1 months; 95% confidence interval [CI], 10.6-21.4 months) versus the docetaxel group (11.0 months; 95% CI, 7.6-16.1 months) with an HR of 0.74 (95% CI, 0.46-1.19; stratified log-rank P = .11). No unexpected or severe adverse events were recorded.Conclusions: Further evaluation of bevacizumab beyond disease progression is warranted for patients with advanced NSCLC whose disease has progressed after treatment with bevacizumab plus a platinum-based doublet. [ABSTRACT FROM AUTHOR]

Background and objective: A multi-institutional phase II trial combining uracil-tegafur (UFT) and cisplatin (CDDP) was conducted in patients with previously untreated advanced non-small cell lung cancer (NSCLC) to evaluate the safety and efficacy of this combined treatment regimen. Methods: The entry criteria for this study were previously untreated NSCLC, measurable disease, age <80 years, performance status <2, and adequate haematological, hepatic and renal function. Patients were treated with 400 mg/m2 oral UFT from day 1 to day 14 and 80 mg/m2 cisplatin on day 15. The treatment course was repeated every 3 weeks. Results: Of the 68 patients enrolled, 64 (27 with stage IIIB and 37 with stage IV disease) were eligible for treatment. Twenty of the 64 patients responded to the chemotherapy (response rate 31.3%; 95% CI 21.2–43.4%). The median survival time was 8.6 months, and the 1-year survival was 41.5%. Haematological toxicity ≥WHO grade 3 was seen in 3 (4.7%) patients. For non-haematological toxicities, anorexia with WHO grade 3 was seen in 8 (12.5%) patients, nausea and vomiting with WHO grade 3 in 4 (6.3%), diarrhoea with WHO grade 4 in 1 (1.6%), and liver dysfunction with WHO grade 4 in 1 (1.6%) patient. Conclusions: The combination of oral UFT plus cisplatin was found to be a safe and active treatment against advanced NSCLC. The observed low toxicity of this combined regimen may warrant its application to the treatment of elderly patients. [ABSTRACT FROM AUTHOR]

To determine the predictive value of the expression of p53 and glutathione S-transferase-π (GST-π) with respect to chemotherapy response, immunostaining was performed on transbronchial biopsy specimens from previously untreated patients with non-small cell lung cancer. Of the 54 patients, 34 patients (63%) and 37 patients (69%) were positive for p53 and GST-π, respectively. The response rates in the p53-positive and p53-negative group were 15 and 45%, and those in GST-π-positive and GST-π-negative groups were 16 and 47%, respectively. A multiple logistic regression analysis revealed that positive immunostaining for GST-π was a significant risk factor for clinical chemotherapy resistance. The combination of these two markers was the most important independent factor in predicting a response to chemotherapy in multiple logistic regression analysis. Immunohistochemical expression of p53 and GST-π was independently related to clinical chemoresistance in patients with non-small cell lung cancer. Combined use of these two biomarkers may be a useful predictor of clinical chemoresistance.Copyright © 1999 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: As docetaxel plus S-1 may be feasible for cancer treatment, we conducted a phase I/II trial to determine the recommended docetaxel dose and the fixed S-1 dose (phase I), as well as confirm the regimen's efficacy and safety (phase II) for previously-treated patients with advanced non-small cell lung cancer. Methods: Patients ≤75 years with performance status ≤1 and adequate organ function were treated at three-week intervals with docetaxel on day 1 and 80 mg/m2 oral S-1 from days 1–14. The starting docetaxel dose was 45 mg/m2 and this was escalated to a maximum of 70 mg/m2. In phase II, response rate, progression-free survival (PFS), overall survival (OS), and safety were assessed. Results: The recommended doses were 50 mg/m2 docetaxel (day 1) and 80 mg/m2 S-1 (days 1–14). Grades 3 and 4 leukocytopenia and neutropenia occurred in 44% and 67% of patients, respectively. Nonhematologic toxicities were generally mild. Overall response to chemotherapy was 7.7% (95% confidence interval (CI), 1.6–20.9%), and median PFS and OS were 18.0 weeks (95% CI; 11.3–22.9 weeks) and 53.0 weeks, respectively. Conclusion: Fifty mg/m2 docetaxel plus 80 mg/m2 oral S-1 had a lower response rate than anticipated; however, the survival data were encouraging. A further investigation is warranted to select the optimal patient population. [ABSTRACT FROM AUTHOR]

We previously validated in European patients with NSCLC treated with programmed death-1 (PD-1) checkpoint inhibitors the cumulative detrimental effect of concomitant medications. We evaluated the prognostic ability of a "drug score" computed on the basis of baseline corticosteroids, proton pump inhibitors, and antibiotics, in an independent cohort of Japanese patients with advanced NSCLC treated with PD-1 monotherapy. Subsequently, we assessed the impact of baseline probiotics on the score's diagnostic ability and their interaction with antibiotics in influencing survival. Among the 293 eligible patients, good (19.5 months), intermediate (13.4 months), and poor (3.7 months) risk groups displayed a significantly different overall survival (OS) (log-rank test for trend: p = 0.016), but with a limited diagnostic ability (C-index: 0.57, 95%CI: 0.53–0.61), while no significant impact on progression-free survival (PFS) was reported (log-rank test for trend: p = 0.080; C-index: 0.55, 95%CI: 0.52–0.58). Considering the impact of the probiotics∗antibiotics interaction (p-value 0.0510) on OS, we implemented the drug score by assigning 0 points to concomitant antibiotics and probiotics. With the adapted drug score good, intermediate, and poor risk patients achieved a median OS of 19.6 months, 13.1 months, and 3.7 months, respectively, with a similar diagnostic ability (log-rank test for trend: p = 0.006; C-index: 0.58, 95%CI: 0.54–0.61). However, the diagnostic ability for PFS of the adapted score was improved (log-rank test for trend: p = 0.034; C-index: 0.62, 95%CI: 0.54–0.69). Although we failed to validate the drug score in this independent Japanese cohort, we showed that probiotics may have an antibiotic-dependent impact on its prognostic value. Further investigation looking at the effect of concomitant medications and probiotics across cohorts of different ethnicities is warranted. • Concomitant medications affect clinical outcomes from immune checkpoint inhibitors. • We previously validated a prognostic drug score in European patients with NSCLC. • We explored the prognostic ability of the drug score in Japanese patients with NSCLC. • The use of probiotics might mitigate the deleterious effect of antibiotics. • Racial differences should be considered when investigating this topic. [ABSTRACT FROM AUTHOR]

• dNLR is a novel serum inflammatory marker. • dNLR is calculated from white blood cell concentration and neutrophil count. • dNLR was associated with treatment response in NSCLC treated with anti-PD-1 drugs. • dNLR was an independent prognostic factor in NSCLC treated with anti-PD-1 drugs. • dNLR might be the most important factor for the efficacy of anti-PD-1 therapy. Several serum markers have been associated with treatment response and clinical outcome in non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors. We performed univariate and multivariate analyses on 226 patients with advanced or recurrent NSCLC treated with anti-programmed cell death-1 (PD-1) therapy. The cut-off values for body mass index (BMI), albumin (Alb), and serum inflammatory markers were determined by receiver operating characteristic curve analyses. Tumor response was assessed by computed tomography according to the Response Evaluation Criteria in Solid Tumors, version 1.1. BMI ≥ 19.1 kg/m2 and derived neutrophil-lymphocyte ratio (dNLR) < 2.79 were independent predictors of overall response, and Alb ≥ 3.5 g/dL and dNLR < 2.79 were independent predictors of disease control. Analyses of survival revealed that Alb < 3.5 g/dL, dNLR ≥ 2.79, lymphocyte-monocyte ratio < 2.12, and red blood cell distribution width ≥ 15.9 % were independent predictors of both progression-free and overall survival. Moreover, these markers tended to have a strong impact on survival, especially among patients with programmed cell death-ligand 1 tumor proportion score ≥ 50 %. dNLR might be the most important factor for predicting the efficacy in NSCLC patients treated with anti-PD-1 therapy. [ABSTRACT FROM AUTHOR]

Objectives We performed an open-label, multicenter, single-arm phase II study (UMIN ID 000010532) to prospectively evaluate the efficacy and safety of nab-paclitaxel for previously treated patients with advanced non–small cell lung cancer (NSCLC). Methods Patients with advanced NSCLC who experienced failure of prior platinum-doublet chemotherapy received weekly nab-paclitaxel (100 mg/m 2 ) on days 1, 8, and 15 of a 21-day cycle until disease progression or the development of unacceptable toxicity. The primary end point of the study was objective response rate (ORR). Results Forty-one patients were enrolled between September 2013 and April 2015. The ORR was 31.7% (90% confidence interval, 19.3%–44.1%), which met the primary objective of the study. Median progression-free survival was 4.9 months (95% confidence interval, 2.4–7.4 months) and median overall survival was 13.0 (95% confidence interval, 8.0–18.0 months) months. The median number of treatment cycles was four (range, 1–17) over the entire study period, and the median dose intensity was 89.1 mg/m 2 per week. Hematologic toxicities of grade 3 or 4 included neutropenia (19.5%) and leukopenia (17.1%), with no cases of febrile neutropenia being observed. Individual nonhematologic toxicities of grade 3 or higher occurred with a frequency of <5%. Conclusion Weekly nab-paclitaxel was associated with acceptable toxicity and a favorable ORR in previously treated patients with advanced NSCLC. Our results justify the undertaking of a phase III trial comparing nab-paclitaxel with docetaxel in this patient population. [ABSTRACT FROM AUTHOR]

Objectives The combination use of gefitinib and epidermal growth factor receptor (EGFR) testing is a standard first-line therapy for patients with non-small cell lung cancer (NSCLC). Here, we examined the cost-effectiveness of this approach in Japan. Materials and methods Our analysis compared the ‘EGFR testing strategy’, in which EGFR mutation testing was performed before treatment and patients with EGFR mutations received gefitinib while those without mutations received standard chemotherapy, to the ‘no-testing strategy,’ in which genetic testing was not conducted and all patients were treated with standard chemotherapy. A three-state Markov model was constructed to predict expected costs and outcomes for each strategy. We included only direct medical costs from the healthcare payer's perspective. Outcomes in the model were based on those reported in the Iressa Pan-Asia Study (IPASS). The incremental cost-effectiveness ratio (ICER) was calculated using quality-adjusted life-years (QALYs) gained. Sensitivity and scenario analyses were conducted. Results The incremental cost and effectiveness per patient of the ‘EGFR testing strategy’ compared to the ‘no-testing strategy’ was estimated to be approximately JP¥122,000 (US$1180; US$1 = JP¥104 as of February 2014) and 0.036 QALYs. The ICER was then calculated to be around JP¥3.38 million (US$32,500) per QALY gained. These results suggest that the ‘EGFR testing strategy’ is cost-effective compared with the ‘no-testing strategy’ when JP¥5.0 million to 6.0 million per QALY gained is considered an acceptable threshold. These results were supported by the sensitivity and scenario analyses. Conclusion The combination use of gefitinib and EGFR testing can be considered a cost-effective first-line therapy compared to chemotherapy such as carboplatin–paclitaxel for the treatment for NSCLC in Japan. [ABSTRACT FROM AUTHOR]