The efficacy of programmed death-1 blockade in epidermal growth factor receptor gene (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) patients with different mechanisms of acquired ...resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR.
We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A). Programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) density in tumor specimens obtained after acquisition of EGFR-TKI resistance were determined by immunohistochemistry. Whole-exome sequencing of tumor DNA was carried out to identify gene alterations. The relation of T790M status to PD-L1 expression or TIL density was also examined in an independent cohort of 60 patients (cohort B).
In cohort A, median progression-free survival (PFS) was 2.1 and 1.3months for T790M-negative and T790M-positive patients, respectively (P=0.099; hazard ratio of 0.48 with a 95% confidence interval of 0.20–1.24). Median PFS was 2.1 and 1.3months for patients with a PD-L1 expression level of≥1% or<1%, respectively (P=0.084; hazard ratio of 0.37, 95% confidence interval of 0.10–1.21). PFS tended to increase as the PD-L1 expression level increased with cutoff values of≥10% and≥50%. The proportion of tumors with a PD-L1 level of≥10% or≥50% was higher among T790M-negative patients than among T790M-positive patients of both cohorts A and B. Nivolumab responders had a significantly higher CD8+ TIL density and nonsynonymous mutation burden.
T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.
Dense ceramic disks of apatite-type lanthanum silicates have been prepared using sol–gel derived powders by sintering at first 1600
°C and then 1750
°C. AC impedance measurements showed that the ...oxide ionic conductivity of La
x
Si
6O
1.5
x+12
increases from ∼1
mS
cm
−1 to a maximum of ∼20
mS
cm
−1 with increasing the La content from
x
=
9.29 to 9.92. Rietveld refinements revealed that the observed powder X-ray diffraction patterns fit to a defect structure model which incorporates La ions into 4f cation vacancy of the apatite phase and contains extra oxide ions in an interstitial site near the conduction channel. The observed increase in the conductivity with the La content is explained by an interstitial conduction mechanism associated with an increase in the extra oxide ions.
Abstract
We identify stochastic process models describing the time series of inflow and outflow discharges of Obara Dam in Hii River, Japan. These models are based on tempered stable ...Ornstein–Uhlenbeck (TSOU) processes that have not been utilized in hydrological analysis but can capture both large and small fluctuation of the time series data. In addition, the models can be exactly simulated in a statistical sense by utilizing a recent tailored discretization algorithm, serving as efficient stochastic tools. We show that the identified models accurately reproduce statistical moments of the time series data and probability density functions. Based on the mathematical framework of backward stochastic differential equation (BSDE), the identified model is applied to a unique dynamic stochastic analysis of dissolved silicon (DSi) load flowing into the reservoir associated with Obara Dam. We thus contribute to the first application of TSOU processes and a BSDE to hydrological analysis.
Primary analysis of the phase III study WJTOG 3405 demonstrated superiority of progression-free survival (PFS) for gefitinib (G) in patients treated with the epidermal growth factor receptor ...(EGFR)-tyrosine kinase inhibitor (TKI) gefitinib compared with cisplatin plus docetaxel (CD) as the first-line treatment of stage IIIB/IV or postoperative recurrent EGFR mutation-positive non-small-cell lung cancer. This report presents final overall survival (OS) data.
Patients were randomized between G (250 mg/day orally) and cisplatin (80 mg/m2 intravenously) plus docetaxel (60 mg/m2 i.v.), administered every 21 days for three to six cycles. After the exclusion of 5 patients, 172 patients (86 in each group, modified intention-to-treat population) were included in the survival analysis. OS was re-evaluated using updated data (data cutoff, 30 September 2013; median follow-up time 59.1 months). The Kaplan–Meier method and the log-rank test were used for analysis, and hazard ratios (HRs) for death were calculated using the Cox proportional hazards model.
OS events in the G group and CD group were 68 (79.1%) out of 86 and 59 (68.6%) out of 86, respectively. Median survival time for G and CD were 34.9 and 37.3 months, respectively, with an HR of 1.252 95% confidence interval (CI): 0.883–1.775, P = 0.2070. Multivariate analysis identified postoperative recurrence and stage IIIB/IV disease as independent prognostic factors, with an HR of 0.459 (95% CI: 0.312–0.673, P < 0.001). Median survival time (postoperative recurrence versus stage IIIB/IV disease) were 44.5 and 27.5 months in the G group and 45.5 and 32.8 months in the CD group, respectively.
G did not show OS benefits over CD as the first-line treatment. OS of patients with postoperative recurrence was better than that of stage IIIB/IV disease, even though both groups had metastatic disease.
This study was registered with UMIN (University Hospital Medical Information Network in Japan), number 000000539.
Summary
Autoantibodies to melanoma differentiation‐associated protein 5 (MDA5) are associated with a subset of patients with dermatomyositis (DM) who have rapidly progressive interstitial lung ...disease (RP‐ILD) with poor prognosis. Intensive immunosuppressive therapy is initiated before irreversible lung damage can occur; however, there are few lines of evidence for the treatment of RP‐ILD. Here, we report three cases of anti‐MDA5 antibody‐associated DM with RP‐ILD in which the patients were treated with combined‐modality therapy, including high‐dose prednisolone, tacrolimus, intravenous cyclophosphamide and intravenous immunoglobulin (IVIG). In all three cases, serum ferritin levels, which are known to represent the disease activity of RP‐ILD, were decreased after IVIG administration. IVIG might contribute to the control of the disease activity of anti‐MDA5 antibody‐positive DM. Moreover, palmar violaceous macules/papules around the interphalangeal joints, which was observed in all three cases in the incipient stage, might be a useful sign in suggesting a diagnosis of anti‐MDA5 antibody‐associated DM.
What's already known about this topic?
Autoantibodies to melanoma differentiation‐associated protein 5 (MDA5) are associated with a subset of patients with dermatomyositis (DM) accompanied by rapidly progressive interstitial lung disease with poor prognosis.
In patients with anti‐MDA5 antibody‐associated DM, serum levels of ferritin and anti‐MDA5 antibodies correlate with disease activity.
What does this study add?
This study reveals that intravenous immunoglobulin (IVIG) contributes to the control of disease activity of anti‐MDA5 antibody‐associated DM.
Combined‐modality therapy including IVIG is recommended for treatment of anti‐MDA5 antibody‐associated DM.
Palmar violaceous macules/papules around the interphalangeal joints might be a useful sign to suggest a diagnosis of anti‐MDA5 antibody‐associated DM.
Linked Comment: Caplan et al. Br J Dermatol 2017; 177:1168–1169.
Antibody-drug conjugates (ADCs) are an established therapeutic entity in which potent cytotoxic drugs are conjugated to a monoclonal antibody. In parallel with the great emphasis put on novel ...site-specific bioconjugation technologies, future advancements in this field also rely on exploring novel linker-drug architectures that improve the efficacy and stability of ADCs. In this context, the use of hydrophilic linkers represents a valid strategy to mask or reduce the inherent hydrophobicity of the most used cytotoxic drugs and positively impact the physical stability and in vivo performance of ADCs. Here, we describe the use of linkers containing monodisperse poly(ethylene glycol) (PEG) moieties for the construction of highly-loaded lysine-conjugated ADCs. The studied ADCs differ in the positioning of PEG (linear or pendant), the bonding type with the antibody (amide or carbamate), and the drug-to-antibody ratio (DAR). These ADCs were first evaluated for their stability in solution under thermal stress, showing that both the drug-linker-polymer design and the nature of the antibody-linker bonding are of great importance for their physical and chemical stability. Amide-coupled ADCs bearing two pendant 12-unit poly(ethylene glycol) chains within the drug-linker structure were the best performing conjugates, distancing themselves from the ADCs obtained with a conventional linear 24-unit PEG oligomer or the linker of Kadcyla®. The pharmacokinetic profiles of amide-linked ADCs, with a linear or pendant configuration of the PEG, were tested in mice in comparison to Kadcyla®. Total antibody pharmacokinetics paralleled the trends in aggregation tendency, with slower clearance rates for the ADCs based on the pendant drug-linker format. The above-mentioned findings have provided important clues on the drug-linker design and revealed that the positioning and configuration of a PEG unit have to be carefully tuned to achieve ADCs with improved stability and pharmacokinetics.
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A previous randomized phase II study demonstrated that the addition of a c-Met inhibitor tivantinib to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib might prolong ...progression-free survival (PFS) in patients with previously treated, nonsquamous nonsmall-cell lung cancer (NSCLC). On a subset analysis, the survival benefit was greater in patients with wild-type EGFR (WT-EGFR) than in those with activating EGFR mutations. Herein, this phase III study compared overall survival (OS) between Asian nonsquamous NSCLC patients with WT-EGFR who received erlotinib plus tivantinib (tivantinib group) or erlotinib plus placebo (placebo group).
A total of 460 NSCLC patients were planned to be randomized to the tivantinib or placebo group. Primary end point was OS. Secondary end points were PFS, tumor response, and safety. Tissue was collected for biomarker analysis, including c-Met and HGF expression.
Enrollment was stopped when 307 patients were randomized, following the Safety Review Committee's recommendation based on an imbalance in the interstitial lung disease (ILD) incidence between the groups. ILD developed in 14 patients (3 deaths) and 6 patients (0 deaths) in the tivantinib and the placebo groups, respectively. In the enrolled patients, median OS was 12.7 and 11.1 months in the tivantinib and the placebo groups, respectively hazard ratio (HR) = 0.891, P = 0.427. Median PFS was 2.9 and 2.0 months in the tivantinib and the placebo groups, respectively (HR = 0.719, P = 0.019). The commonly observed grade ≥3 adverse events in the tivantinib group were neutropenia (24.3%), leukopenia (18.4%), febrile neutropenia (13.8%), and anemia (13.2%).
This study was prematurely terminated due to the increased ILD incidence in the tivantinib group. Although this study lacked statistical power because of the premature termination and did not demonstrate an improvement in OS, our results suggest that tivantinib plus erlotinib might improve PFS than erlotinib alone in nonsquamous NSCLC patients with WT-EGFR.
NCT01377376.
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