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On November 14, 2022, the U.S. Food and Drug Administration (FDA) granted accelerated approval to mirvetuximab soravtansine-gynx for treatment of adult patients with folate receptor-α (FRα)-positive, platinum-resistant epithelial ovarian, fallopian tube or primary peritoneal cancer who have received one to three prior systemic therapies. The VENTANA FOLR1 (FOLR-2.1) RxDx Assay was approved as a companion diagnostic device to select patients for this indication. Approval was based on Study 0417 (SORAYA, NCT04296890), a single-arm, multicenter trial. In 104 patients with measurable disease who received mirvetuximab soravtansine-gynx, the overall response rate was 31.7% (95% CI: 22.9, 41.6) with a median duration of response of 6.9 months (95% CI: 5.6, 9.7). Ocular toxicity was included as a Boxed Warning in the U.S. Prescribing Information (USPI) to alert providers of the risks of developing severe ocular toxicity including vision impairment and corneal disorders. Pneumonitis and peripheral neuropathy were additional important safety risks included as Warnings and Precautions in the USPI. This is the first approval of a targeted therapy for FRα-positive, platinum-resistant ovarian cancer and the first antibody-drug conjugate approved for ovarian cancer. This article summarizes the favorable benefit-risk assessment leading to FDA’s approval of mirvetuximab soravtansine-gynx.

On March 10, 2021, the FDA granted regular approval to tivozanib for treatment of patients with relapsed or refractory (R/R) advanced renal cell carcinoma (RCC) following two or more prior systemic therapies. Approval was based on the TIVO-3 study, a randomized trial of tivozanib versus sorafenib in patients with R/R advanced RCC. In TIVO-3, patients were randomized to receive either tivozanib 1.34 mg orally once daily for 21 consecutive days of every 28-day cycle or sorafenib 400 mg orally twice daily continuously. The primary endpoint was progression-free survival (PFS) per RECIST v1.1. Tivozanib demonstrated efficacy compared with sorafenib with an improvement in PFS [HR, 0.73; 95% confidence interval (CI), 0.56–0.95; P = 0.016]. The estimated median PFS was 5.6 months and 3.9 months in the tivozanib and sorafenib arms, respectively. There was no evidence of a detrimental effect on overall survival: HR, 0.97 (95% CI, 0.75–1.24). The most common grade 3 to 4 adverse reaction on the tivozanib arm was hypertension (24%). Compared with sorafenib, tivozanib was associated with lower rates of grade 3 to 4 diarrhea, rash, and palmar-plantar erythrodysesthesia. Patients receiving tivozanib in TIVO-3 had lower rates of dose reduction, interruption, or permanent discontinuation than those receiving sorafenib.

On December 16, 2020, the FDA granted regular approval to margetuximab-cmkb (MARGENZA), in combination with chemotherapy, for the treatment of adult patients with HER2-positive (HER2+) metastatic breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. Approval was based on data from SOPHIA, a multicenter, randomized, open-label, active controlled study comparing margetuximab with trastuzumab, in combination with chemotherapy. The primary efficacy endpoint was progression-free survival (PFS) by blinded independent central review. SOPHIA demonstrated a 0.9-month difference in median PFS between the two treatment arms [5.8 vs. 4.9 months, respectively; stratified HR, 0.76 (95% confidence interval: 0.59–0.98; P = 0.0334)]. Overall survival (OS) was immature at the data cut-off date of September 10, 2019. Infusion-related reactions (IRR) are an important safety signal associated with margetuximab plus chemotherapy. In SOPHIA, 13% of patients treated with margetuximab plus chemotherapy reported IRRs, of which 1.5% were grade 3. The most commonly reported adverse drug reactions (>10%) with margetuximab in combination with chemotherapy were fatigue/asthenia, nausea, diarrhea, vomiting, constipation, headache, pyrexia, alopecia, abdominal pain, peripheral neuropathy, arthralgia/myalgia, cough, decreased appetite, dyspnea, IRR, palmar-plantar erythrodysesthesia, and extremity pain. Overall, the favorable risk-benefit profile for margetuximab when added to chemotherapy supported its approval for the intended indication.

A 3D digital model of a small Unmanned Aerial Vehicle (UAV) is obtained by using the method of scanning reverse modeling and joint mapping. A numerical simulation of a small UAV strikes on rotary engine blades, presented in this paper, was performed with a Transient Nonlinear Finite Element code PAM-CRASH software. A test of motor strike on plate was developed and the dynamic response of the plate were obtained to validate the numerical simulation method of a UAV strike on blades. Based on this, dynamic damage response caused by UAV on the engine blades were studied. It is indicated that the impact process between the UAV and a single blade can be divided into two typical stages: cutting and impact. Cutting mainly leads to the failure of the leading edge material, and impact mainly leads to the plastic deformation of the blade. At the same time, it is compared with the damage impacted by bird with the same mass. For the same mass of bird and UAV, the damage caused by UAV striking fan blade is more serious, and 1.345 kg UAV striking fan blade of typical civil aviation engine is enough to cause damage to flight safety.

Unmanned Aerial Vehicles (UAV) may lose control and collide with other objects in the air, thus causing serious flight safety accidents. In this paper, the impact load and damage mechanism of 4.78 ...

Purpose Airports are booming in China, to enlarge their capacities and stimulate economic development. Large-span spatial steel structures are commonly used in the terminal buildings of airport projects. Their advantages include prefabrication, strength, usability, adaptability and aesthetic quality. To manage large-span spatial steel structure projects, building information modeling (BIM) is recommended. Although there are plenty of studies on BIM application in steel structure projects, it is still rare to apply BIM to optimize the schedule and cost of steel structures, especially for airport projects. Design/methodology/approach This paper aims to develop a framework in which BIM and a time-cost optimization model are integrated to optimize construction costs and the duration of large-span spatial steel structure projects. A real case study was conducted to verify the feasibility of the BIM-based time-cost optimization model in an airport terminal building, which was built with a large-span spatial steel structure. Findings The results preliminarily support the reliability of the proposed BIM-based time-cost optimization model. The BIM-based time-cost optimization model will benefit construction planning for professionals and enrich relevant research on the application of BIM in large-span spatial steel structure projects. Originality/value The steel structure is difficult to control budgets and progress. This paper is expected to be adopted for optimizing the time and cost plans for projects involving steel structures in airport terminal buildings.

On April 17, 2020, the FDA approved tucatinib in combination with trastuzumab and capecitabine for the treatment of patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting. This was the first new molecular entity evaluated under Project Orbis, an FDA Oncology Center of Excellence initiative, which supports concurrent review of oncology drugs by multiple global health authorities. Approval was based on the HER2CLIMB trial, which randomized patients to receive tucatinib or placebo with trastuzumab and capecitabine. Tucatinib demonstrated efficacy compared with placebo in progression-free survival [PFS; HR: 0.54; 95% confidence interval (CI): 0.42–0.71; P < 0.00001] and overall survival (OS; HR: 0.66; 95% CI, 0.50–0.87; P = 0.00480). Patients with either treated and stable or active brain metastases made up 48% of the study population. PFS in patients with brain metastases confirmed benefit (HR: 0.48; 95% CI, 0.34–0.69; P < 0.00001). The benefit in patients with brain metastases allowed for inclusion of this specific population in the indication. Important safety signals included diarrhea and hepatotoxicity which are listed under Warnings and Precautions. This article summarizes the FDA thought process and data supporting the favorable benefit–risk profile and approval of tucatinib.

On June 29, 2020, the FDA approved pertuzumab, trastuzumab, and hyaluronidase-zzxf subcutaneous injection (Phesgo) for the treatment of patients with HER2-positive early-stage and metastatic breast cancer. Patients should be selected for therapy based on an FDA-approved companion diagnostic test. Approval was primarily based on the FeDeriCa trial, a randomized, open-label, multicenter comparability study of pertuzumab, trastuzumab, and hyaluronidase-zzxf subcutaneous injection compared with intravenous pertuzumab and intravenous trastuzumab administered in the neoadjuvant and adjuvant settings with chemotherapy for the treatment of patients with early breast cancer. The pharmacokinetic endpoints were, first, to demonstrate that the exposure of subcutaneous pertuzumab was not inferior to that of intravenous pertuzumab, and then to demonstrate that the exposure of subcutaneous trastuzumab was not inferior to that of intravenous trastuzumab. The primary endpoints were met with the observed lower limit of the two-sided 90% confidence intervals above the prespecified noninferiority margins. The most common adverse reactions were alopecia, nausea, diarrhea, anemia, and asthenia. The totality of the evidence demonstrated comparability of the subcutaneous product to intravenous, allowing for extrapolation and approval of all breast cancer indications for which intravenous trastuzumab and pertuzumab are approved.

Public engagement and public consultation are increasingly applied to involve stakeholders in the decision making process of construction projects. However, it is difficult for multiple stakeholder...

Background Pyroptosis could regulate tumor cell trafficking, invasion, and metastasis, as well as tumor microenvironment (TME). However, prognostic characteristics of pyroptosis-related genes (PRGs) and their impact on the progression of glioma remain insufficient. Methods The genetic, transcriptional, and survival data of glioma patients used for bioinformatics analysis were obtained from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) databases. Results We first screened two different molecular subtypes and found that PRG variations were associated with the characteristics of TME cell infiltration, clinicopathological characteristics, and prognosis of patients with glioma. After Cox regression of differentially expressed genes, a risk-score for predicting overall survival (OS) and progression-free survival (PFS) was calculated and its predictive accuracy in glioma patients was then validated. The high-risk group of PRGs signature showed a significantly poor OS compared to the low-risk group (training cohort, p

Due to the rapid growth of the ageing population and the shrinking of family size in China, there has been a steady increase in the demand for nursing homes. The Chinese government has encouraged the development of nursing homes. However, there is no clear understanding of the thermal environment of nursing homes and the thermal comfort of their residents. Therefore, this paper describes a pilot study that was undertaken to investigate the thermal comfort of senior residents living in nursing homes. A wireless sensor network system was developed to continuously monitor the thermal environment of nursing homes for an entire year. Site measurements and a questionnaire also were conducted. The results revealed significant seasonal variations in the thermal environment of nursing homes and in the thermal comfort, thermal sensation and adaptive behaviours of older adults. The calculation of thermal comfort was modified according to the older adults’ behaviour patterns. The knowledge acquired in this initial study will enrich knowledge of the thermal comfort of older adults living in nursing homes. It also will provide preliminary insights for caregivers, designers and policymakers in their efforts to deliver a more comfortable, healthy and sustainable environment in nursing homes in China.

Purpose Aging-friendly environments have been encouraged to develop at the city level, district level and community level in China. In the process of rapid urbanization, the state of aging-friendly communities in old and new neighborhoods is disparate. Hence, the purpose of this paper is to investigate aging-friendly communities and identify the disparities in old and new neighborhoods. Design/methodology/approach A total of 1,172 elderly respondents completed the survey. Of these, 576 seniors lived in an old community developed before 2000, and 596 lived in a new community developed after 2000. In total, 17 physical environment factors and 10 social environment factors were identified. Findings The results indicated that public spaces, facilities and transportation in old neighborhoods were inferior to those in new neighborhoods. Most social environment factors in new neighborhoods achieved higher satisfaction levels than those in old neighborhoods. The satisfaction levels of aging-friendly community factors in both old and new neighborhoods were below the expectation levels of elders. Practical implications In order to improve physical aging-friendly environments in old neighborhoods, it is suggested that full use is made of school facilities and the renovation of old buildings. The locations of public transportation stations in new neighborhoods are recommended to be revised within 5-min walking distances of senior residents. Both old and new neighborhoods are encouraged to improve social aging-friendly environments by increasing the coverage of medical services and creating multiple approaches to recreation activities. Originality/value These findings have empirical significance for urban planners and policy makers, in regard to identifying disparities between old and new neighborhoods, and understanding the equitable allocation and distribution of urban resources.

An airborne collision between civil Unmanned Aerial Systems (UASs) and manned aircraft is a potential threat to the aircraft operation safety. In this paper, a structure level UAS collision ground test was performed on a commercial airliner horizontal stabilizer section to investigate the dynamic response of this primary operation component. The projectile was a 3.4 kg quadcopter named ‘Inspire I’. Explicit dynamic code PAM-CRASHR was employed to simulate the collision process and the modeling procedures were modified through comparison with test data, followed by series of simulations to assess the hazard of different collision scenarios. The results showed that 3.4 kg drone impact at the airliner cruising speed could cause some damage on the horizontal stabilizer front spar and the situation is more serious than 3.6 kg bird strike in which the hardness of drone components rather than kinetic energy is a decisive factor. The lithium-ion battery penetrated into the airframe had a smoke sign in the test, which might be a potential ignition source.

Background A nivolumab dosage regimen of 480mg intravenously (i.v.) every 4weeks (Q4W) was approved by FDA for the majority of the approved indications for nivolumab. Methods The proposed new dosage regimen was supported by pharmacokinetic modeling and simulation, dose/exposure–response relationships for efficacy and safety in the indicated patient populations, and the clinical safety data with the 480mg Q4W dosage regimen. Pharmacokinetic exposures achieved with 480mg Q4W were predicted for 4166 patients in 21 clinical studies with various types of solid and hematological tumors. Exposure–response analyses were conducted to predict 480mg Q4W safety and efficacy across all FDA-approved indications for nivolumab. Results For the overall population, the geometric mean exposure achieved with 480mg i.v. Q4W was 5.2% higher for steady state Cavg and 15.6% lower for Ctrough than those with 3mg/kg i.v. Q2W, the approved dosage regimen. The simulated concentration–time course achieved with 480mg Q4W regimen was below the median concentration achieved with 10mg/kg i.v. Q2W that was also studied in clinical trials. The predicted probability of adverse events was similar between 480mg Q4W and that observed with the 3mg/kg Q2W regimen. Efficacy results were found to be similar between Q2W and Q3W dosage regimens in patients with renal cell carcinoma. The predicted efficacy for each indication suggested that the efficacy with 480mg Q4W is unlikely to be compromised compared with that observed with 3mg/kg Q2W. Conclusions The model-informed analyses of predicted exposure, efficacy and safety based on data from extensive clinical experience with nivolumab suggest that the benefit–risk profile of 480mg Q4W regimen is comparable to the approved 3mg/kg Q2W regimen, thus providing the regulatory basis for the approval of 480mg Q4W regimen in the absence of clinical efficacy data with this new dosage regimen.

The aging population in rural areas of China faces serious challenges due to urban–rural disparities. In order to improve the active aging of rural older adults, the establishment of age-friendly communities is encouraged. However, globally, the focus is on age-friendly communities in urban areas, not reflecting rural communities. Hence, we addressed the importance of age-friendly rural communities (AFRCs) and aimed to investigate their impact on the quality of life (QoL) of older adults. We examined different perceptions of AFRCs among older adults (aged over 60) and middle-aged people (45–60) in rural communities with questionnaire surveys (n = 470 and 393, respectively). Several statistical methods, such as Chi-squared test, t-test, reliability test, and multiple regression, were adopted to investigate and compare the perceptions of these two. The results indicated that (1) middle-aged people were more satisfied with AFRC components and had a higher QoL than older adults, (2) the QoL of middle-aged people was predicted by housing, accessibility, and outdoor spaces, (3) the QoL of older adults was affected by housing, outdoor spaces, social participation, and public transportation. These findings aid in our understanding of rural communities and the QoL of rural residents. They are helpful for urban planners and policymakers to improve the planning of AFRCs and supplement research on age-friendly communities in rural areas. Practical implementations are proposed for the planning of AFRCs, such as the passive design of residential housing, grouping of community facilities together, and improvement in the hygiene of outdoor spaces in rural areas.

Model-informed drug development (MIDD) has been a powerful and efficient tool applied widely in pediatric drug development due to its ability to integrate and leverage existing knowledge from different sources to narrow knowledge gaps. The dose selection is the most common MIDD application in regulatory submission related to pediatric drug development. This article aims to give an overview of the 3 broad categories of use of MIDD in pediatric dose selection: leveraging from adults to pediatric patients, leveraging from animals to pediatric patients, and integrating mechanism in infants and neonates. Population pharmacokinetic analyses with allometric scaling can reasonably predict the clearance in pediatric patients aged >5 years. A mechanistic-based approach, such as physiologically based pharmacokinetic accounting for ontogeny, or an allometric model with age-dependent exponent, can be applied to select the dose in pediatric patients aged ≤2 years. The exposure-response relationship from adults or from other drugs in the same class may be useful in aiding the pediatric dose selection and benefit-risk assessment. Increasing application and understanding of use of MIDD have contributed greatly to several policy developments in the pediatric field. With the increasing efforts of MIDD under the Prescription Drug User Fee Act VI, bigger impacts of MIDD approaches in pediatric dose selection can be expected. Due to the complexity of model-based analyses, early engagement between drug developers and regulatory agencies to discuss MIDD issues is highly encouraged, as it is expected to increase the efficiency and reduce the uncertainty.

On December 20, 2019, the FDA granted accelerated approval to fam-trastuzumab deruxtecan-nxki [DS-8201a; T-DXd; tradename ENHERTU (Daiichi Sankyo)] for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2–based regimens in the metastatic setting. Approval was based on data from study DS8201-A-U201 (DESTINY-Breast01) with supportive safety data from study DS8201-A-J101. The primary efficacy endpoint in DESTINY-Breast01 was overall response rate (ORR) based on confirmed responses by blinded independent central review (ICR) using RECIST v1.1 in all participants who were assigned to receive the recommended dose of 5.4 mg/kg while secondary endpoints included duration of response (DoR). The confirmed ORR based on ICR in these 184 patients was 60.3% [95% confidence interval (CI): 52.9–67.4] and the median DoR was 14.8 months (95% CI: 13.8–16.9). Interstitial lung disease, including pneumonitis, was experienced in patients treated with T-DXd and can be severe, life threatening, or fatal. In addition, neutropenia and left ventricular dysfunction were included as Warnings and Precautions in labeling. Other important common adverse reactions were nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, diarrhea, and thrombocytopenia. Overall, the totality of efficacy and safety data supported the accelerated approval of T-DXd for the intended indication.

On May 24, 2019, the FDA granted regular approval to alpelisib in combination with fulvestrant for postmenopausal women, and men, with hormone receptor (HR)-positive, HER2-negative, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen. Approval was based on the SOLAR-1 study, a randomized, double-blind, placebo-controlled trial of alpelisib plus fulvestrant versus placebo plus fulvestrant. The primary endpoint was investigator-assessed progression-free survival (PFS) per RECIST v1.1 in the cohort of trial participants whose tumors had a PIK3CA mutation. The estimated median PFS by investigator assessment in the alpelisib plus fulvestrant arm was 11 months [95% confidence interval (CI), 7.5–14.5] compared with 5.7 months (95% CI, 3.7–7.4) in the placebo plus fulvestrant arm (HR, 0.65; 95% CI, 0.50–0.85; two-sided P = 0.001). The median overall survival was not yet reached for the alpelisib plus fulvestrant arm (95% CI, 28.1–NE) and was 26.9 months (95% CI, 21.9–NE) for the fulvestrant control arm. No PFS benefit was observed in trial participants whose tumors did not have a PIK3CA mutation (HR, 0.85; 95% CI, 0.58–1.25). The most common adverse reactions, including laboratory abnormalities, on the alpelisib plus fulvestrant arm were increased glucose, increased creatinine, diarrhea, rash, decreased lymphocyte count, increased gamma glutamyl transferase, nausea, increased alanine aminotransferase, fatigue, decreased hemoglobin, increased lipase, decreased appetite, stomatitis, vomiting, decreased weight, decreased calcium, decreased glucose, prolonged activated partial thromboplastin time, and alopecia.

On December 18, 2019, the FDA granted accelerated approval to enfortumab vedotin-ejfv (PADCEV; Astellas and Seattle Genetics) for treatment of patients with locally advanced or metastatic urothelial cancer who have previously received a programmed cell death protein 1 or programmed death ligand 1 inhibitor, and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting. Substantial evidence of effectiveness for this application is obtained from Cohort 1 of the single-arm, multicenter Study EV-201. Patients received enfortumab vedotin (EV) 1.25 mg/kg (up to a maximum dose of 125 mg) intravenously on days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity. Confirmed objective response rate in the 125-patient efficacy population determined by blinded independent central review was 44% [95% confidence interval (CI), 35.1–53.2], with complete responses in 12%. Median response duration was 7.6 months (95% CI, 6.3–not estimable). Grade 3–4 adverse reactions occurred in 73% of patients. Hyperglycemia, peripheral neuropathy, ocular disorders, skin reactions, infusion site extravasations, and embryo-fetal toxicity are labeled as warnings and precautions for EV. The article summarizes the data and the FDA thought process supporting accelerated approval of EV. This approval may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

Phenytoin demonstrates time-dependent and nonlinear pharmacokinetics (PK) within the therapeutic range of 10 to 20 μg/mL. There are discussions on the relevance of bioequivalence (BE) demonstrated in a single-dose BE study in healthy subjects to exposure under chronic use conditions in patients, particularly given that phenytoin has a narrow therapeutic index. The objective of this study was to quantitatively evaluate the appropriateness of single-dose PK BE through simulations for the phenytoin extended-capsule products. A previously published population PK model was updated to account for the interoccasion variability using the dense PK data of the reference listed drug (Dilantin) from 5 single-dose, fully replicated BE studies (n = 124). BE studies with alternative designs were simulated using the developed PK model and subsequently analyzed accordingly: Scenario 1, multiple-dose, 2-period, crossover BE studies with an average BE approach; Scenario 2, single-dose, 4-period, fully replicated BE studies with a reference-scaled average BE approach as recommended in the product-specific guidance. In both scenarios, hypothetical phenytoin capsules with different formulation-related PK parameters, such as relative bioavailability and absorption rates, were included in the simulations. The results showed that the both scenarios provided the same results with respect to BE conclusions.

Periodic fever syndromes are a group of rare diseases with a highly variable onset, yet limited treatment options are available for children at an early age. Canakinumab has been approved to treat patients with cryopyrin-associated periodic syndrome, a periodic fever syndrome, and systemic juvenile systemic arthritis, with age cutoffs of 4 years and 2 years, respectively. In 2016, the US Food and Drug Administration (FDA) approved canakinumab, without an age restriction, for the treatment of three conditions of periodic fever syndromes, including familial Mediterranean fever, hyperimmunoglobulin D syndrome/mevalonate kinase deficiency, and tumor necrosis factor receptor-associated periodic syndrome. This review discusses the pharmacokinetic (PK), efficacy, safety, and exposure-response relationship of canakinumab and provides the rationale for dosage recommendation in children younger than 2 years of age with the three conditions of periodic fever syndromes. The approval of canakinumab for these pediatric patients addresses a critical unmet medical need.

On July 17, 2017, the FDA approved neratinib (NERLYNX; Puma Biotechnology, Inc.) for the extended adjuvant treatment of adult patients with early-stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy. Approval was based on data from ExteNET, a randomized, double-blind, placebo-controlled multicenter trial. Women with early-stage HER2-positive breast cancer and within 2 years of completing adjuvant trastuzumab were randomized to neratinib (n = 1,420) or placebo (n = 1,420) for 1 year. The primary endpoint was invasive disease-free survival (iDFS), defined as the time between randomization date to first occurrence of invasive recurrence (local/regional, ipsilateral, or contralateral breast cancer), distant recurrence, or death from any cause, with 2 years and 28 days of follow-up. The trial showed a statistically significant treatment effect favoring neratinib with a stratified HR of 0.66 [95% confidence interval (CI), 0.49–0.90, P = 0.008]. The estimated iDFS rate at 2 years was 94.2% (95% CI, 92.6%–95.4%) in patients treated with neratinib versus 91.9% (95% CI, 90.2%–93.2%) in those receiving placebo. Diarrhea was the most common adverse event (AE), with a 40% incidence of grade 3 or 4 diarrhea, and represents the most common AE leading to treatment discontinuation. Other frequent AEs (>10% incidence) were nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, and muscle spasms. Other than diarrhea, neratinib is associated with a low incidence of severe AEs; toxicities are generally reversible and manageable with dose interruptions, dose reductions, and/or standard medical care. This article summarizes FDA decision-making and data supporting the neratinib approval. Clin Cancer Res; 24(15); 3486–91. ©2018 AACR. See related commentary by Unni et al., p. 3483

Due to accelerated population ageing, the demand for nursing homes has greatly increased in China. As older adults spend most of the day indoors, it is of great importance to improve indoor environmental quality (IEQ) to provide a comfortable living environment for senior residents in nursing homes. Therefore, this study aims to investigate older adults' acceptance of the IEQ in nursing homes using both subjective and objective methods. A questionnaire survey was conducted to collect subjective acceptance levels regarding IEQ in nursing homes (including air temperature, relative humidity, indoor air quality (IAQ), visual environment, and acoustic environment). Objective data on five environmental parameters (i.e., air temperature, relative humidity, CO2 concentration, illuminance level, and noise level) were collected using a wireless sensor network (WSN) system. A machine learning predictive model was established to assess IEQ acceptance on the basis of the data from the questionnaire survey and the WSN. The results showed that subjective assessments on five aspects of IEQ and objective measurements on five environmental parameters were related to overall IEQ acceptance. Air temperature had the greatest impact on the overall IEQ acceptance, while visual environment and illuminance level had the least influence. The study offers useful information on improving IEQ in nursing homes and helping to enhance older adults’ quality of life.

On December 19, 2016, the FDA granted accelerated approval to rucaparib (RUBRACA; Clovis Oncology, Inc.) for the treatment of patients with deleterious BRCA mutation (germline and/or somatic)–associated advanced ovarian cancer who have been treated with two or more chemotherapies. The FDA also approved the FoundationFocus CDxBRCA test (Foundation Medicine, Inc.), the first next-generation sequencing-based companion diagnostic, for identifying patients with advanced ovarian cancer eligible for treatment with rucaparib based on detection of deleterious BRCA1 and/or BRCA2 mutations in tumor tissue. Rucaparib's approval was based primarily on efficacy data from 106 patients with BRCA mutation–associated ovarian cancer who had prior treatment with two or more chemotherapies and safety data from 377 patients with ovarian cancer treated with rucaparib 600 mg orally twice daily on two open-label, single-arm trials. Investigator-assessed objective response rate was 54% [57/106; 95% confidence interval (CI), 44–64], and median duration of response was 9.2 months (95% CI, 6.6–11.7). The approved companion diagnostic verified tumor BRCA mutation status retrospectively in 96% (64/67) of patients. Common adverse reactions (≥20%) to rucaparib were nausea, fatigue, vomiting, anemia, abdominal pain, dysgeusia, constipation, decreased appetite, diarrhea, thrombocytopenia, and dyspnea. This article summarizes the FDA review and data supporting rucaparib's accelerated approval. Clin Cancer Res; 23(23); 7165–70. ©2017 AACR. See related commentary by Kohn et al., p. 7155

Purpose The ageing of rural Chinese populations is challenging health and social policy, driving growth in rural nursing homes. Living environment plays a role in enhancing elderly quality of life (QoL), however, the impact of the built environment and care services are under-studied. The purpose of this paper is to investigate the influence of the built environment and care services on the QoL of elderly people within rural nursing homes in China. Design/methodology/approach A total of 242 residents of nursing home were surveyed, of which 76 percent were male and 24 percent were female. In total, 25.6 percent were aged between 60 and 69, 40.1 percent between 70 and 79, 31 percent between 80 and 89, and 3.3 percent were 90 or above. Quantitative data were analyzed through factor analysis, reliability test and multiple regression modeling. Findings The authors identified six built environment factors (room distance, space, barrier-free design, indoor environment, fire safety, and support facilities) and three services factors (i.e. daily care services, cleaning services, and healthcare services). QoL was measured over four dimensions: QoL, physical health, psychological health, and social relationships. Elderly QoL could be accurately predicted from room distance, space, barrier-free design, indoor environment, daily care services, and cleaning services. Practical implications Interventions in design of the built environment and the provision of care services are proposed, including dimensions of living space, heating, and provisions for qualified care providers. Originality/value This paper provides a clear picture about elderly special requirements on their built environment and healthcare services, helping architects, engineers and facilities managers understand elderly needs and improve built environment during design and operation stages.

On September 4, 2014, the FDA approved pembrolizumab (KEYTRUDA; Merck Sharp & Dohme Corp.) with a recommended dose of 2 mg/kg every 3 weeks by intravenous infusion for the treatment of patients with unresectable or metastatic melanoma who have progressed following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on demonstration of objective tumor responses with prolonged response durations in 89 patients enrolled in a randomized, multicenter, open-label, dose-finding, and activity-estimating phase 1 trial. The overall response rate (ORR) by blinded independent central review per RECIST v1.1 was 24% (95% confidence interval, 15–34); with 6 months of follow-up, 86% of responses were ongoing. The most common (≥20%) adverse reactions were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. Immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, hypophysitis, and thyroid disorders. The benefits of the observed ORR with prolonged duration of responses outweighed the risks of immune-mediated adverse reactions in this life-threatening disease and represented an improvement over available therapy. Important regulatory issues in this application were role of durability of response in the evaluation of ORR for accelerated approval, reliance on data from a first-in-human trial, and strategies for dose selection. Clin Cancer Res; 23(19); 5666–70. ©2017 AACR.

This FDA approval summary provides an update on approval of pembrolizumab for treatment of patients with metastatic non‐small cell lung cancer whose tumors express PD‐L1 as determined by an FDA‐approved test. The results of KEYNOTE‐010 and KEYNOTE‐024 trials are presented., On October 24, 2016, the U.S. Food and Drug Administration (FDA) approved pembrolizumab (Keytruda; Merck & Co., Inc., https://www.merck.com) for treatment of patients with metastatic non‐small cell lung cancer (mNSCLC) whose tumors express programmed death‐ligand 1 (PD‐L1) as determined by an FDA‐approved test, as follows: (a) first‐line treatment of patients with mNSCLC whose tumors have high PD‐L1 expression (tumor proportion score [TPS] ≥50%), with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations, and (b) treatment of patients with mNSCLC whose tumors express PD‐L1 (TPS ≥1%), with disease progression on or after platinum‐containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA‐approved therapy for these aberrations prior to receiving pembrolizumab. Approval was based on two randomized, open‐label, active‐controlled trials demonstrating statistically significant improvements in progression‐free survival (PFS) and overall survival (OS) for patients randomized to pembrolizumab compared with chemotherapy. In KEYNOTE−024, patients with previously untreated mNSCLC who received pembrolizumab (200 mg intravenously [IV] every 3 weeks) had a statistically significant improvement in OS (hazard ratio [HR] 0.60; 95% confidence interval [CI]: 0.41–0.89; p = .005), and significant improvement in PFS (HR 0.50; 95% CI: 0.37–0.68; p

The FDA approved TAS-102 (Lonsurf; Taiho Oncology, Inc.) for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti-VEGF biological therapy; and if RAS wild type, an anti-EGFR therapy. In an international, multicenter, double-blinded, placebo-controlled trial (TPU-TAS-102-301, herein referred to as RECOURSE), 800 patients with previously treated mCRC were randomly allocated (2:1) to receive either TAS-102 35 mg/m2 orally twice daily after meals on days 1 through 5 and 8 through 12 of each 28-day cycle (n = 534) or matching placebo (n = 266). The trial demonstrated a statistically significant improvement in overall survival for those randomized to receive TAS-102, with a median survival of 7.1 months in the TAS-102 arm [confidence interval (CI), 6.5–7.8] and 5.3 months in the placebo arm [CI, 4.6–6.0; hazard ratio (HR), 0.68; 95% CI, 0.58–0.81; P < 0.001, stratified log-rank test]. The trial also demonstrated a statistically significant prolongation of progression-free survival (HR, 0.47; 95% CI, 0.40–0.55; P < 0.001). The most common adverse reactions, in order of decreasing frequency, observed in the patients who received TAS-102 were anemia, neutropenia, asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, and pyrexia. Adverse events led to discontinuation of TAS-102 in 3.6% of patients, and 13.7% required a dose reduction. The most common adverse reactions leading to dose reduction were neutropenia, anemia, febrile neutropenia, fatigue, and diarrhea. Clin Cancer Res; 23(12); 2924–7. ©2017 AACR.

Pembrolizumab is a monoclonal antibody that targets the programmed death-1 receptor to induce immune-mediated clearance (CL) of tumor cells. Originally approved by the US Food and Drug Administration in 2014 for treating patients with unresectable or metastatic melanoma, pembrolizumab is now also used to treat patients with non-small-cell lung cancer, classical Hodgkin lymphoma, head and neck cancer, and urothelial cancer. This paper describes the recently identified feature of pembrolizumab pharmacokinetics, the time-dependent or time-varying CL. Overall results indicate that CL decreases over the treatment period of a typical patient in a pattern well described by a sigmoidal function of time with three parameters: the maximum proportion change in CL from baseline (approximately Imax or exactly eImax − 1), the time to reach Imax/2 (TI50), and a Hill coefficient. Best overall response per response evaluation criteria in solid tumor category was found to be associated with the magnitude of Imax.

This article summarizes the evidence for the impact of BRAF mutations on treatment outcome of anti‐EGFR monoclonal antibodies. Based on a review of literature, eight meta‐analyses were included in this study, which consistently show that patients with BRAF mutations have a lack of treatment benefit of anti‐EGFR monoclonal antibodies. Considering the quality and quantity of available evidence, current guidelines may be revised., On August 5, 2016, the U.S. Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA injection, Merck Sharp & Dohme Corp., Kenilworth, NJ) for treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum‐containing chemotherapy. Approval was based on the objective response rate (ORR) and duration of response (DoR) in a cohort of patients in a nonrandomized multi‐cohort trial (KEYNOTE‐012) that included 174 patients with recurrent or metastatic HNSCC who had disease progression on or after platinum‐containing chemotherapy. Patients received either intravenous pembrolizumab 10 mg/kg every 2 weeks or 200 mg every 3 weeks. ORR was determined by independent review according to Response Evaluation Criteria in Solid Tumors 1.1. ORR was 16% (95% confidence interval 11, 22) with a complete response rate of 5%. DoR ranged from 2.4+ months to 27.7+ months. Twenty‐three of 28 responding patients (82%) had response durations of ≥6 months. Safety was evaluated in 192 patients with HNSCC receiving at least one dose of pembrolizumab. Frequent (≥2%) serious adverse reactions were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. Clinically significant immune‐mediated adverse reactions included pneumonitis, colitis, hepatitis, adrenal insufficiency, diabetes mellitus, skin toxicity, myositis, and thyroid disorders. The benefit‐risk profile of pembrolizumab was considered acceptable in this patient population. As a condition of accelerated approval, Merck is required to conduct a confirmatory trial; this trial, KEYNOTE‐040, is ongoing. Implications for Practice. This accelerated approval expands the U.S. Food and Drug Administration‐approved indications for pembrolizumab, providing health care providers with new information regarding pembrolizumab for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum‐containing chemotherapy. Pembrolizumab is the first drug to receive approval for treatment of patients with HNSCC since cetuximab was approved for this indication in 2006.

The unique challenges in pediatric drug development require efficient and innovative tools. Model-informed drug development (MIDD) offers many powerful tools that have been frequently applied in pediatric drug development. MIDD refers to the application of quantitative models to integrate and leverage existing knowledge to bridge knowledge gaps and facilitate development and decision-making processes. This article discusses the current practices and visions of applying MIDD in pediatric drug development, regulatory evaluation, and labeling, with detailed examples. The application of MIDD in pediatric drug development can be broadly classified into 3 categories: leveraging knowledge for bridging the gap, dose selection and optimization, and informing clinical trial design. In particular, MIDD can provide evidence for the assumption of exposure-response similarity in bridging existing knowledge from reference to target population, support the dose selection and optimization based on the "exposure-matching" principle in the pediatric population, and increase the efficiency and success rate of pediatric trials. In addition, the role of physiologically based pharmacokinetics in drug-drug interaction in children and adolescents and in utilizing ontogeny data to predict pharmacokinetics in neonates and infants has also been illustrated. Moving forward, MIDD should be incorporated into all pediatric drug development programs at every stage to inform clinical trial design and dose selection, with both its strengths and limitations clearly laid out. The accumulated experience and knowledge of MIDD has and will continue to drive regulatory policy development and refinement, which will ultimately improve the consistency and efficiency of pediatric drug development.

Traffic prediction is the key to intelligent traffic guidance, management and control. Aiming at the spatiotemporal characteristics of urban traffic and the complexity of nonlinear variation of traffic parameters, a long short-term memory network (LSTM) urban traffic condition prediction model (SA-LSTM) based on self-attention mechanism is proposed. SA-LSTM uses the self-attention mechanism to assign different weights to traffic state information in different space and time, reflecting the spatio-temporal correlation of traffic data prediction. It can also avoid the vanishing gradient problem faced by traditional RNN and improve the defect that LSTM cannot accurately express the different importance and spacio-temporal characteristic of traffic information. Based on SA-LSTM, experiments were conducted on the Shenzhen road network data and floating car data. LSTM and SA-LSTM were selected for Comparative verification experiments, and the results confirmed that SA-LSTM is superior to LSTM in multiple evaluation indicators. Moreover, the road spatio-temporal correlations obtained by traffic data analysis and obtained by model learning are highly consistent, which proves that SA-LSTM can precisely learn and express the spatio-temporal characteristics and changing trend of the traffic.

The rapid increase in elderly population has increased demand on care services and care and attention homes in Hong Kong. Elderly residents in care and attention homes rely heavily on facilities to maintain their quality of life. However, many care and attention homes are not purpose-built for elderly people. This paper investigates the relationship between facilities management of care and attention homes and elderly quality of life using both quantitative and qualitative data. A questionnaire was distributed among elders of eight recruited care and attention homes with four categories (government-financed non-purpose-built, government-financed purpose-built, self-financed non-purpose-built and self-financed purpose-built) in Hong Kong. Selected care and attention homes were a good mixture of operating types, building age and building types. A total of 56 questionnaires were completed by both elderly residents and staff in care and attention homes (37.5% were male and 62.5% were female), followed by semi-structured interviews; 48.2% of respondents were over 80 years of age and 93% had lived in C&A homes for more than one year. The findings identified 19 indoor facilities factors and also measured elderly quality of life. The results showed that space identification, distance, ventilation, furniture, non-slip floors and recreation facilities were positively related to elderly quality of life. Based on these findings, several practical recommendations are proposed, including allocating larger spaces for bedrooms, designing ventilation, installation of non-slip flooring, family-like furniture and the arrangement of recreational facilities.

Purpose The aging population is growing rapidly, causing significant increases in the demand for public housing. Normally, the elderly rely heavily on the facilities available in their living environment to maintain their quality of life (QoL). However, most public housing is not purposely designed for the elderly, and, thus, has inappropriate facilities, which often have a negative impact upon the physical and psychological health of residents. This paper aims to investigate the relationships between the indoor facilities management (FM) of public housing and the QoL of elderly persons. Design/methodology/approach Based on an extensive literature review, a questionnaire has been designed and distributed among elderly residents of different public housing buildings. To investigate the impact of indoor FM on the QoL of the senior residents in public housing, statistical analysis methods including reliability analysis and multiple regression modeling were adopted. Findings The study identified 12 indoor FM factors and six QoL domains (i.e. overall QoL, physical and psychological health, independence, social relationship and living environment). The results also reveal that space planning and bathroom influence most QoL domains, including overall QoL, physical/psychological health, independence and living environment of the elderly; electricity and noise mainly affect physical health and independence, while noise is negatively related to elderly QoL; and supporting facilities (including windows and doors, indoor decoration, non-slip floors and accessibility) have a positive impact on psychological health and social relationships. Practical implications Based on the current findings, several practical recommendations are made for the designers and facilities managers, including wide corridors for individuals with wheelchairs, the installation of single-lever-type mixers to provide a stable hot water supply and a window designed to get as much natural light as possible. Originality/value This paper provides a clear picture about elderly special requirements on indoor FM and their QoL. It can assist architects, engineers and facilities managers in public housing to understand elderly needs and improve FM during design and operation stages for enhancing QoL of elderly residents in public housing buildings.