Implications of all the available evidence Entrectinib is an important therapeutic option for patients with ROS1 TKI-naïve ROS1 fusion-positive NSCLC. The intracranial activity of entrectinib is of particular importance, given the frequency of CNS involvement in ROS1 fusion-positive NSCLC and the limited ability of crizotinib to penetrate the CNS.
Objective
Accumulating preclinical and epidemiologic evidence has emerged to suggest that modulation of cytochrome P450 (CYP)-mediated eicosanoid metabolism may be a viable vascular protective therapeutic strategy for the secondary prevention of coronary artery disease (CAD). The functional relationship between CYP-derived eicosanoid metabolite levels and vascular dysfunction in humans with established CAD, however, has not been evaluated. Therefore, we characterized the relationship between inter-individual variation in soluble epoxide hydrolase (sEH) and CYP ω-hydroxylase metabolism and established vascular function phenotypes predictive of prognosis in a cohort of patients with atherosclerotic cardiovascular disease.
Methods
Plasma epoxyeicosatrienoic acid (EET), dihydroxyeicosatrienoic acid (DHET), and 20-hydroxyeicosatetraenoic acid (20-HETE) levels were quantified by HPLC-MS/MS in 106 patients with stable, angiographically-confirmed CAD. Relationships between biomarkers of CYP-mediated eicosanoid metabolism and vascular function phenotypes were evaluated by Pearson’s correlation.
Results
A significant inverse association was observed between 20-HETE levels (a biomarker of CYP ω-hydroxylase metabolism) and brachial artery flow-mediated dilation (r = −0.255, p = 0.010). An inverse association was also observed between 14,15-EET:DHET ratios (a biomarker of sEH metabolism) and both monocyte chemoattractant protein-1 levels (r = −0.252, p = 0.009) and a consolidated cellular adhesion molecule ‘score’ reflecting the levels of E-selectin and P-selectin (r = −0.216, p = 0.027). No associations with C-reactive protein or epithelial neutrophil-activating protein-78 levels were observed.
Conclusions
Collectively, these findings demonstrate that enhanced CYP ω-hydroxylase and sEH metabolic function are associated with more advanced endothelial dysfunction and vascular inflammation, respectively, in patients with established atherosclerotic cardiovascular disease. These findings lay the foundation for future clinical research in this area.
Adverse events were mostly low grade. The most common grade 3 toxicities with olaparib were anaemia (22%) and neutropenia (8%). Olaparib dose reductions, interruptions and discontinuations occurred in 28%, 52% and 12%, respectively. There was no approximately 3 years.
We describe a new imaging method for detecting prostate cancer, whether localized or disseminated and metastatic to soft tissues and bone. The method relies on the use of imaging reporter genes under the control of the promoter of AEG-1 (MTDH), which is selectively active only in malignant cells. Through systemic, nanoparticle-based delivery of the imaging construct, lesions can be identified through bioluminescence imaging and single photon emission-computed tomography in the PC3-ML murine model of prostate cancer at high sensitivity. This approach is applicable for the detection of prostate cancer metastases, including bone lesions for which there is no current reliable agent for non-invasive clinical imaging. Further, the approach compares favorably to accepted and emerging clinical standards, including positron emission tomography with [18F]fluorodeoxyglucose and [18F]sodium fluoride. Our results offer a preclinical proof of concept that rationalizes clinical evaluation in patients with advanced prostate cancer.
3605 Background: NTRK gene fusions lead to transcription of chimeric TRK proteins with overexpressed kinase function. Entrectinib is a potent inhibitor of TRKA/B/C. In phase 1/2 studies (ALKA, STARTRK-1, STARTRK-2; EudraCT 2012-000148-88; NCT02097810; NCT02568267), entrectinib was effective in pts with NTRK-fp solid tumors. We present updated data in a larger population with longer follow-up. Methods: In this integrated analysis of adult pts from 3 phase 1/2 trials (data cut-off 31 Oct 2018), tumors were assessed by blinded independent central review (BICR) with RECIST v1.1 (end of cycle 1; then every 8 wks). Primary endpoints were overall response rate (ORR) and duration of response (DOR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), efficacy in pts with/without baseline CNS disease, and safety. Results: There were 74 evaluable pts with advanced/metastatic NTRK-fp solid tumors (Table). Median duration of survival follow-up in all pts was 14.2 mo (range 0.1–29.7). BICR ORR was 63.5% (95% CI 51.5–74.4), with 5 complete responses (6.8%). Median BICR DOR was 12.9 mo (95% CI 9.3–NE); median BICR PFS was 11.2 mo (95% CI 8.0–15.7); median OS was 23.9 mo (16.0–NE). In pts with no baseline CNS disease (investigator-assessed; n=55), BICR ORR was 65.5% (95% CI 51.4–77.8) and median BICR DOR in responders was 12.9 mo (95% CI 9.3–NE). In pts with baseline CNS disease (investigator-assessed; n=19), BICR ORR was 57.9% (95% CI 33.5–79.8) and median BICR DOR in responders was 6.0 mo (95% CI 4.2–NE). Safety was in line with that previously reported; the most common ≥grade 3 treatment-related AEs were weight gain (8, 7.1%), anemia (8, 7.1%), and fatigue (7, 6.2%). Conclusions: In this updated analysis, including more pts and longer follow-up, entrectinib continued to demonstrate clinically meaningful responses in pts with NTRK-fp solid tumors, with and without baseline CNS disease. Clinical trial information: NCT02097810, NCT02568267 . [Table: see text]
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.