Purpose: To determine the safety, dose-limiting toxicity, maximum tolerated dose, and pharmacokinetic and pharmacodynamic profiles of the novel hydroxamate histone deacetylase inhibitor belinostat (previously named PXD101) in patients with advanced refractory solid tumors. Experimental Design: Sequential dose-escalating cohorts of three to six patients received belinostat administered as a 30-min i.v. infusion on days 1to 5 of a 21-day cycle. Pharmacokinetic variables were evaluated at all dose levels. Pharmacodynamic measurements included acetylation of histones extracted from peripheral blood mononuclear cells, caspase-dependent cleavage of cytokeratin-18, and interleukin-6 levels.

Multiple DNA methylation changes in the cancer methylome are associated with the acquisition of drug resistance; however it remains uncertain how many represent critical DNA methylation drivers of chemoresistance. Using isogenic, cisplatin-sensitive/resistant ovarian cancer cell lines and inducing resensitizaton with demethylating agents, we aimed to identify consistent methylation and expression changes associated with chemoresistance. Using genome-wide DNA methylation profiling across 27 578 CpG sites, we identified loci at 4092 genes becoming hypermethylated in chemoresistant A2780/cp70 compared with the parental-sensitive A2780 cell line. Hypermethylation at gene promoter regions is often associated with transcriptional silencing; however, expression of only 245 of these hypermethylated genes becomes downregulated in A2780/cp70 as measured by microarray expression profiling. Treatment of A2780/ cp70 with the demethylating agent 2-deoxy-5 0 -azacytidine induces resensitization to cisplatin and re-expression of 41 of the downregulated genes. A total of 13/41 genes were consistently hypermethylated in further independent cisplatin-resistant A2780 cell derivatives. CpG sites at 9 of the 13 genes (ARHGDIB, ARMCX2, COL1A, FLNA, FLNC, MEST, MLH1, NTS and PSMB9) acquired methylation in ovarian tumours at relapse following chemotherapy or chemoresistant cell lines derived at the time of patient relapse. Furthermore, 5/13 genes (ARMCX2, COL1A1, MDK, MEST and MLH1) acquired methylation in drug-resistant ovarian cancersustaining (side population) cells. MLH1 has a direct role in conferring cisplatin sensitivity when reintroduced into cells in vitro. This combined genomics approach has identified further potential key drivers of chemoresistance whose expression is silenced by DNA methylation that should be further evaluated as clinical biomarkers of drug resistance.

Introduction: For patients with recurrent SCLC, topotecan remains the only approved second-line treatment, and the outcomes are poor. CheckMate 032 is a phase 1/2, multicenter, open-label study of nivolumab or nivolumab plus ipilimumab in SCLC or other advanced/metastatic solid tumors previously treated with one or more platinum-based chemotherapies. We report results of third-or later-line nivolumab monotherapy treatment in SCLC.Methods: In this analysis, patients with limited-stage or extensive-stage SCLC and disease progression after two or more chemotherapy regimens received nivolumab monotherapy, 3 mg/kg every 2 weeks, until disease progression or unacceptable toxicity. The primary end point was objective response rate. Secondary end points included duration of response, progression-free survival, overall survival, and safety.Results: Between December 4, 2013, and November 30, 2016, 109 patients began receiving third-or later-line nivolumab monotherapy. At a median follow-up of 28.3 months (from first dose to database lock), the objective response rate was 11.9% (95% confidence interval: 6.5-19.5) with a median duration of response of 17.9 months (range 3.0-42.1). At 6 months, 17.2% of patients were progression-free. The 12-month and 18-month overall survival rates were 28.3% and 20.0%, respectively. Grade 3 to 4 treatment-related adverse events occurred in 11.9% of patients. Three patients (2.8%) discontinued because of treatment-related adverse events.Conclusions: Nivolumab monotherapy provided durable responses and was well tolerated as a third-or later-line treatment for recurrent SCLC. These results suggest that nivolumab monotherapy is an effective third-or later-line treatment for this patient population. Ó 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

Background No phase 3 trial has yet shown improved survival for patients with pleural or peritoneal malignant mesothelioma who have progressed following platinum-based chemotherapy. The aim of this study was to assess the efficacy and safety of nivolumab, an anti-PD-1 antibody, in these patients.Methods This was a multicentre, placebo-controlled, double-blind, parallel group, randomised, phase 3 trial done in 24 hospitals in the UK. Adult patients (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1, with histologically confirmed pleural or peritoneal mesothelioma, who had received previous first-line platinum-based chemotherapy and had radiological evidence of disease progression, were randomly assigned (2:1) to receive nivolumab at a flat dose of 240 mg every 2 weeks over 30 min intravenously or placebo until disease progression or a maximum of 12 months. The randomisation sequence was generated within an interactive web response system (Alea); patients were stratified according to epithelioid versus non-epithelioid histology and were assigned in random block sizes of 3 and 6. Participants and treating clinicians were masked to group allocation. The co-primary endpoints were investigator-assessed progression-free survival and overall survival, analysed according to the treatment policy estimand (an equivalent of the intention-to-treat principle). All patients who were randomly assigned were included in the safety population, reported according to group allocation. This trial is registered with Clinicaltrials.gov, NCT03063450.

Purpose LUME-Meso is a phase II/III randomized, double-blind trial designed to assess efficacy and safety of nintedanib plus chemotherapy as first-line treatment of malignant pleural mesothelioma (MPM).Phase II results are reported here. Patients and MethodsChemotherapy-naïve patients with unresectable, nonsarcomatoid MPM (Eastern Cooperative Oncology Group performance status 0 to 1), stratified by histology (epithelioid or biphasic), were randomly assigned in a 1:1 ratio to up to six cycles of pemetrexed and cisplatin plus nintedanib (200 mg twice daily) or placebo followed by nintedanib plus placebo monotherapy until progression. The primary end point was progression-free survival (PFS). ResultsEighty-seven patients were randomly assigned. The median number of pemetrexed and cisplatin cycles was six; the median treatment duration for nintedanib was 7.8 months and 5.3 months for placebo. Primary PFS favored nintedanib (hazard ratio [HR], 0.56; 95% CI, 0.34 to 0.91; P = .017), which was confirmed in updated PFS analyses (HR, 0.54; 95% CI, 0.33 to 0.87; P = .010). A trend toward improved overall survival also favored nintedanib (HR, 0.77; 95% CI, 0.46 to 1.29; P = .319). Benefit was evident in epithelioid histology, with a median overall survival gain of 5.4 months (HR, 0.70; 95% CI, 0.40 to 1.21; P = .197; median [nintedanib v placebo], 20.6 months v 15.2 months) and median PFS gain of 4.0 months (HR, 0.49; 95% CI, 0.30 to 0.82; P = .006; median [nintedanib v placebo], 9.7 v 5.7 months). Neutropenia was the most frequent grade $ 3 adverse event (AE; nintedanib 43.2% v placebo 12.2%); rates of febrile neutropenia were low (4.5% in nintedanib group v 0% in placebo group). AEs leading to discontinuation were reported in 6.8% of those receiving nintedanib versus 17.1% of those in the placebo group. ConclusionAddition of nintedanib to pemetrexed plus cisplatin resulted in PFS improvement. AEs were manageable. The clinical benefit was evident in patients with epithelioid histology. The confirmatory phase III part of the study is ongoing.