ABSTRACT
PURPOSE: Treatment options are limited in patients with metastatic neuroendocrine neoplasms (NEN). We present the results for a phase II trial of combination nivolumab and temozolomide in patients with advanced NEN along with results of immune changes in peripheral blood. PATIENTS AND METHODS: NCT03728361 is a nonrandomized, phase II study of nivolumab and temozolomide in patients with NEN. The primary endpoint was response rate using RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Immune profiling was performed by mass cytometry to evaluate the effect on peripheral blood immune cell subsets. RESULTS: Among all 28 patients with NEN, the confirmed response rate was 9/28 [32.1%, 95% confidence interval (CI): 15.9-52.4]. Of 11 patients with lung NEN, the response rate was 64% (n = 7); there was a significant difference in responses by primary tumor location (lung vs. others, P = 0.020). The median PFS was 8.8 months (95% CI: 3.9-11.1 months), and median OS was 32.3 months (95% CI: 20.7-not reached months). Exploratory blood immune cell profiling revealed an increase in circulating CD8+ T cells (27.9% ± 13.4% vs. 31.7% ± 14.6%, P = 0.03) and a decrease in CD4+ T cells (59.6% ± 13.1% vs. 56.5% ± 13.0%, P = 0.001) after 2 weeks of treatment. LAG-3-expressing total T cells were lower in patients experiencing a partial response (0.18% ± 0.24% vs. 0.83% ± 0.55%, P = 0.028). Myeloid-derived suppressor cell levels increased during the study and did not correlate with response. CONCLUSIONS: Combination nivolumab and temozolomide demonstrated promising activity in NEN. See related commentary by Velez and Garon, p. 691.
Subject(s)
Lung Neoplasms , Neuroendocrine Tumors , Humans , Nivolumab/therapeutic use , Temozolomide/therapeutic use , Lung Neoplasms/drug therapy , Neuroendocrine Tumors/drug therapy , Progression-Free SurvivalSubject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Lung Neoplasms/drug therapy , Small Cell Lung Carcinoma/drug therapy , Aged , Humans , Lung Neoplasms/pathology , Male , Myeloid-Derived Suppressor Cells/metabolism , Nivolumab/administration & dosage , Small Cell Lung Carcinoma/pathology , Temozolomide/administration & dosage , Treatment OutcomeABSTRACT
Evidence for proximal risk factors for suicide is based on case-control psychological autopsy studies, with these reports showing that mood and substance use disorders are the most prevalent mental disorders among suicide decedents worldwide and are associated with marked risk. However, moderators of risk and the degree of risk associated with (nonalcohol) drug use disorder are unknown. A comprehensive search was used to identify 35 case-control psychological autopsy studies published worldwide over a 30-year period that were metaanalyzed using random effects models. Major depression, odds ratio (95% confidence interval) = 9.14 (5.53, 15.09), and drug use disorder, OR (95% CI) = 7.18 (3.22, 16.01), had large effect sizes, among other results. Risk estimates associated with major depression were greater in studies with a larger proportion of women and those conducted in Asia compared with other regions. There was no evidence of publication bias or that any one study had a disproportionate impact on findings. Risk for suicide associated with major depression appears to be moderated by sex and/or world region. Drug use disorder is a potent risk factor, illustrating the importance of assessing drug use in clinical risk assessment.
