Summary Background Osimertinib (AZD9291) is an oral, potent, irreversible EGFR tyrosine-kinase inhibitor selective for EGFR tyrosine-kinase inhibitor sensitising mutations, and the EGFR Thr790Met ...resistance mutation. We assessed the efficacy and safety of osimertinib in patients with EGFR Thr790Met-positive non-small-cell lung cancer (NSCLC), who had progressed after previous therapy with an approved EGFR tyrosine-kinase inhibitor. Methods In this phase 2, open-label, single-arm study (AURA2), patients aged at least 18 years with centrally confirmed EGFR Thr790Met-positive mutations, locally advanced or metastatic (stage IIIB/IV) NSCLC who progressed on previous EGFR tyrosine-kinase inhibitor therapy received osimertinib 80 mg orally once daily; treatment could continue beyond progression if the investigator observed a clinical benefit. Patients with asymptomatic, stable CNS metastases not requiring steroids were allowed to enrol. The primary endpoint was the proportion of patients achieving an objective response by blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1. Response endpoints were assessed in the evaluable for response analysis set (ie, all patients who received at least one dose of osimertinib and had measurable disease at baseline according to blinded independent central review). Other endpoints and safety were assessed in all patients receiving at least one osimertinib dose (full analysis set). The study is ongoing and patients are still receiving treatment. This study is registered with ClinicalTrials.gov , number NCT02094261. Findings Between May 20, 2014, and Sept 12, 2014, 472 patients were screened, of whom 210 started osimertinib treatment between June 13, 2014, and Oct 27, 2014; 11 patients were excluded from the evaluable for response analysis set (n=199) due to absence of measurable disease at baseline by blinded independent central review. At data cutoff (Nov 1, 2015), 122 (58%) patients remained on treatment. The median duration of follow-up was 13·0 months (IQR 7·6–14·2). 140 (70%; 95% CI 64–77) of 199 patients achieved an objective response by blinded independent central review: confirmed complete responses were achieved in six (3%) patients and partial responses were achieved in 134 (67%) patients. The most common all-causality grade 3 and 4 adverse events were pulmonary embolism (seven 3%), prolonged electrocardiogram QT (five 2%), decreased neutrophil count (four 2%), anaemia, dyspnoea, hyponatraemia, increased alanine aminotransferase, and thrombocytopenia (three 1% each). Serious adverse events were reported in 52 (25%) patients, of which 11 (5%) were investigator assessed as possibly treatment-related to osimertinib. Seven deaths were due to adverse events; these were pneumonia (n=2), pneumonia aspiration (n=1), rectal haemorrhage (n=1), dyspnoea (n=1), failure to thrive (n=1), and interstitial lung disease (n=1). The only fatal event assessed as possibly treatment-related by the investigator was due to interstitial lung disease. Interpretation Osimertinib showed clinical activity with manageable side-effects in patients with EGFR Thr790Met-positive NSCLC. Therefore, osimertinib could be a suitable treatment for patients with EGFR Thr790Met-positive disease who have progressed on an EGFR tyrosine-kinase inhibitor. Funding AstraZeneca.
Dual blockade of the EGFR and VEGF pathways in EGFR-mutated metastatic non-small-cell lung cancer (NSCLC) is supported by preclinical and clinical data, yet the approach is not widely implemented. ...RELAY assessed erlotinib, an EGFR tyrosine kinase inhibitor (TKI) standard of care, plus ramucirumab, a human IgG1 VEGFR2 antagonist, or placebo in patients with untreated EGFR-mutated metastatic NSCLC.
This is a worldwide, double-blind, phase 3 trial done in 100 hospitals, clinics, and medical centres in 13 countries. Eligible patients were aged 18 years or older (20 years or older in Japan and Taiwan) at the time of study entry, had stage IV NSCLC, with an EGFR exon 19 deletion (ex19del) or exon 21 substitution (Leu858Arg) mutation, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no CNS metastases. We randomly assigned eligible patients in a 1:1 ratio to receive oral erlotinib (150 mg/day) plus either intravenous ramucirumab (10 mg/kg) or matching placebo once every 2 weeks. Randomisation was done by an interactive web response system with a computer-generated sequence and stratified by sex, geographical region, EGFR mutation type, and EGFR testing method. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov, NCT02411448, and is ongoing for long-term survival follow-up.
Between Jan 28, 2016, and Feb 1, 2018, 449 eligible patients were enrolled and randomly assigned to treatment with ramucirumab plus erlotinib (n=224) or placebo plus erlotinib (n=225). Median duration of follow-up was 20·7 months (IQR 15·8–27·2). At the time of primary analysis, progression-free survival was significantly longer in the ramucirumab plus erlotinib group (19·4 months 95% CI 15·4–21·6) than in the placebo plus erlotinib group (12·4 months 11·0–13·5), with a stratified hazard ratio of 0·59 (95% CI 0·46–0·76; p<0·0001). Grade 3–4 treatment-emergent adverse events were reported in 159 (72%) of 221 patients in the ramucirumab plus erlotinib group versus 121 (54%) of 225 in the placebo plus erlotinib group. The most common grade 3–4 treatment-emergent adverse events in the ramucirumab plus erlotinib group were hypertension (52 24%; grade 3 only) and dermatitis acneiform (33 15%), and in the placebo plus erlotinib group were dermatitis acneiform (20 9%) and increased alanine aminotransferase (17 8%). Treatment-emergent serious adverse events were reported in 65 (29%) of 221 patients in the ramucirumab plus erlotinib group and 47 (21%) of 225 in the placebo plus erlotinib group. The most common serious adverse events of any grade in the ramucirumab plus erlotinib group were pneumonia (seven 3%) and cellulitis and pneumothorax (four 2%, each); the most common in the placebo plus erlotinib group were pyrexia (four 2%) and pneumothorax (three 1%). One on-study treatment-related death due to an adverse event occurred (haemothorax after a thoracic drainage procedure for a pleural empyema) in the ramucirumab plus erlotinib group.
Ramucirumab plus erlotinib demonstrated superior progression-free survival compared with placebo plus erlotinib in patients with untreated EGFR-mutated metastatic NSCLC. Safety was consistent with the safety profiles of the individual compounds in advanced lung cancer. The RELAY regimen is a viable new treatment option for the initial treatment of EGFR-mutated metastatic NSCLC.
Eli Lilly.
The galvanostatic lithiation/sodiation voltage profiles of hard carbon anodes are simple, with a sloping drop followed by a plateau. However, a precise understanding of the corresponding redox sites ...and storage mechanisms is still elusive, which hinders further development in commercial applications. Here, a comprehensive comparison of the lithium‐ and sodium‐ion storage behaviors of hard carbon is conducted, yielding the following key findings: 1) the sloping voltage section is presented by the lithium‐ion intercalation in the graphitic lattices of hard carbons, whereas it mainly arises from the chemisorption of sodium ions on their inner surfaces constituting closed pores, even if the graphitic lattices are unoccupied; 2) the redox sites for the plateau capacities are the same as those for the closed pores regardless of the alkali ions; 3) the sodiation plateau capacities are mostly determined by the volume of the available closed pore, whereas the lithiation plateau capacities are primarily affected by the intercalation propensity; and 4) the intercalation preference and the plateau capacity have an inverse correlation. These findings from extensive characterizations and theoretical investigations provide a relatively clear elucidation of the electrochemical footprint of hard carbon anodes in relation to the redox mechanisms and storage sites for lithium and sodium ions, thereby providing a more rational design strategy for constructing better hard carbon anodes.
A comprehensive comparison of the lithium‐ and sodium‐ion storage behaviors of hard carbon is conducted, yielding the key findings: the sloping voltage section is presented by the lithium‐ion intercalation in the graphitic lattices of hard carbons, whereas it mainly arises from the chemisorption of sodium ions. The intercalation preference and the plateau capacity have an inverse correlation.
There has been a tremendous amount of research in the past decade to optimize the mechanical properties and degradation behavior of the biodegradable Mg alloy for orthopedic implant. Despite the ...feasibility of degrading implant, the lack of fundamental understanding about biocompatibility and underlying bone formation mechanism is currently limiting the use in clinical applications. Herein, we report the result of long-term clinical study and systematic investigation of bone formation mechanism of the biodegradable Mg-5wt%Ca-1wt%Zn alloy implant through simultaneous observation of changes in element composition and crystallinity within degrading interface at hierarchical levels. Controlled degradation of Mg-5wt%Ca-1wt%Zn alloy results in the formation of biomimicking calcification matrix at the degrading interface to initiate the bone formation process. This process facilitates early bone healing and allows the complete replacement of biodegradable Mg implant by the new bone within 1 y of implantation, as demonstrated in 53 cases of successful long-term clinical study.
All cancers harbor molecular alterations in their genomes. The transcriptional consequences of these somatic mutations have not yet been comprehensively explored in lung cancer. Here we present the ...first large scale RNA sequencing study of lung adenocarcinoma, demonstrating its power to identify somatic point mutations as well as transcriptional variants such as gene fusions, alternative splicing events, and expression outliers. Our results reveal the genetic basis of 200 lung adenocarcinomas in Koreans including deep characterization of 87 surgical specimens by transcriptome sequencing. We identified driver somatic mutations in cancer genes including EGFR, KRAS, NRAS, BRAF, PIK3CA, MET, and CTNNB1. Candidates for novel driver mutations were also identified in genes newly implicated in lung adenocarcinoma such as LMTK2, ARID1A, NOTCH2, and SMARCA4. We found 45 fusion genes, eight of which were chimeric tyrosine kinases involving ALK, RET, ROS1, FGFR2, AXL, and PDGFRA. Among 17 recurrent alternative splicing events, we identified exon 14 skipping in the proto-oncogene MET as highly likely to be a cancer driver. The number of somatic mutations and expression outliers varied markedly between individual cancers and was strongly correlated with smoking history of patients. We identified genomic blocks within which gene expression levels were consistently increased or decreased that could be explained by copy number alterations in samples. We also found an association between lymph node metastasis and somatic mutations in TP53. These findings broaden our understanding of lung adenocarcinoma and may also lead to new diagnostic and therapeutic approaches.
The identification of the molecular events that drive cancer transformation is essential to the development of targeted agents that improve the clinical outcome of lung cancer. Many studies have ...reported genomic driver mutations in non-small-cell lung cancers (NSCLCs) over the past decade; however, the molecular pathogenesis of >40% of NSCLCs is still unknown. To identify new molecular targets in NSCLCs, we performed the combined analysis of massively parallel whole-genome and transcriptome sequencing for cancer and paired normal tissue of a 33-yr-old lung adenocarcinoma patient, who is a never-smoker and has no familial cancer history. The cancer showed no known driver mutation in EGFR or KRAS and no EML4-ALK fusion. Here we report a novel fusion gene between KIF5B and the RET proto-oncogene caused by a pericentric inversion of 10p11.22-q11.21. This fusion gene overexpresses chimeric RET receptor tyrosine kinase, which could spontaneously induce cellular transformation. We identified the KIF5B-RET fusion in two more cases out of 20 primary lung adenocarcinomas in the replication study. Our data demonstrate that a subset of NSCLCs could be caused by a fusion of KIF5B and RET, and suggest the chimeric oncogene as a promising molecular target for the personalized diagnosis and treatment of lung cancer.
Graphene-based nanosheets (GNS) have been studied for use in electrochemical energy storage devices. A deeper understanding about the system is required for achieving enhanced power output and high ...energy storage. The effects of sulfur doping on the electrochemical properties of GNS are studied for their use as an anode material in lithium-ion batteries. Sulfur doping in GNS contributes to the high specific capacity by providing more lithium storage sites due to Faradaic reactions. In addition, superior rate performance of sulfur-doped GNS (S-GNS) is achieved through the improved electrical conductivity of S-GNS (1743 S m super(-1)), which is two orders of magnitude higher than that of GNS (32 S rrr super(1)). In addition, good cyclic stability of S-GNS is maintained even after 500 cycles at a high current density of 1488 mA g super(-1) (4 C).
Magnetorheological (MR) elastomers become one of the most powerful smart and advanced materials that can be tuned reversibly, finely, and quickly in terms of their mechanical and viscoelastic ...properties by an input magnetic field. They are composite materials in which magnetizable particles are dispersed in solid base elastomers. Their distinctive behaviors are relying on the type and size of dispersed magnetic particles, the type of elastomer matrix, and the type of non-magnetic fillers such as plasticizer, carbon black, and crosslink agent. With these controllable characteristics, they can be applied to various applications such as vibration absorber, isolator, magnetoresistor, and electromagnetic wave absorption. This review provides a summary of the fabrication, properties, and applications of MR elastomers made of various elastomeric materials.
Background
In this open‐label, international phase 2 study, the authors assessed the efficacy and safety of olmutinib in patients with locally advanced or metastatic non–small cell lung cancer ...(NSCLC) who had a confirmed T790M mutation and disease progression on previous epidermal growth factor receptor‐tyrosine kinase inhibitor therapy.
Methods
Patients aged ≥20 years received once‐daily oral olmutinib 800 mg continuously in 21‐day cycles. The primary endpoint was the objective response rate (patients who had a confirmed best overall response of a complete or partial response), assessed by central review. Secondary endpoints included the disease control rate, the duration of objective response, progression‐free survival, and overall survival. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03).
Results
Overall, 162 patients (median age, 63 years; women, >60%) were enrolled from 68 sites in 9 countries. At the time of database cutoff, 23.5% of enrolled patients remained on treatment. The median treatment duration was 6.5 months (range, 0.03‐21.68 months). Overall, 46.3% of patients (95% CI, 38.4%‐54.3%) had a confirmed objective response (all partial responses). The best overall response (the objective response rate regardless of confirmation) was 51.9% (84 patients; 95% CI, 43.9%‐59.8%). The confirmed disease control rate for all patients was 86.4% (95% CI, 80.2%‐91.3%). The median duration of objective response was 12.7 months (95% CI, 8.3‐15.4 months). Estimated median progression‐free survival was 9.4 months (95% CI, 6.9‐12.3 months), and estimated median overall survival was 19.7 months (95% CI, 15.1 months to not reached). All patients experienced treatment‐emergent adverse events, and 71.6% of patients had grade ≥3 treatment‐emergent adverse events.
Conclusions
Olmutinib has meaningful clinical activity and a manageable safety profile in patients with T790M‐positive non–small cell lung cancer who received previous epidermal growth factor receptor‐tyrosine kinase inhibitor therapy.
Olmutinib (HM61713) is a third‐generation, mutation‐specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that targets mutant‐type EGFR and has minimal activity against wild‐type EGFR. This open‐label, international phase 2 study demonstrates the efficacy and safety of oral olmutinib 800 mg once daily in patients with locally advanced or metastatic non–small cell lung cancer who have a confirmed T790M mutation and disease progression on previous EGFR tyrosine kinase inhibitor therapy.
Objective
To investigate the accuracy of automated identification of cephalometric landmarks using the cascade convolutional neural networks (CNN) on lateral cephalograms acquired from nationwide ...multi‐centres.
Settings and sample population
A total of 3150 lateral cephalograms were acquired from 10 university hospitals in South Korea for training.
Materials and Methods
We evaluated the accuracy of the developed model with independent 100 lateral cephalograms as an external validation. Two orthodontists independently identified the anatomic landmarks of the test data set using the V‐ceph software (version 8.0, Osstem, Seoul, Korea). The mean positions of the landmarks identified by two orthodontists were regarded as the gold standard. The performance of the CNN model was evaluated by calculating the mean absolute distance between the gold standard and the automatically detected positions. Factors associated with the detection accuracy for landmarks were analysed using the linear regression models.
Results
The mean inter‐examiner difference was 1.31 ± 1.13 mm. The overall automated detection error was 1.36 ± 0.98 mm. The mean detection error for each landmark ranged between 0.46 ± 0.37 mm (maxillary incisor crown tip) and 2.09 ± 1.91 mm (distal root tip of the mandibular first molar). A significant difference in the detection accuracy among cephalograms was noted according to hospital (P = .011), sensor type (P < .01), and cephalography machine model (P < .01).
Conclusion
The automated cephalometric landmark detection model may aid in preliminary screening for patient diagnosis and mid‐treatment assessment, independent of the type of the radiography machines tested.
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