Interleukin-2 receptor antagonist therapy leads to increased tacrolimus levels after kidney transplantation.

BACKGROUND: Tacrolimus (TAC) is a known substrate for cytochrome P450 (CYP) enzyme. CYP enzyme activity can be modulated by activation of IL-2 receptors (IL-2R) expressed on hepatocytes and intestinal cells. IL-2R antagonists (IL-2RA) may promote preferential binding of circulating IL-2 to IL-2Rs on these cells by blocking IL-2Rs on activated T cells. This downregulates CYP enzymes, leading to increased calcineurin inhibitor levels. This analysis evaluates the significance of this drug-drug interaction in kidney transplant recipients. METHODS: Data were used from a previous 5-year randomized, controlled study comparing outcomes associated with maintenance immunosuppression using 2 corticosteroid regimens: long-term therapy versus early withdrawal. Patients received either IL-2RAs or rabbit anti-thymocyte globulin (rATG) for induction. Serial TAC trough levels and doses were compared between induction agents within each corticosteroid arm. Rejection rates, patient/graft survival, and TAC adverse effects were also evaluated. RESULTS: In the first week, IL-2RA-treated patients achieved significantly higher trough levels and required lower doses (in milligram per kilogram) to achieve target levels than rATG-treated patients. No significant differences in rejection rates, patient/graft survival, or rate of adverse effects were observed through 1 year.

Treatment Patterns and Clinical Outcomes Among Metastatic Non-Small-Cell Lung Cancer Patients Treated in the Community Practice Setting.

INTRODUCTION: Multiple therapeutic options now exist for metastatic non-small-cell lung cancer (mNSCLC). In this study we evaluated treatment patterns and outcomes in mNSCLC patients who received first-line (1L), second-line (2L), and third-line (3L) therapy. PATIENTS AND METHODS: A retrospective, observational cohort study was conducted using an electronic health record database of mNSCLC patients who received initial treatment from January 2012 through April 2016, with follow-up through June 2016. Patient characteristics and treatment patterns were characterized. Overall survival (OS) was assessed using the Kaplan-Meier method. RESULTS: We identified 10,689 1L patients. Median age was 68 years, and 5816 (54%) were male. Most patients (6337; 59%) had a performance status of 1, and 8282 (77%) had nonsquamous histology. 1L treatment was chemotherapy in 9969 (93%) patients, and targeted therapy in 685 (6%). Median OS (mOS) for all patients in 1L was 12.3 months (95% confidence interval [CI], 11.9-12.7), and 24.3 months in 1L patients receiving targeted therapy. Among patients who received 2L therapy (n = 4235), 2790 (66%), 718 (17%), and 727 (17%) received chemotherapy, targeted therapy, and immunotherapy, respectively. mOS from 2L therapy was 9.6 months (95% CI, 9.1-10.1). In patients receiving 3L therapy (n = 1580), 921 (58%), 355 (22%), and 304 (19%) received chemotherapy, targeted therapy, and immunotherapy, respectively. mOS from 3L therapy was 8.2 months (95% CI, 7.3-8.7). CONCLUSION: Targeted therapy and immunotherapy was most frequently used in the 2L and 3L setting during the study time frame. Survival differences observed according to treatment types are likely because of biologic differences, and suggest that patients with actionable mutations have a survival advantage.

Evaluation of classical clinical endpoints as surrogates for overall survival in patients treated with immune checkpoint blockers: a systematic review and meta-analysis.

PURPOSE: Classical clinical endpoints [e.g., objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS)] may not be appropriate for immune checkpoint blockers (ICBs). We evaluated correlations between these endpoints and overall survival (OS) for surrogacy. METHODS: Randomized controlled trials (RCTs) of solid tumors patients treated with ICBs published between 01/2005 and 03/2017, and congress proceedings (2014-2016) were included. Arm-level analyses measured 6-month PFS rate to predict 18-month OS rate. Comparison-level analyses measured ORR odds ratio (OR), DCR OR, and 6-month PFS hazard ratio (HR) to predict OS HR. A pooled analysis for single-agent ICBs and ICBs plus chemotherapy vs chemotherapy was conducted. Studies of single-agent ICBs vs chemotherapy were separately analyzed. RESULTS: 27 RCTs involving 61 treatment arms and 10,300 patients were included. Arm-level analysis showed higher 6- or 9-month PFS rates predicted better 18-month OS rates for ICB arms and/or chemotherapy arms. ICB arms had a higher average OS rate vs chemotherapy for all PFS rates. Comparison-level analysis showed a nonsignificant/weak correlation between ORR OR (adjusted R2 = - 0.069; P = 0.866) or DCR OR (adjusted R2 = 0.271; P = 0.107) and OS HR. PFS HR correlated weakly with OS HR in the pooled (adjusted R2 = 0.366; P = 0.005) and single-agent (adjusted R2 = 0.452; P = 0.005) ICB studies. Six-month PFS HR was highly predictive of OS HR for single-agent ICBs (adjusted R2 = 0.907; P < 0.001), but weakly predictive in the pooled analysis (adjusted R2 = 0.333; P = 0.023). CONCLUSIONS: PFS was an imperfect surrogate for OS. Predictive value of 6-month PFS HR for OS HR in the single-agent ICB analysis requires further exploration.

Compartmentalized Eph receptor and ephrin expression in the thymus.

The maturation of T cells is an intricate process involving the interaction of developing thymocytes with discrete microenvironments within the thymus. Numerous studies have indicated that distinct thymic compartments provide signals required for each stage of thymocyte maturation. In this study we performed a comprehensive analysis of the expression patterns of Eph-A receptors and ephrins-A in the thymus using in situ hybridization and reverse transcription-polymerase chain reaction, and show that expression of these molecules is highly compartmentalized. Based on these expression patterns and the known mechanisms of action of Eph receptor/ephrin interactions in other organs, these data suggest that differential Eph receptor expression on discrete subsets of thymic stromal cells may be important in establishing compartment boundaries and preventing intermingling of stromal cell subtypes. Further, together with chemotactic signals such as those provided by chemokines, regulated Eph receptor/ephrin expression on thymocytes may play a role in thymocyte migration.

Compartmentalized Eph receptor and ephrin expression in the thymus.

The maturation of T cells is an intricate process involving the interaction of developing thymocytes with discrete microenvironments within the thymus. Numerous studies have indicated that distinct thymic compartments provide signals required for each stage of thymocyte maturation. In this study we performed a comprehensive analysis of the expression patterns of Eph-A receptors and ephrins-A in the thymus using in situ hybridization and reverse transcription-polymerase chain reaction, and show that expression of these molecules is highly compartmentalized. Based on these expression patterns and the known mechanisms of action of Eph receptor/ephrin interactions in other organs, these data suggest that differential Eph receptor expression on discrete subsets of thymic stromal cells may be important in establishing compartment boundaries and preventing intermingling of stromal cell subtypes. Further, together with chemotactic signals such as those provided by chemokines, regulated Eph receptor/ephrin expression on thymocytes may play a role in thymocyte migration.