Population pharmacokinetic modelling of tremelimumab in patients with advanced solid tumours and the impact of disease status on time-varying clearance.

AIMS: Tremelimumab, a cytotoxic T-lymphocyte-associated protein 4 human monoclonal antibody of the immunoglobulin G2 κ isotype, has been studied in oncology clinical trials as both monotherapy and in combination with durvalumab. This study characterized the pharmacokinetics of tremelimumab as monotherapy and in combination with durvalumab and evaluated the impact of patient covariates on pharmacokinetics. METHODS: A pooled-analysis population pharmacokinetics model was built using NONMEM methodology. Pharmacokinetic data from 5 studies spanning different tumour types and therapy regimens were pooled for model development (956 patients). A dataset pooled from 4 additional studies was used for external validation (554 patients). Demographic and relevant clinical covariates were explored during model development. RESULTS: Tremelimumab exhibited linear pharmacokinetics, well described by a 2-compartment model, with time-varying clearance (0.276 L/day at baseline) associated primarily with therapy regimen and linked with changes in disease status. As monotherapy and combination therapy, tremelimumab clearance over 1 year increased by ~16% and decreased by ~17%, respectively. Pharmacokinetic behaviour was consistent across patient demographics and cancer subtypes. Patients with higher bodyweight and lower albumin levels at baseline had significantly higher clearance; however, no dosage adjustments are warranted. A flat dose (75 mg) was projected to provide comparable exposure to weight-based dosing (1 mg/kg) in adults. CONCLUSION: Tremelimumab exhibited linear pharmacokinetics but consistently opposite trends of time-varying clearance as monotherapy and in combination with durvalumab. Baseline bodyweight and albumin were significant covariates, but conversion from weight-based dosing at 1 mg/kg to flat dosing at 75 mg had no clinically relevant impact.

Applications of Model-Based Meta-Analysis in Drug Development.

Model-based meta-analysis (MBMA) is a quantitative approach that leverages published summary data along with internal data and can be applied to inform key drug development decisions, including the benefit-risk assessment of a treatment under investigation. These risk-benefit assessments may involve determining an optimal dose compared against historic external comparators of a particular disease indication. MBMA can provide a flexible framework for interpreting aggregated data from historic reference studies and therefore should be a standard tool for the model-informed drug development (MIDD) framework.In addition to pairwise and network meta-analyses, MBMA provides further contributions in the quantitative approaches with its ability to incorporate longitudinal data and the pharmacologic concept of dose-response relationship, as well as to combine individual- and summary-level data and routinely incorporate covariates in the analysis.A common application of MBMA is the selection of optimal dose and dosing regimen of the internal investigational molecule to evaluate external benchmarking and to support comparator selection. Two case studies provided examples in applications of MBMA in biologics (durvalumab + tremelimumab for safety) and small molecule (fenebrutinib for efficacy) to support drug development decision-making in two different but well-studied disease areas, i.e., oncology and rheumatoid arthritis, respectively.Important to the future directions of MBMA include additional recognition and engagement from drug development stakeholders for the MBMA approach, stronger collaboration between pharmacometrics and statistics, expanded data access, and the use of machine learning for database building. Timely, cost-effective, and successful application of MBMA should be part of providing an integrated view of MIDD.

Knockdown of circ_0004104 Alleviates Oxidized Low-Density Lipoprotein-Induced Vascular Endothelial Cell Injury by Regulating miR-100/TNFAIP8 Axis.

ABSTRACT: Coronary artery disease (CAD) is a common cardiovascular disease, mainly due to vascular endothelial cell (VEC) injury caused by atherosclerosis. Circular RNA has been shown to be involved in the regulation of various diseases. However, the role and mechanism of circ_0004104 in CAD are still unclear. Oxidized low-density lipoprotein (ox-LDL) was used to construct the VEC injury model in vitro. The expression levels of circ_0004104 and miR-100 were measured by quantitative real-time polymerase chain reaction. The proliferation of VECs was determined using 3-(45)-dimethylthiahiazo (-z-y1)-35-di-phenytetrazoliumromide assay and 5-ethynyl-2'-deoxyuridine staining assay. VEC apoptosis rate was assessed using flow cytometry, and caspase-3 activity was measured using a Caspase-3 Assay Kit. The protein expression levels of Ki-67, cleaved-caspase3, and tumor necrosis factor-α-induced protein 8 (TNFAIP8) were detected by western blot analysis. Furthermore, enzyme-linked immunosorbent assay was performed to assess the concentrations of inflammatory cytokines. In addition, the relationship between miR-100 and circ_0004104 or TNFAIP8 was confirmed by dual-luciferase reporter assay and biotin-labeled RNA pull-down assay. Our results revealed that circ_0004104 was upregulated and miR-100 was downregulated in patients with CAD and ox-LDL-induced VECs. Ox-LDL could inhibit the proliferation and promote the apoptosis and inflammation of VECs to induce VEC injury. However, silenced circ_0004104 could alleviate VEC injury induced by ox-LDL. Moreover, we found that circ_0004104 could sponge miR-100 and a miR-100 inhibitor could reverse the inhibition effect of circ_0004104 knockdown on ox-LDL-induced VEC injury. In addition, TNFAIP8 was a target of miR-100, and miR-100 alleviated ox-LDL-induced VEC injury by targeting TNFAIP8. Our data suggested that circ_0004104 promoted ox-LDL-induced VEC injury by the miR-100/TNFAIP8 axis, indicating that circ_0004104 might be a potential biomarker for CAD treatment.

PA5001 gene involves in swimming motility and biofilm formation in Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a nosocomial human pathogen causing infections in immunocompromised patients. To explore new genes involved in P. aeruginosa swimming motility, Mu transposon mutagenesis library was screened for isolates with altered swimming motility. Eleven nonmobile mutants were identified. Sequence analysis shows the nonmobile phenotype of one isolate was attributed to the inactivation of PA5001 gene. PA5001 knockout mutant based on the PAK lab strain also displayed comparable phenotypes suggesting the universal gene function regardless of strain. Exotic PA5001 gene fragment provided on expressing plasmid was capable of storing nonmobile phenotype of PA5001 mutant, suggesting the functional involvement of PA5001 gene on bacterial swimming. Impact of PA5001 inactivation on biofilm formation was examined, as adhesion and interaction during biofilm formation is highly dependent of bacterial mobility. The result shows that normal architecture of biofilm was disrupted in the mutant. Complementing by exotic PA5001 gene fragment resulted in the restoration of biofilm phenotype. Our results provide evidences suggesting the functional participation of PA5001 gene in bacterial mobility and biofilm formation. The critical function by PA5001 in bacterial motility and biofilm might serve as hint for the novel target for the treatment of chronic infections caused by P. aeruginosa.

Longitudinal model-based meta-analysis for survival probabilities in patients with castration-resistant prostate cancer.

PURPOSE: The aims of this longitudinal model-based meta-analysis (MBMA) were to indirectly compare the time courses of survival probabilities and to identify corresponding potential significant covariates across approved drugs in patients with castration-resistant prostate cancer (CRPC). METHODS: A systematic literature review for monotherapy studies in patients with CRPC was conducted up to August 8, 2018. The time courses of progression-free survival (PFS) and overall survival (OS) were fitted with parametric survival models. Covariate analyses were performed to determine the impact of treatment drugs, dosing regimens, and patient characteristics on the survival probabilities. Simulations were carried out to quantify the magnitude of covariate effects. RESULTS: A total of 146 studies including clinical trials and real-world data on longitudinal survival probabilities in 20,712 patients with CRPC were included in our meta-database. The time courses of PFS and OS probabilities were best described by the log-logistic model. There was no significant difference in median OS and PFS between docetaxel, cabazitaxel, abiraterone acetate, and enzalutamide. There was no significant dose-response relationship in PFS or OS for docetaxel at 50 to 120 mg/m2 every 3 weeks (Q3W) and cabazitaxel at 20 to 25 mg/m2 Q3W. Model-based simulations indicated that PFS probability was associated with chemotherapy, Gleason score, and baseline prostate-specific antigen (BLPSA), while OS probability was associated with chemotherapy, Gleason score, visceral metastasis, Eastern Cooperative Oncology Group performance status, and BLPSA. CONCLUSION: Our modeling and simulation framework can be applied to support indirect comparison, dose selection, and go/no-go decision-making for new agents targeting CRPC.

Evaluation of potential surrogate endpoints for prediction of overall survival in patients with castration-resistant prostate cancer: trial-level meta-analysis.

PURPOSE: Overall survival (OS) has traditionally been the primary endpoint to evaluate drug efficiency in oncology but is often limited by the long observation period and high cost. The aims of this study were to perform a comprehensive meta-analysis at a clinical trial level to investigate the potential surrogate endpoints of OS in patients with castration-resistant prostate cancer (CRPC), and to predict OS based on the relationships associated with the potential surrogate endpoints. METHODS: A systematic literature search was conducted in the PubMed database up to August 2018. Correlations between OS and potential surrogate endpoints were determined by linear regression analysis weighted by the square roots of sample size. Simulations were conducted to assess the effect of covariates on the relationships between OS and surrogate endpoints. RESULTS: A total of 233 studies including clinical trials and real-world data were included in our dataset. The correlations between median OS and potential surrogate endpoints for androgen-targeting therapy (R2 = 0.58-0.92) were generally stronger than those for taxane chemotherapy (R2 = 0.37-0.71). Median radiographic progression-free survival (rPFS) showed the strongest correlations with median OS (R2 = 0.94) in patients treated with novel androgen-targeting therapy. CONCLUSION: The meta-analysis demonstrated that rPFS might serve as a potential surrogate endpoint of OS and offer opportunity to facilitate the interim analyses and decision-making during the early stage of clinical trials for androgen-targeting agents.

Pediatric Emergency Room Transfers: Are They Warranted?

BACKGROUND: Emergency room transfers to a higher level of care are a vital component of modern health care, as optimal care of patients requires providing access to specialized personnel and facilities. However, literature has shown that orthopaedic transfers to a higher level of care facility are frequently unnecessary. The purpose of this study was to assess the appropriateness of pediatric orthopaedic transfers to a tertiary care center and the factors surrounding these transfers. METHODS: All pediatric orthopaedic transfers to the pediatric emergency department (ED) were evaluated over a 4-year period. A retrospective chart review was performed to assess the factors surrounding the transfer including patient demographics, time of transfer, day of transfer, insurance status, outcome of transfer, and diagnosis. Three independent variables were utilized to assess the appropriateness of the transfer: the need for an operative procedure, the need for conscious sedation, and the need for a closed reduction in the ED. RESULTS: A total of 218 pediatric orthopaedic emergency room transfers were evaluated, of which 86% of them involved an acute fracture. Twenty-seven percent (59/218) of the transfers occurred on the weekend, with over half (61%) of these transfers being initiated between 6 PM and 6 AM. Approximately half (47%) of the transfers involved patients with Medicaid. Fifty-five percent (120/218) of cases required a procedure in the operating room and 22% (49/218) had a closed reduction performed in the ED. Conscious sedation was provided in the ED for 22% (48/218) of patients. Twenty-two percent (47/218) of transfers did not require a trip to the operating room, conscious sedation, nor a closed reduction procedure in the ED. CONCLUSION: The vast majority of pediatric orthopaedic transfers are warranted as they required operative intervention, a closed reduction maneuver, or conscious sedation in the ED. LEVEL OF EVIDENCE: Level III-Therapeutic.

Os acromiale fixation: a biomechanical comparison of polyethylene suture versus stainless steel wire tension band.

BACKGROUND: Symptomatic hardware is a commonly reported complication after surgical fixation of an unstable meso-type os acromiale. This study compared the biomechanical properties of a cannulated screw tension band construct using a metal wire tension band vs. a suture tension band, considering that the suture construct could allow for decreased hardware burden in the clinical setting. METHODS: A meso-type os acromiale was created in 16 cadaveric shoulders. Two cannulated 4-mm screws were placed in each specimen. Tension band augmentation was accomplished with a 1-mm stainless steel wire (wire group) or a #5 braided polyethylene suture (suture group), with 8 specimens in each group. An inferiorly directed force was applied to the anterior acromion at 1 mm/s on a materials testing machine. Stiffness and ultimate failure load were recorded and analyzed. RESULTS: No significant difference (P = .22) was observed in the ultimate failure load between the wire (228 ± 85 N; range, 114-397 N) and the suture (275 ± 139 N; range, 112-530 N). No significant difference (P = .17) was observed in the stiffness between the wire (28 ± 12 N/mm; range, 18-53 N/mm) and the suture (38 ± 25 N/mm; range, 10-83 N/mm). CONCLUSIONS: Stainless steel wire and polyethylene suture have similar biomechanical strength in the cannulated screw tension band fixation of meso-type os acromiale at time zero.

Modeling of Proliferating CD4 and CD8 T-Cell Changes to Tremelimumab Exposure in Patients with Unresectable Hepatocellular Carcinoma.

The STRIDE (Single Tremelimumab Regular Interval Durvalumab) regimen of single-dose tremelimumab 300 mg, plus durvalumab 1,500 mg every 4 weeks demonstrated potential for long-term survival in studies of unresectable hepatocellular carcinoma (uHCC; Study 22 and HIMALAYA). The aim of this analysis was to investigate changes in proliferating CD4+ Ki67+ and CD8+ Ki67+ T cells and their relationship with tremelimumab exposure in patients with uHCC. Median cell count, change from baseline, and percent change from baseline in CD4+ and CD8+ T cells peaked around 14 days after STRIDE. A model of CD4+ and CD8+ T cell response to tremelimumab exposure was developed. Patients with lower baseline T cell counts had a greater percent change from baseline in T cell response to tremelimumab, and baseline T-cell count was included in the final model. With the full covariate model, the half-maximal effective concentration (EC50 ) of tremelimumab was 6.10 µg/mL (standard error = 1.07 µg/mL); > 98.0% of patients were predicted to have a minimum plasma concentration greater than EC50 with tremelimumab 300 or 750 mg. For EC75 (9.82 µg/mL), 69.5% and 98.2% of patients were predicted to exceed the EC75 with tremelimumab 300 and 750 mg, respectively. This analysis supports the clinical hypothesis that combination anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) and anti-programmed cell death ligand-1 (anti-PD-L1) therapy primes an immune response that may then be sustained by anti-PD-L1 monotherapy and supports the clinical utility of the STRIDE regimen in patients with uHCC. These insights may also help inform dose selection of anti-CTLA-4 plus anti-PD-L1 combination strategies.

Exposure-Response Analyses of Tremelimumab Monotherapy or in Combination with Durvalumab in Patients with Unresectable Hepatocellular Carcinoma.

PURPOSE: A novel single-dose regimen of 300 mg tremelimumab in combination with durvalumab [Single Tremelimumab Regular Interval Durvalumab (STRIDE)] has demonstrated a favorable benefit-risk profile in the phase I/II Study 22 (NCT02519348) and phase III HIMALAYA study (NCT03298451). This study evaluated the pharmacokinetics, exposure-response, and exposure-pharmacodynamics relationships of tremelimumab in patients with unresectable hepatocellular carcinoma (uHCC). PATIENTS AND METHODS: A previous tremelimumab population pharmacokinetic model was validated using data from parts 2 and 3 of Study 22. Exposure-response analyses explored relationships of tremelimumab exposure with efficacy and safety. Pharmacokinetics and pharmacodynamics relationships were evaluated using linear and nonlinear regression models. RESULTS: The observed pharmacokinetics of tremelimumab in uHCC were consistent with predictions; no significant covariates were identified. Tremelimumab exposure was not significantly associated with adverse events, objective response rate, or progression-free survival. Overall survival (OS) was longer for patients with tremelimumab exposure, minimum serum drug concentration (Cmin1) ≥ median versus Cmin1 < median (18.99 months vs. 10.97 months), but this exposure-survival analysis might be confounded with baseline characteristics of albumin level and neutrophil to lymphocyte ratio, which had a significant impact on OS (P = 0.0004 and 0.0001, respectively). The predicted Cmin1 of tremelimumab in STRIDE regimen (12.9 µg/mL) was greater than the estimated concentration of tremelimumab eliciting half-maximal increases (EC50 = 5.24 µg/mL) in CD8+Ki67+ T-cell counts. CONCLUSIONS: Our findings support novel insights into tremelimumab pharmacokinetics and exposure-response relationships in HCC and support the clinical utility of the STRIDE regimen in patients with uHCC.

Population Pharmacokinetics and Exposure-Response Analysis of Tremelimumab 300 mg Single Dose Combined with Durvalumab 1500 mg Q4W (STRIDE) in Patients with Unresectable Hepatocellular Carcinoma.

A novel single-dose regimen of 300 mg tremelimumab in combination with durvalumab (STRIDE) has demonstrated a favorable benefit-risk profile in the phase 1/2 Study 22 trial (in patients with unresectable hepatocellular carcinoma, uHCC) and in the phase 3 HIMALAYA study. The current analysis evaluated the population pharmacokinetics (PopPK) of tremelimumab and durvalumab, and the exposure-response (ER) relationship for efficacy and safety of STRIDE in patients with uHCC. Previous PopPK models for tremelimumab and durvalumab were updated using data from previous studies in various cancers combined with data from Study 22 and HIMALAYA. Typical population mean parameters and associated inter- and intra-individual variability were assessed, as was the influence of covariates. Individual exposure metrics were derived from the individual empirical Bayes estimates as drivers for ER analysis related to efficacy and safety from HIMALAYA. The observed pharmacokinetics of tremelimumab in uHCC were well described by a 2-compartment model with both linear and time-dependent clearance. All identified covariates changed tremelimumab PK parameters by <25%, and thus had minimal clinical relevance; similar results were obtained from durvalumab PopPK analysis. None of tremelimumab or durvalumab exposure metrics were significantly associated with overall survival (OS), progression-free survival (PFS), or adverse events. Baseline aspartate aminotransferase and neutrophil-to-lymphocyte ratio (NLR) were associated with OS (P < .001) by the Cox proportional hazards model. No covariate was identified as a significant factor for PFS. No dose adjustment for tremelimumab or durvalumab is needed based on PopPK covariate analyses or ER analyses. Our findings support the novel STRIDE dosing regimen in patients with uHCC.

Population Pharmacokinetics and Exposure-Response Analysis for the CTLA-4 Inhibitor Tremelimumab in Metastatic NSCLC Patients in the Phase III POSEIDON Study.

Blockade of CTLA-4 by tremelimumab combined with anti-PD-L1 durvalumab and chemotherapy provided increased antitumor activity and long-term survival benefits in first-line metastatic non-small cell lung cancer (mNSCLC) in the phase III POSEIDON study. We performed population pharmacokinetic modeling for tremelimumab using data from 1,605 patients across 6 studies (including POSEIDON) in multiple tumors (lung cancer, bladder cancer, malignant mesothelioma, and other solid tumors), and identified a 2-compartment model with linear and time-varying clearance for tremelimumab. Cox proportional hazard regression models were applied to 326 patients with mNSCLC from POSEIDON to evaluate the association between exposure metrics and efficacy end points, adjusting for baseline prognostic covariates. Improved progression-free survival (PFS) and overall survival (OS) in the tremelimumab arm (in combination with durvalumab and chemotherapy) was associated with higher tremelimumab exposure (e.g., minimum concentration at 5th dose (Cmin,dose5 ) and area under the curve at 5th dose (AUCdose5 )). However, further case-matching analyses yielded hazard ratios for the comparison of tremelimumab-treated patients in the Cmin,dose5 quartile 1 (Q1) subgroup with matched chemotherapy-treated patients of 1.04 (95% confidence interval (CI): 0.76-1.44) for OS and 0.99 (95% CI: 0.72-1.36) for PFS, suggesting that the observed apparent exposure-response relationship might be confounded. No relationship between tremelimumab exposure and safety (grade ≥3 treatment-emergent adverse events [AEs], AEs of special interest, or discontinuation due to AEs) was identified. These results support the consistent benefit observed with tremelimumab 75 mg every 3 weeks for up to 5 doses in combination with durvalumab and chemotherapy in POSEIDON as first-line therapy for mNSCLC.

Population Pharmacokinetics of Monalizumab in Patients With Advanced Solid Tumors.

Monalizumab is a novel, first-in-class humanized immunoglobulin G4 monoclonal antibody immune checkpoint inhibitor that targets the inhibitory CD94/NKG2A receptors. The objectives of this analysis were to develop a population pharmacokinetic (PK) model of monalizumab, evaluate the impact of clinically relevant covariates on monalizumab PK, and provide dose justification for clinical trials. We developed a monalizumab population PK model to characterize the PK properties of monalizumab in patients with advanced solid tumors or head and neck squamous cell carcinoma. Data from clinical studies D419NC00001 (NCT02671435) and IPH2201-203 (NCT02643550) were pooled for the analysis, resulting in a data set of 3066 PK samples derived from 507 subjects. The PK of monalizumab were reasonably described by a 2-compartment model with first-order elimination. Monalizumab generally exhibited linear PK over a dose range of 22.5-750 mg or 10 mg/kg every 2 weeks. The estimate of clearance was ≈0.255 L/day, and apparent volume of distribution was 6.36 L for a typical individual, consistent with previous findings for endogenous immunoglobulin Gs and other therapeutic monoclonal antibodies. Baseline albumin and body weight were identified as significant covariates of clearance; body weight, sex, and smoking status had a significant impact on volume of distribution; and none of these covariates had impact on peripheral volume of distribution. Although these covariates were identified as statistically significant, they are considered to be not clinically meaningful, as changes in monalizumab exposure were <30%. Therefore, no dose adjustments of monalizumab based on patient or disease characteristics are recommended.

Hypoxic Microenvironment-Induced Reduction in PTEN-L Secretion Promotes Non-Small Cell Lung Cancer Metastasis through PI3K/AKT Pathway.

Objective: Lung cancer is the leading cause of cancer-related deaths worldwide. The aim of this study was to investigate the effects of hypoxic microenvironment on PTEN-L secretion and the effects of PTEN-L on the metastasis of non-small cell lung cancer (NSCLC) and the potential mechanisms. Methods: The expression levels of PTEN-L in NSCLC tissues, cells, and cell culture media were detected. The transfection of PTEN-L overexpression construct or HIF-1α-siRNAs was conducted to manipulate the expression of PTEN-L or HIF-1α. NSCLC cells were introduced into 200 µM CoCl2 medium for 72 hours under 37°C to simulate hypoxia. The proliferation and apoptosis of the A549 cells were determined by the Cell Counting Kit-8 assay and Annexin V-FITC/PI-stained flow cytometry assay, respectively. Wound healing assay and transwell invasion assay were used to measure the migration and invasion of A549 cells. The protein expression of PTEN, PTEN-L, PI3K/AKT pathway-related proteins, and HIF-1α was detected by Western blot. Results: PTEN and PTEN-L are downregulated in lung cancer tissues and cells. The protein expression of PTEN-L in the culture medium of lung cancer cell lines is decreased. The hypoxic microenvironment inhibits PTEN-L secretion. The low level of PTEN-L promotes cell proliferation, migration, and invasion, as well as inhibits apoptosis of A549 cells. The overexpression of PTEN-L attenuated the activation of the PI3K/AKT pathway by the hypoxic microenvironment. The knockdown of HIF-1α upregulates PTEN-L secretion under hypoxia. Conclusions: The hypoxic microenvironment inhibits PTEN-L secretion and thus activates PI3K/AKT pathway to induce proliferation, migration, and invasion promotion, and apoptosis inhibition in NSCLC cells.

Pharmacokinetics and pharmacodynamics of MEDI0680, a fully human anti-PD-1 monoclonal antibody, in patients with advanced malignancies.

MEDI0680 is a humanized immunoglobulin monoclonal antibody that targets human programmed cell death protein 1 (PD-1) for the treatment of cancer. A population two-compartmental pharmacokinetic (PK) model and a sequential direct maximal effective drug concentration receptor occupancy (RO) model with baseline parameters were developed to quantify PK variability, identify significant covariates, and characterize the relationship between the PK and the RO of MEDI0680. A total of 58 patients with advanced malignancies received MEDI0680 by intravenous infusion at a dose of 0.1-20 mg/kg in a phase 1 study. The clearance was 0.27 L per day and the central volume of distribution (V1) was 3.14 L, with a modest between-subject variability of 30 and 19%, respectively. None of the evaluated covariates showed any impact on PK parameters except for a nonclinically meaningful relevant impact of body weight on V1. The estimated half-maximal effective concentration for MEDI0680 binding to the PD-1 antigen was approximately 1.88 µg/mL. Visual predictive check results demonstrated good predictability of the final population PK-RO model. PK-RO simulations demonstrated that > 90% RO could be maintained in all subjects after a 20-mg/kg dose every 2 weeks (Q2W). Therefore, 20 mg/kg Q2W and an equivalently fixed dose of 1500 mg was recommended for phase 2 studies.

A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma.

PURPOSE: MEDI0680 is a humanized anti-programmed cell death-1 (PD-1) antibody, and durvalumab is an anti-PD-L1 antibody. Combining treatment using these antibodies may improve efficacy versus blockade of PD-1 alone. This phase II study evaluated antitumor activity and safety of MEDI0680 plus durvalumab versus nivolumab monotherapy in immunotherapy-naïve patients with advanced clear-cell renal cell carcinoma who received at least one prior line of antiangiogenic therapy. PATIENTS AND METHODS: Patients received either MEDI0680 (20 mg/kg) with durvalumab (750 mg) or nivolumab (240 mg), all intravenous, every 2 weeks. The primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints included best overall response, progression-free survival (PFS), safety, overall survival (OS), and immunogenicity. Exploratory endpoints included changes in circulating tumor DNA (ctDNA), baseline tumor mutational burden, and tumor-infiltrated immune cell profiles. RESULTS: Sixty-three patients were randomized (combination, n = 42; nivolumab, n = 21). ORR was 16.7% [7/42; 95% confidence interval (CI), 7.0-31.4] with combination treatment and 23.8% (5/21; 95% CI, 8.2-47.2) with nivolumab. Median PFS was 3.6 months in both arms; median OS was not reached in either arm. Because of adverse events, 23.8% of patients discontinued MEDI0680 and durvalumab and 14.3% of patients discontinued nivolumab. In the combination arm, reduction in ctDNA fraction was associated with longer PFS. ctDNA mutational analysis did not demonstrate an association with response in either arm. Tumor-infiltrated immune profiles showed an association between immune cell activation and response in the combination arm. CONCLUSIONS: MEDI0680 combined with durvalumab was safe and tolerable; however, it did not improve efficacy versus nivolumab monotherapy.

Impact of Postoperative Opioid Use on 2-Year Patient-Reported Outcomes in Knee Surgery Patients.

The purposes of this study were to identify the patient characteristics associated with refilling a postoperative opioid prescription after knee surgery and to determine whether refilling opioids is associated with 2-year patient-reported outcomes. We hypothesized that postoperative refill of opioids would be associated with worse 2-year patient-reported outcomes. We studied 192 patients undergoing knee surgery at a single urban academic institution. Patients completed multiple patient-reported outcome measures preoperatively and 2 years postoperatively, including six Patient-Reported Outcomes Measurement Information System (PROMIS) domains, the International Knee Documentation Committee (IKDC) questionnaire, numeric pain scale scores for the operative knee and the rest of the body, Marx Activity Rating Scale, as well as measures of met expectations, improvement, and satisfaction. Total morphine equivalents (TMEs) were calculated from a regional prescription monitoring program. Patients who refilled a postoperative opioid prescription were compared with those who did not, and TMEs were calculated for those who refilled (Refill TMEs). One hundred twenty-nine patients (67%) refilled at least one postoperative opioid prescription. Black race, older age, higher average body mass index (BMI), smoking, greater medical comorbidities, preoperative opioid use, lower income, government insurance, and knee arthroplasty were associated with refilling opioids. Greater Refill TMEs was associated with black or white race, older age, higher average BMI, smoking, greater medical comorbidities, preoperative opioid use, government insurance, and unemployment. Refilling opioids and greater Refill TMEs were associated with worse postoperative scores on most patient-reported outcome measures 2 years after knee surgery. However, refilling opioids and greater Refill TMEs did not have a significant association with improvement after surgery. Multivariable analysis controlling for potential confounding variables confirmed that greater postoperative Refill TMEs independently predicted worse 2-year PROMIS Physical Function, 2-year PROMIS Pain Interference, and 2-year IKDC knee function scores. Postoperative refill of opioids was associated with worse 2-year patient-reported outcomes in a dose-dependent fashion. These findings reinforce the importance of counseling patients regarding opioid use and optimizing opioid-sparing pain management postoperatively.

Preoperative Expectations of Patients Undergoing Knee Surgery.

There is limited validated data regarding the relationship between preoperative expectations and patient-reported outcomes (PROs) in patients undergoing knee surgery. The purpose of this study was to (1) assess the preoperative expectations of patients undergoing knee surgery and (2) determine the relationship between preoperative patient demographics, PROs, and preoperative patient expectations. We hypothesized that younger patients with worse function and worse general health status would have greater expectations of knee surgery. We analyzed data from 399 patients undergoing knee surgery at an urban academic medical center. We utilized the Musculoskeletal Outcomes Data Evaluation and Management System to measure preoperative expectations. Multiple legacy PRO measures were recorded, as well as the new Patient-Reported Outcomes Measurement Information Systems (PROMIS) Computer Adaptive Testing. Nonparametric statistical analyses were performed to determine significance. Overall, patients undergoing knee surgery had high expectations, with a mean of 88.0 (95% confidence interval [CI], 86.7-89.3) and median of 91.7 (95% CI, 89.2-94.3). Greater preoperative expectations of knee surgery were associated with higher income, surgically naïve knee, lower Charlson Comorbidity Index, better PROMIS Depression and Anxiety scores, greater Marx knee activity scores, and lower total body pain (p < 0.05). Preoperative expectations of patients undergoing knee surgery are associated with a history of prior knee surgery, income, general and mental health, activity, and pain. Expectations were also found to be associated with PRO measures of function and psychological well-being. These findings may have implications for patient education and shared decision-making preoperatively. The level of evidence for the study is IV.

Evolving drug regulatory landscape in China: A clinical pharmacology perspective.

In order to encourage innovative medicine to address Chinese unmet medical needs, China has changed its drug regulatory landscape to speed up access to new medicines. In order to understand the fast-changing landscape and to enable planning of more global drug development programs and study designs in China, we reviewed 15 published clinical pharmacology-related guidances by the National Medical Products Administration (NMPA), and compared them with reference guidances from the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the International Conference on Harmonization (ICH), to understand the similarities and differences, especially any China-specific requirements, such as ethnic sensitivity analysis. Overall, by reviewing these clinical pharmacology-related NMPA guidances, it is clear that NMPA guidances are very similar to FDA, EMA, and ICH guidances. There are no relevant differences in the major principles, but some differences in structure, contents, and focus were noted. The NMPA is adapting flexibility statements into newly published guidances. Ethnic sensitivity analysis needs to be implemented early in drug development plans. The NMPA encourages sponsors to conduct early clinical trials in China or include China early in multiregional clinical trials, and to obtain safety, efficacy, and pharmacokinetic data for ethnic sensitivity analysis. Depending on the stage of development, ethnic sensitivity analysis can be conducted using in vitro or literature data, other Asian clinical data, or Chinese clinical data.