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Objectives To describe the treatment patterns and determine the effectiveness and safety of nivolumab treatment for non-small cell lung cancer (NSCLC) in real-world setting in Japan. Materials and methods Japanese patients with NSCLC who received nivolumab were analyzed retrospectively. Patients who had started nivolumab treatment between April 2016 and December 2016 were enrolled. Information regarding patient demographics and clinical backgrounds, treatment patterns from diagnosis to post-nivolumab treatment, effectiveness and safety of nivolumab treatment and that of treatments just before and after nivolumab treatment, and programmed death-ligand 1 (PD-L1) expression status, if available, were collected. Factors associated with nivolumab effectiveness identified by univariate and multivariate analyses were further investigated for plotting Kaplan-Meier curves of epidermal growth factor receptor (EGFR) gene mutation status, PD-L1 expression status, and Eastern Cooperative Oncology Group performance status (ECOG PS). Results In this study, 901 NSCLC patients were enrolled. Nivolumab was used the most as a second line treatment with a median number of nivolumab doses of five. The median overall survival (OS) was 14.6 months, one-year survival rate was 54.3 %, and median progression-free survival (PFS) was 2.1 months. The objective response rate was 20.5 % and disease control rate was 57.4 %. According to multivariate analyses, better OS and PFS were associated with favorable ECOG PS and absence of liver metastasis. Better PFS was observed in patients without EGFR mutation and patients with smoking history. PFS and best overall response in PD-L1 expression subgroups were expression level-dependent. The overall incidence of irAEs was 45.8 %, and the incidence of adverse events of grade 3 or higher was 14.0 %. Conclusion The real-world effectiveness and safety of nivolumab is consistent with that reported by previous clinical trials and other real-world data. Subgroup analysis showed that ECOG PS, EGFR mutation status, smoking status, and PD-L1 were associated with the effectiveness of nivolumab.

Background Since its approval in December 2015, nivolumab has been widely used as a second-line treatment for non-small cell lung cancer (NSCLC) patients regardless of tumor PD-L1 expression or histology. However, the relationship between nivolumab effectiveness and PD-L1 expression using 22C3 PharmDx in the real-world setting is unclear. Methods Data from patient who initiated nivolumab treatment from April 1, 2016 to December 31, 2016 were collected at 23 regional medical institutions across Japan. Tumor PD-L1 expression was determined using PD-L1 IHC 22C3 PharmDx or 28-8 PharmDx assays. Here, we report the relationship between nivolumab effectiveness/safety and PD-L1 expression using 22C3 PharmDx, from a multicenter, observational study; CA209-9CR (NCT03273790). Results PD-L1 expression in 348 cases of NSCLC was determined using the 22C3 PharmDx assay. The propotion of cases with PD-L1 negative ( Conclusion These real-world data show relationship of nivolumab effectiveness and PD-L1 expression using 22C3 PharmDx.

Background In December 2015, nivolumab was approved as treatment for previously treated NSCLC irrespective of PD-L1 expression or histology in Japan. There are few reports that include real-world data on large cohorts of patients from Japan. Method Data from patients who initiated nivolumab treatment from April 1, 2016 to December 31, 2016 were collected at 23 regional medical institutions across Japan. Here we report a retrospective data analysis accessing effectiveness and safety of nivolumab in 901 Japanese NSCLC pts from a multicenter, observational study; CA209-9CR (NCT03273790). Result Among 901 pts, median age of the pts treated with nivolumab was 67 ys old and proportion of 75 ys or over was 19.8%. Pts with ECOG PS 0 or 1 account for 75.8%, and pts with SQ and adeno histology were 24.5% and 67.7%, respectively. Pts with EGFR mutation account for 12.9%. Median numbers of nivolumab dose was five and nivolumab was most frequently used at 2nd line (46.8%) and followed by at 3rd line (26.5%). Rate of 1 yr overall survival (OS) was 54.3% and, median PFS was 2.1 months and overall ORR was 20.6%. There was no significant difference in effectiveness among histology. Although there was no difference in effectiveness of nivolumab by age, ECOG PS status significantly influence effectiveness of nivolumab. Analysis is ongoing to access various factors that may be associated with the effectiveness of nivolumab. Overall irAE incidence for all grade and grade 3-4 will be reported as well as categorized irAE. Further analysis is planned for safety management of irAEs and prognosis. Conclusion The effectiveness and safety of nivolumab observed in real-world data from NSCLC patients in Japan was comparable to results observed in clinical trials. ECOG PS status was identified as a factor influencing effectiveness of nivolumab.

Background In December 2015, nivolumab was approved for previously treated advanced NSCLC irrespective of PD-L1 expression or histology in Japan. Real-world data can provide insights beyond the clinical trial, and in this analysis we study a large Japanese patient cohort. Methods Data for 901 patients who initiated nivolumab treatment for advanced NSCLC from April 1, 2016 to December 31, 2016 were collected at 23 regional medical institutions across Japan, including clinical laboratory data before and all the available data during nivolumab treatment. Here we report an exploratory analysis on the association of nivolumab effectiveness with the clinical laboratory data of the Japanese advanced NSCLC patients from a multicenter, observational study; CA209-9CR (NCT03273790). Results Analysis on association of objective response rate (ORR) with each clinical laboratory data at baseline among responders and non-responders suggested that neutrophils, lymphocytes, neutrophil/lymphocyte ratio (NLR), albumin, sodium, CYFRA, and uric acid at baseline were associated with significantly improved ORR. Further analyses on those multiple factors are planned to identify associations with improved outcome of with nivolumab treatment beyond ORR.

Background In December 2015, nivolumab was approved as treatment for previously treated NSCLC irrespective of PD-L1 expression or histology in Japan. There are few reports that include real-world data on large-scale cohorts of patients with special backgrounds from Japan. Method Data from patients who initiated nivolumab treatment from April 1, 2016 to December 31, 2016 were collected at 23 regional medical institutions across Japan. Here we report retrospective analysis of all 901 pts data and focus on effectiveness and safety in special subgroups of the Japanese NSCLC patients, from a multicenter, observational study; CA209-9CR (NCT03273790). Result Patients with EGFR mutations showed significantly shorter PFS as compared to EGFR wild-type patients. Among other special groups, 316 pts with high blood pressure, in which 272 pts was on antihypertensive, showed superior ORR as compared to 585 pts with normal pressure at baseline. Safety analysis showed higher pulmonary toxicity in patients with pulmonary infection at baseline and higher hepatotoxicity in a group of pts infected with hepatitis virus. In this presentation, further analysis on the other subgroups will be presented.

To determine ligand-binding sites of a platelet-activating factor (PAF) receptor, alanine-scanning mutagenesis was carried out. All 23 polar amino acids in the putative 7-transmembrane (TM) domains of a guinea pig PAF receptor were individually replaced with alanine. The ligand-binding properties of mutant receptors were determined after transient expression in COS-7 cells. Mutants in TM II (N58A, D63A), TM III (N100A, T101A, S104A) and TM VII (D289A) displayed higher PAF-binding affinities than seen with the wild-type receptor. In contrast, mutants in TM V (H188A), TM VI (H248A, H249A, Q252A), and TM VII (Q276A, T278A) showed lower affinities. Representative mutants were then stably expressed in Chinese hamster ovary cells to observe PAF-induced cellular signals (arachidonate release, phosphatidylinositol hydrolysis, adenylyl cyclase inhibition). An N100A mutant with the highest affinity was constitutively active and was responsive to lyso-PAF, an inactive derivative of PAF. One nanomolar PAF induced no signals in low affinity mutants, an EC50 value for the wild-type receptor. Three histidines (His-188, His-248, His-249) might form a binding pocket for the phosphate group of PAF, since zinc effectively inhibited ligand binding. Based on these results, a three-dimensional molecular model of PAF and its receptor was generated using bacteriorhodopsin as a reference protein.