Exosomes derived from lung cancer cells confer cisplatin (DDP) resistance to other cancer cells. However, the underlying mechanism is still unknown. A549 resistance to DDP (A549/DDP) was established. Microarray was used to analyze microRNA (miRNA) expression profiles of A549 cells, A549/DDP cells, A549 exosomes, and A549/DDP exosomes. There was a strong correlation of miRNA profiles between exosomes and their maternal cells. A total of 11 miRNAs were significantly upregulated both in A549/DDP cells compared with A549 cells and in exosomes derived from A549/DDP cells in contrast to exosomes from A549 cells. A total of 31 downregulated miRNAs were also observed. miR-100–5p was the most prominent decreased miRNA in DDP-resistant exosomes compared with the corresponding sensitive ones. Downregulated miR-100–5p was proved to be involved in DDP resistance in A549 cells, and mammalian target of rapamycin (mTOR) expression was reverse regulated by miR-100–5p. Exosomes confer recipient cells’ resistance to DDP in an exosomal miR-100–5p-dependent manner with mTOR as its potential target both in vitro and in vivo. Exosomes from DDP-resistant lung cancer cells A549 can alter other lung cancer cells’ sensitivity to DDP in exosomal miR-100–5p-dependent manner. Our study provides new insights into the molecular mechanism of DDP resistance in lung cancer.

Background: Patients with relapsed small-cell lung cancer (SCLC) have few treatment options and dismal survival. Phase I/II data show activity of nivolumab in previously treated SCLC.Patients and methods: CheckMate 331 is a randomized, open-label, phase III trial of nivolumab versus standard chemotherapy in relapsed SCLC. Patients with relapse after first-line, platinum-based chemotherapy were randomized 1 : 1 to nivolumab 240 mg every 2 weeks or chemotherapy (topotecan or amrubicin) until progression or unacceptable toxicity. Primary endpoint was overall survival (OS). Results: Overall, 284 patients were randomized to nivolumab and 285 to chemotherapy. Minimum follow-up was 15.8 months. No significant improvement in OS was seen with nivolumab versus chemotherapy [median OS, 7.5 versus 8.4 months; hazard ratio (HR), 0.86; 95% confidence interval (CI), 0.72-1.04; P ¼ 0.11]. A survival benefit with nivolumab was suggested in patients with baseline lactate dehydrogenase upper limit of normal and in those without baseline liver metastases. OS (nivolumab versus chemotherapy) was similar in patients with programmed death-ligand 1 combined positive score !1% versus <1%. Median progression-free survival was 1.4 versus 3.8 months (HR, 1.41; 95% CI, 1.18-1.69). Objective response rate was 13.7% versus 16.5% (odds ratio, 0.80; 95% CI, 0.50-1.27); median duration of response was 8.3 versus 4.5 months. Rates of grade 3 or 4 treatment-related adverse events were 13.8% versus 73.2%. Conclusion: Nivolumab did not improve survival versus chemotherapy in relapsed SCLC. No new safety signals were seen. In exploratory analyses, select baseline characteristics were associated with improved OS for nivolumab.

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7548 Background: Apatinib is an oral, small molecular tyrosine-kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor (VEGFR). Phase II study has showed that apatinib significantly improved the outcome of patients with advanced or metastatic gastric cancer (Li J, et al. ASCO 2011). The primary object of this study is to determine whether apatinib can improve progression free survival (PFS) compared with placebo in patients with advanced non-squamous NSCLC who failed two lines of treatment. Methods: This study recruited histologically diagnosed advanced non-squamous NSCLC patients who failed more than two lines of treatment including EGFR TKIs. Other eligible criteria included ECOG ≤1, adequate organ function and no prior exposure to VEGFR-TKI. The patients were randomized to receive apatinib at a dose of 750 mg or placebo (at allocation ratio of 2:1) orally once daily until the disease progression or unacceptable toxicity. Results: 135 patients (90 in apatinib arm, 45 in placebo arm) were included at 20 centers in China until Aug 2011. Median PFS was 4.7 months for apatinib group versus 1.9 months for placebo group, hazard ratio (HR) was 0.278 (95% CI 0.170, 0.455) (p<0.0001). The response rate (RR) and disease control rate (DCR) were also significantly better in study arm (12.2% and 68.9%) than in placebo arm (0% and 24.4%)(P=0.0158 and P<0.0001). The most frequently observed AEs were hypertension, proteinuria, and hand-foot syndrome (HFS). These AEs were generally mild or moderate in severity and were manageable. Conclusions: This randomized phase II trial shows that apatinib has substantial clinical activity without significant additional toxicity in patients with advanced non-squamous and non-small cell lung cancer. Continued investigation of apatinib is warranted in future clinical studies.

The published data on the predictive value of polymorphism of ERCC1 and XPD in patients with advanced non-small cell lung cancer receiving platinum-based chemotherapy are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Relevant studies were identified by searching the Medline, Embase, CNKI and American Society of Clinical Oncology abstract databases. Inclusion criteria were patients with advanced NSCLC, received platinum-based chemotherapy, evaluation of polymorphism of ERCC1 and XPD and overall response rate (ORR). A total of 12 studies were included in this meta-analysis. For studies evaluating ERCC1 polymorphism at codon 118, the ORR for the wild-type C/C genotype versus the heterozygous C/T and T/T genotype was 2.17 (95% confidence interval (CI), 1.43-3.33; P = 0.000). For studies evaluating XPD Asp312Asn and XPD Lys751Gln, the pooled OR was 1.33 (95% CI, 0.92-1.91; P = 0.13) and 1.02 (95% CI, 0.72-1.45; P = 0.915), respectively. The results indicated that platinum-based chemotherapy sensitivity was significantly associated with polymorphism of ERCC1 C118T. However, XPD Asp312Asn and XPD Lys751Gln were not predictive makers for platinum-based chemotherapy in patients with advanced NSCLC.

PURPOSE The CHOICE-01 study investigated the efficacy and safety of toripalimab in combination with chemotherapy as a first-line treatment for advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients (N = 465) with treatment-naive, advanced NSCLC without EGFR/ALK mutations were randomly assigned 2:1 to receive toripalimab 240 mg (n = 309) or placebo (n = 156) once every 3 weeks in combination with chemotherapy for 4-6 cycles, followed by the maintenance of toripalimab or placebo once every 3 weeks plus standard care. Stratification factors included programmed death ligand-1 expression status, histology, and smoking status. The primary end point was progression-free survival (PFS) by investigator per RECIST v1.1. Secondary end points included overall survival and safety. RESULTS At the final PFS analysis, PFS was significantly longer in the toripalimab arm than in the placebo arm (median PFS 8.4 v 5.6 months, hazard ratio = 0.49; 95% CI, 0.39 to 0.61; two-sided P < .0001). At the interim OS analysis, the toripalimab arm had a significantly longer OS than the placebo arm (median OS not reached v 17.1 months, hazard ratio = 0.69; 95% CI, 0.53 to 0.92; two-sided P = .0099). The incidence of grade ≥ 3 adverse events was similar between the two arms. Treatment effects were similar regardless of programmed death ligand-1 status. Genomic analysis using whole-exome sequencing from 394 available tumor samples revealed that patients with high tumor mutational burden were associated with significantly better PFS in the toripalimab arm (median PFS 13.1 v 5.5 months, interaction P = .026). Notably, patients with mutations in the focal adhesion-PI3K-Akt signaling pathway achieved significantly better PFS and OS in the toripalimab arm (interaction P values ≤ .001). CONCLUSION Toripalimab plus chemotherapy significantly improves PFS and OS in patients with treatment-naive advanced NSCLC while having a manageable safety profile. Subgroup analysis showed the OS benefit was mainly driven by the nonsquamous subpopulation.

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Background: Polymeric micellar paclitaxel (pm-Pac) is a novel Cremophor EL-free, nanoparticle micellar formulation of paclitaxel. We aimed to compare the efficacy and safety between pm-Pac plus cisplatin and solvent-based paclitaxel (sb-Pac) plus cisplatin in advanced non-small-cell lung cancer (NSCLC). Patients and methods: A total of 448 stage IIIB to IV NSCLC patients were randomly assigned (2:1) to receive six 3-week cycles of either pm-Pac (230 mg/m 2 ) plus cisplatin (70 mg/m 2 ; n ¼ 300), followed by dose escalation of pm-Pac to 300 mg/m 2 from the second 3-week cycle if prespecified toxic effects were not observed after the first cycle, or sb-Pac (175 mg/m 2 ) plus cisplatin (70 mg/m 2 ; n ¼ 148). The primary end point was objective response rate (ORR) assessed by independent review committees (IRCs). The secondary end points included IRC-assessed progression-free survival (PFS), overall survival (OS), and safety. Results: Patients in the pm-Pac-plus-cisplatin group showed significant improvements in IRC-assessed ORR compared with those in the sb-Pac-plus-cisplatin group (50% versus 26%; rate ratio 1.91; P < 0.0001). Additionally, subgroup analysis showed that a higher ORR was consistently observed in both squamous and nonsquamous histological types. IRC-assessed median PFS was significantly higher in the pm-Pac-plus-cisplatin group than in the sb-Pac-pluscisplatin group (6.4-month versus 5.3-month; hazard ratio 0.63; P ¼ 0.0001). Median OS was not significantly