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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.

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.

P-nitrophenol (PNP) is a carcinogenic, teratogenic, and mutagenic compound that can cause serious harm to the environment. A strain of Pseudomonas putida DLL-E4, can efficiently degrade PNP in a complex process that is influenced by many factors. Previous studies showed that the expression level of pnpA, a key gene involved in PNP degradation, was upregulated significantly and the degradation of PNP was obviously accelerated in the presence of glucose. In addition, the expression of crc, crcY, and crcZ, key genes involved in catabolite repression, was downregulated, upregulated, and upregulated, respectively. To investigate the effect of the carbon catabolite repression (CCR) system on PNP degradation, the crc, crcY, and crcZ genes were successfully knocked out by conjugation experiments. Our results showed that the knockout of crc accelerated PNP degradation but slowed down the cell growth. However, the knockout of crcY or crcZ alone accelerated PNP degradation when PNP as the sole carbon source, but that knockout slowed down PNP degradation when glucose was added. The results indicate that the CCR system is involved in the regulation of PNP degradation, and further work is required to determine the details of the specific regulatory mechanism.

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 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.

Purpose: This article reports on a pilot study of a smart home for elders (SHfE) designed to continuously monitor senior adults’ daily behaviors and the living environment of their residential homes using the application of unobtrusive sensors. SHfE users include older adults, their family members, and healthcare staff. Background: Globally, countries are experiencing the challenges of an increasingly aging population. A healthy environment is essential to support aging in place. By applying information and communications technology to building environments to support health, smart homes may be an option to provide a low-cost, comfortable, and user-friendly living environment for older adults. Method: A pilot study was conducted in a capital city in the Yangtze River Delta Agglomerations in China to verify the feasibility of the SHfE. One female older adult participated in the pilot study, which was conducted from November 2015 to January 2016. Results: The results indicated that the SHfE is a feasible way to analyze the behaviors (e.g., sleeping, cooking, water usage) of the elder and monitor the built environment (e.g., temperature, windows, and doors). Conclusions: The pilot study can be used as a baseline for further comprehensive experiments, case studies, and surveys to gain a better understanding of a smart healthy environment for older adults. On the basis of the current study, several recommendations are put forward for further implementation of the SHfE, including integrating multiple unobtrusive sensing devices; detecting fall accidents; monitoring indoor lighting, noise, and ventilation; remotely controlling electrical appliances; and developing the system with various languages. It is anticipated that the SHfE will be adopted in seniors’ residential homes in countries around the world which face an increasingly aging population.

Time-varying clearance (CL) has been recently recognized in U.S. Food and Drug Administration drug labels for oncology monoclonal antibodies. Pembrolizumab population CL at steady state decreased about 20% from the first dose, and individual CL changes varied from 75% decrease to 25% increase, which were correlating with disease conditions. From mechanism of action perspective, this research explored the longitudinal covariate effect on pembrolizumab CL based on data from a phase II/III clinical trial in patients with non-small cell lung cancer. Time courses of sum of the longest tumor dimensions, lymphocyte count, albumin, and lactate dehydrogenase were first characterized separately, and the post hoc parameters of each individual patient were fixed in the subsequent semimechanistically based modeling analysis. Pembrolizumab time-varying CL was assumed to be associated with the patient's sum of the longest tumor dimensions, lymphocyte count, albumin, and lactate dehydrogenase, and tumor-related pembrolizumab CL was assumed to be a fraction of total pembrolizumab CL in the semimechanistically based modeling.

The FDA approved niraparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, on March 27, 2017, for maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response to platinum-based chemotherapy. Approval was based on data from the NOVA trial comparing niraparib with placebo in two independent cohorts, based on germline BRCA mutation status (gBRCAm vs. non-gBRCAm). Progression-free survival (PFS) in each cohort was the primary endpoint. In the gBRCAm cohort, estimated median PFS on niraparib was 21 months versus 5.5 months on placebo [HR, 0.26; 95% confidence interval (CI), 0.17–0.41; P < 0.0001]. In the non-gBRCAm cohort, estimated median PFS for niraparib and placebo was 9.3 and 3.9 months, respectively (HR, 0.45; 95% CI, 0.34–0.61; P < 0.0001). Common adverse reactions (>20% and higher incidence in the niraparib arm) with niraparib included thrombocytopenia, anemia, neutropenia, nausea, constipation, vomiting, mucositis, fatigue, decreased appetite, headache, insomnia, nasopharyngitis, dyspnea, rash, and hypertension. There were five cases of myelodysplastic syndrome and acute myeloid leukemia (1.4%) in patients treated with niraparib compared with two cases (1.1%) on placebo. Niraparib is the first PARP inhibitor approved as maintenance therapy for patients with ovarian, fallopian tube, or primary peritoneal cancer, with improvement in PFS, regardless of gBRCAm status. Clin Cancer Res; 24(17); 4066–71. ©2018 AACR. See related commentary by Konstantinopoulos and Matulonis, p. 4062

On March 13, 2017, the FDA approved ribociclib (KISQALI; Novartis Pharmaceuticals Corp.), a cyclin-dependent kinase 4/6 inhibitor, in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)–positive, HER2-negative advanced or metastatic breast cancer. The approval was based on a randomized, double-blind, placebo-controlled, international clinical trial (MONALEESA-2). A total of 668 patients were randomized to receive either ribociclib plus letrozole (n = 334) or placebo plus letrozole (n = 334). An improvement in progression-free survival (PFS) was observed in patients receiving ribociclib plus letrozole compared with patients receiving placebo plus letrozole [HR = 0.556; 95% confidence interval (CI), 0.429–0.720]. Overall response rate (ORR) in patients with measurable disease was 52.7% (95% CI, 46.6–58.9) in the ribociclib plus letrozole arm and 37.1% (95% CI, 31.1–43.2) in the placebo plus letrozole arm. Overall survival data were immature. The most common adverse reactions observed in 20% or more of patients taking ribociclib were neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, and back pain. This article summarizes FDA decision-making and data supporting the approval of ribociclib. Clin Cancer Res; 24(13); 2999–3004. ©2018 AACR. See related commentary by Spring and Bardia, p. 2981

Nivolumab is a human monoclonal antibody that blocks the interaction between PD-1 programmed death-1 (PD-1) and its ligands, PD-L1 and PD-L2. Nivolumab demonstrated efficacy in clinical trials for various types of cancer. A time-varying clearance was identified for nivolumab. We show that the change of clearance over time is associated with the post-treatment effects: clearance decreases when disease status improves. This interaction between posttreatment effects and drug exposure may lead to a biased steep estimate of the exposure-response (E-R) relationship for efficacy. Under this scenario, simulations were performed to develop a proposed methodology to assess the causal effect of drug exposure upon clinical response. Data from nivolumab trials were subsequently used to verify the proposed methodology for E-R analysis. The results showed that E-R analysis results based on pharmacokinetic (PK) metrics derived from the first dose are more consistent with the true E-R or dose-response relationship than the steady-state PK metrics.

On April 25, 2016, the FDA approved cabozantinib (Cabometyx; Exelixis, Inc.) for the treatment of advanced renal cell carcinoma (RCC) in patients who have received prior antiangiogenic therapy. The approval was based on data from one randomized, open-label, multicenter study in which patients with RCC who had received prior antiangiogenic therapy were treated with either cabozantinib 60 mg orally once daily (n = 330) or everolimus 10 mg orally once daily (n = 328). The major efficacy outcome measure was progression-free survival (PFS) as assessed by a blinded independent radiology review committee in the first 375 randomized patients. A statistically significant improvement in PFS was seen, with a median PFS of 7.4 and 3.8 months in the cabozantinib and everolimus arms, respectively [hazard ratio (HR), 0.58; 95% confidence interval (CI), 0.45–0.74; P < 0.0001]. At a second interim analysis, a statistically significant improvement in overall survival (OS) in the intent-to-treat population was also demonstrated, with a median OS of 21.4 and 16.5 months in the cabozantinib and everolimus arms, respectively (HR, 0.66; 95% CI, 0.53–0.83; P = 0.0003). The most common (greater than or equal to 25%) adverse reactions included diarrhea, fatigue, nausea, decreased appetite, palmar–plantar erythrodysesthesia syndrome, hypertension, vomiting, weight loss, and constipation. Clin Cancer Res; 23(2); 330–5. ©2016 AACR.

On December 11, 2015, the FDA granted accelerated approval to alectinib (Alecensa; Genentech) for the treatment of patients with anaplastic lymphoma receptor tyrosine kinase (ALK)-positive, metastatic non–small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This approval was based on two single-arm trials including 225 patients treated with alectinib 600 mg orally twice daily. The objective response rates (ORR) by an independent review committee in these studies were 38% [95% confidence interval (CI), 28–49] and 44% (95% CI, 36–53); the median durations of response (DOR) were 7.5 months and 11.2 months. In a pooled analysis of 51 patients with measurable disease in the central nervous system (CNS) at baseline, the CNS ORR was 61% (95% CI, 46–74); the CNS DOR was 9.1 months. The primary safety analysis population included 253 patients. The most common adverse reactions were fatigue (41%), constipation (34%), edema (30%), and myalgia (29%). The most common laboratory abnormalities were anemia (56%), increased aspartate aminotransferase (51%), increased alkaline phosphatase (47%), increased creatine phosphokinase (43%), hyperbilirubinemia (39%), hyperglycemia (36%), increased alanine aminotransferase (34%), and hypocalcemia (32%). Dose reductions due to adverse reactions occurred in 12% of patients, whereas 27% of patients had alectinib dosing interrupted for adverse reactions. Permanent discontinuation of alectinib due to adverse reactions occurred in only 6% of patients. With the clinically meaningful ORR and DOR as well as the safety profile observed in these trials, alectinib was determined to have a favorable benefit–risk profile for the treatment of the indicated population. Clin Cancer Res; 22(21); 5171–6. ©2016 AACR.

Construction workers (CWs) are positioned at the lowest level of an organization and thus have limited control over their work. For this reason, they are often deprived of their due rewards and training or sometimes are even compelled to focus on production at the expense of their own safety. These organizational stressors not only cause the CWs stress but also impair their safety behaviors. The impairment of safety behaviors is the major cause of CW injury incidents. Hence, to prevent injury incidents and enhance safety behaviors of CWs, the current study aimed to identify the impact of various organizational stressors and stress on CW safety behaviors and injury incidents. To achieve this aim, we surveyed 395 CWs. Using factor analysis, we identified five organizational stressors (unfair reward and treatment, inappropriate safety equipment, provision of training, lack of goal setting, and poor physical environment), two types of stress (emotional and physical), and safety behaviors. The results of correlation and regression analyses revealed the following: (1) injury incidents were minimized by safety behaviors but escalated by a lack of goal setting, (2) safety behaviors were maximized by moderate levels of emotional stress (i.e., an inverted U-shape relationship between these two variables) and increased in line with physical stress and inappropriate safety equipment, (3) emotional stress was positively predicted by the provision of training and inappropriate safety equipment, and (4) physical stress was predicted only by inappropriate safety equipment. Based on these results, we suggest various recommendations to construction stakeholders on how to prevent CW injury incidents.

Dose selection is one of the key decisions made during drug development in pediatrics. There are regulatory initiatives that promote the use of model-based drug development in pediatrics. Pharmacometrics or quantitative clinical pharmacology enables development of models that can describe factors affecting pharmacokinetics and/or pharmacodynamics in pediatric patients. This manuscript describes some examples in which pharmacometric analysis was used to support approval and labeling in pediatrics. In particular, the role of pharmacokinetic (PK) comparison of pediatric PK to adults and utilization of dose/exposure-response analysis for dose selection are highlighted. Dose selection for esomeprazole in pediatrics was based on PK matching to adults, whereas for adalimumab, exposure-response, PK, efficacy, and safety data together were useful to recommend doses for pediatric Crohn's disease. For vigabatrin, demonstration of similar dose-response between pediatrics and adults allowed for selection of a pediatric dose. Based on model-based pharmacokinetic simulations and safety data from darunavir pediatric clinical studies with a twice-daily regimen, different once-daily dosing regimens for treatment-naive human immunodeficiency virus 1-infected pediatric subjects 3 to

On February 3, 2015, the FDA granted accelerated approval to palbociclib (IBRANCE, Pfizer Inc.), an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. The approval is based on a randomized, multicenter, open-label phase I/II trial (PALOMA-1) in 165 patients randomized to palbociclib (125 mg orally daily for 21 consecutive days, followed by 7 days off treatment) plus letrozole (2.5 mg orally daily) or letrozole alone. The phase II portion of the trial was divided into two cohorts: cohort 1 enrolled 66 biomarker-unselected patients and cohort 2 enrolled 99 biomarker-positive patients. The major efficacy outcome measure was investigator-assessed progression-free survival (PFS). A large magnitude of improvement in PFS was observed in patients receiving palbociclib plus letrozole compared with patients receiving letrozole alone (HR, 0.488; 95% confidence interval, 0.319–0.748). Multiple sensitivity analyses were supportive of clinical benefit. The most common adverse reaction in patients receiving palbociclib plus letrozole was neutropenia. This article summarizes the FDA thought process and data supporting accelerated approval based on PALOMA-1 that may be contingent upon verification and description of clinical benefit in the ongoing and fully accrued confirmatory trial PALOMA-2. Clin Cancer Res; 21(21); 4760–6. ©2015 AACR.