Multi-Targeted Antiangiogenic Tyrosine Kinase Inhibitors in Advanced Non-Small Cell Lung Cancer: Meta-Analyses of 20 Randomized Controlled Trials and Subgroup Analyses

<div><p>Background</p><p>Multi-targeted antiangiogenic tyrosine kinase inhibitors (MATKIs) have been studied in many randomized controlled trials (RCTs) for treatment of advanced non-small cell lung cancer (NSCLC). We seek to summarize the most up-to-date evidences and perform a timely meta-analysis.</p><p>Methods</p><p>Electronic databases were searched for eligible studies. We defined the experimental arm as MATKI-containing group and the control arm as MATKI-free group. The extracted data on objective response rates (ORR), disease control rates (DCR), progression-free survival (PFS) and overall survival (OS) were pooled. Subgroup and sensitivity analyses were conducted.</p><p>Results</p><p>Twenty phase II/III RCTs that involved a total of 10834 participants were included. Overall, MATKI-containing group was associated with significant superior ORR (OR 1.29, 95% CI 1.08 to 1.55, <i>P</i> = 0.006) and prolonged PFS (HR 0.83, 0.78 to 0.90, <i>P</i> = 0.005) compared to the MATKI-free group. However, no significant improvements in DCR (OR 1.08, 1.00 to 1.17, <i>P</i> = 0.054) or OS (HR 0.97, 0.93 to 1.01, P = 0.106) were observed. Subgroup analyses showed that the benefits were predominantly presented in pooled results of studies enrolling previously-treated patients, studies not limiting to enroll non-squamous NSCLC, and studies using MATKIs in combination with the control regimens as experimental therapies.</p><p>Conclusions</p><p>This up-to-date meta-analysis showed that MATKIs did increase ORR and prolong PFS, with no significant improvement in DCR and OS. The advantages of MATKIs were most prominent in patients who received a MATKI in combination with standard treatments and in patients who had previously experienced chemotherapy. We suggest further discussion as to the inclusion criteria of future studies on MATKIs regarding histology.</p></div

Meta-analyses of MATKIs-containing regimens versus MATKIs-free regimens.

<p>A, ORR; B, DCR; C, PFS; D, OS.</p

Subgroup analyses of each endpoint (number of studies or arms).

<p>A, ORR; B, DCR; C, PFS; D, OS.</p

Construction of Hierarchical CNT/rGO-Supported MnMoO₄ Nanosheets on Ni Foam for High-Performance Aqueous Hybrid Supercapacitors

Rationally designed conductive hierarchical nanostructures are highly desirable for supporting pseudocapacitive materials to achieve high-performance electrodes for supercapacitors. Herein, manganese molybdate nanosheets were hydrothermally grown with graphene oxide (GO) on three-dimensional nickel foam-supported carbon nanotube structures. Under the optimal graphene oxide concentration, the obtained carbon nanotubes/reduced graphene oxide/MnMoO₄ composites (CNT/rGO/MnMoO₄) as binder-free supercapacitor cathodes perform with a high specific capacitance of 2374.9 F g^–1 at the scan rate of 2 mV s^–1 and good long-term stability (97.1% of the initial specific capacitance can be maintained after 3000 charge/discharge cycles). The asymmetric device with CNT/rGO/MnMoO₄ as the cathode electrode and the carbon nanotubes/activated carbon on nickel foam (CNT-AC) as the anode electrode can deliver an energy density of 59.4 Wh kg^–1 at the power density of 1367.9 W kg^–1. These superior performances can be attributed to the synergistic effects from each component of the composite electrodes: highly pseudocapacitive MnMoO₄ nanosheets and three-dimensional conductive Ni foam/CNTs/rGO networks. These results suggest that the fabricated asymmetric supercapacitor can be a promising candidate for energy storage devices

Flow chart of study selection.

<p>Flow chart of study selection.</p

Features of included agents and studies.

<p>N-S, non-squamous cell carcinoma; TC, paclitaxel+carboplatin; GP, gemcitabine+cisplatin; DOC, docetaxol; PEM, pemetrxed.</p><p>Features of included agents and studies.</p

Patients with Exon 19 Deletion Were Associated with Longer Progression-Free Survival Compared to Those with L858R Mutation after First-Line EGFR-TKIs for Advanced Non-Small Cell Lung Cancer: A Meta-Analysis

<div><p>Backgrounds</p><p>It has been extensively proved that the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is superior to that of cytotoxic chemotherapy in advanced non-small cell lung cancer (NSCLC) patients harboring sensitive EGFR mutations. However, the question of whether the efficacy of EGFR-TKIs differs between exon 19 deletion and exon 21 L858R mutation has not been yet statistically answered.</p><p>Methods</p><p>Subgroup data on hazard ratio (HR) for progression-free survival (PFS) of correlative studies were extracted and synthesized based on random-effect model. Comparison of outcomes between specific mutations was estimated through indirect and direct methods, respectively.</p><p>Results</p><p>A total of 13 studies of advanced NSCLC patients with either 19 or 21 exon alteration receiving first-line EGFR-TKIs were included. Based on the data from six clinical trials for indirect meta-analysis, the pooled HRTKI/chemotherapy for PFS were 0.28 (95% CI 0.20–0.38, P<0.001) in patients with 19 exon deletion and 0.47 (95% CI 0.35–0.64, P<0.001) in those with exon 21 L858R mutation. Indirect comparison revealed that the patients with exon 19 deletion had longer PFS than those with exon 21 L858R mutation (HR19 exon deletion/exon 21 L858R mutation  = 0.59, 95% CI 0.38–0.92; P = 0.019). Additionally, direct meta-analysis showed similar result (HR19 exon deletion/exon 21 L858R mutation  = 0.75, 95% CI 0.65 to 0.85; P<0.001) by incorporating another seven studies.</p><p>Conclusions</p><p>For advanced NSCLC patients, exon 19 deletion might be associated with longer PFS compared to L858 mutation at exon 21 after first-line EGFR-TKIs.</p></div

Direct comparison of TKI versus chemotherapy in EGFR exon 21 L858R mutations cohort in terms of HR for PFS. CI = confidence interval; EGFR = epidermal growth factor receptor; HR = Hazard ratio; PFS = progression-free survival; TKI = tyrosine kinase inhibitor.

<p>Direct comparison of TKI versus chemotherapy in EGFR exon 21 L858R mutations cohort in terms of HR for PFS. CI  =  confidence interval; EGFR  =  epidermal growth factor receptor; HR  =  Hazard ratio; PFS  =  progression-free survival; TKI  =  tyrosine kinase inhibitor.</p

Profile summarizing the trial flow.

<p>CI  =  confidence interval; EGFR  =  epidermal growth factor receptor; HR  =  Hazard ratio; PFS  =  progression-free survival; TKI  =  tyrosine kinase inhibitor.</p