Durvalumab with first-line chemotherapy in previously untreated malignant pleural mesothelioma (DREAM): a multicentre, single-arm, phase 2 trial with a safety run-in.

BACKGROUND: There is a strong unmet need to improve systemic therapy in mesothelioma. Chemotherapy with cisplatin and pemetrexed improves survival in malignant pleural mesothelioma, and immune checkpoint inhibitors are an emerging treatment in this disease. We aimed to evaluate the activity of durvalumab, an anti-PD-L1 antibody, given during and after first-line chemotherapy with cisplatin and pemetrexed in patients with advanced malignant pleural mesothelioma. METHODS: DREAM was a multicentre, single-arm, open-label, phase 2 trial done in nine hospitals in Australia. Eligible patients were aged 18 years or older and had histologically confirmed malignant pleural mesothelioma considered unsuitable for cancer-directed surgery, an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease as per the modified Response Evaluation Criteria in Solid Tumors version 1.0 (mRECIST) for mesothelioma that was previously untreated with systemic therapy. All histological subtypes were eligible. The first six participants were treated for two cycles in a safety run-in. All participants received cisplatin 75 mg/m2, pemetrexed 500 mg/m2, and durvalumab 1125 mg intravenously on day 1 of a 3-weekly schedule for a maximum of six cycles. Change from cisplatin to carboplatin with an area under the curve of 5 was permitted. Durvalumab was continued for a maximum of 12 months. The primary endpoint was progression-free survival at 6 months, measured according to mRECIST for malignant pleural mesothelioma and analysed in the intention-to-treat population. Safety analyses included all participants who receive at least one dose of any study drug. This study is registered with the Australia New Zealand Clinical Trials Registry, ACTRN12616001170415. FINDINGS: Between Dec 28, 2016, and Sept 27, 2017, 55 participants were enrolled. 54 patients were eligible and were followed up for a median of 28·2 months (IQR 26·5-30·2). 31 (57%; 95% CI 44-70) of 54 patients were alive and progression-free at 6 months. The most common grade 3-4 adverse events were neutropenia (seven [13%] patients), nausea (six [11%]), and anaemia (four [7%]). A total of 60 serious adverse events occurred in 29 participants, five of which were considered possibly related to durvalumab. Five patients died during the study treatment; none of these five deaths were attributed to study treatment. INTERPRETATION: The combination of durvalumab, cisplatin, and pemetrexed has promising activity and an acceptable safety profile that warrants further investigation in a randomised phase 3 trial. FUNDING: AstraZeneca.

The Impact of Hemolysis on Cell-Free microRNA Biomarkers.

Cell-free microRNAs in plasma and serum have become a promising source of biomarkers for various diseases. Despite rapid progress in this field, there remains a lack of consensus regarding optimal quantification methods, reference genes, and quality control of samples. Recent studies have shown that hemolysis occurring during blood collection has substantial impact on the microRNA content in plasma/serum. To date, the impact of hemolysis has only been investigated for a limited number of microRNAs, mainly the red blood cell (RBC)-enriched miRs-16 and -451. In contrast, the effect of hemolysis on other microRNAs - in particular those proposed as biomarkers - has not been addressed. In this study we profiled the microRNA content of hemolyzed and non-hemolyzed plasma as well as RBCs to obtain a profile of microRNAs in the circulation affected or unaffected by hemolysis. Profiling by TaqMan Array Microfluidic Cards was used to compare three pairs of hemolyzed and non-hemolyzed plasma (with varying degrees of hemolysis) and one RBC sample. A total of 136 microRNAs were detectable in at least two of the samples, and of those 15 were at least twofold elevated in all three hemolyzed samples. This number increased to 88 microRNAs for the sample with the highest level of hemolysis, with all of these also detected in the RBC profile. Thus these microRNAs represent a large proportion of detectable microRNAs and those most likely to be affected by hemolysis. Several of the hemolysis-susceptible microRNAs (e.g., miRs-21, -106a, -92a, -17, -16) have also been previously proposed as plasma/serum biomarkers of disease, highlighting the importance of rigorous quality control of plasma/serum samples used for measurement of circulating microRNAs. As low-level hemolysis is a frequent occurrence during plasma/serum collection it is critical that this is taken into account in the measurement of any candidate circulating microRNA.

Excision repair cross complementation group 1 and thymidylate synthase expression in patients with mesothelioma.

BACKGROUND: We hypothesized that in patients with malignant pleural mesothelioma (MPM) undergoing extrapleural pneumonectomy (EPP), high expression of excision repair cross complementation group 1 (ERCC1) and low expression of thymidylate synthase (TS) are associated with prolonged survival. PATIENTS AND METHODS: Consecutive patients undergoing EPP at our institutions were reviewed. Tissue microarrays were constructed using five 1-mm cores per patient. TS and ERCC1 protein expression was evaluated by immunohistochemical techniques. The average percentage scores from evaluable cores were assessed and the median score was used to divide the group. Overall survival (OS) from the time of surgery was determined by the Kaplan-Meier method and results were compared by the log-rank test. RESULTS: Eighty patients were included: median age, 58 years; 79% men; 76% epithelial and 24% biphasic subtypes; 25% and pathologic stage I/II and 73% stage III/IV. The median OS was 18.2 months (80% deceased at the censor date). Nineteen patients received neoadjuvant chemotherapy; 2 patients received chemotherapy with adjuvant intent and 28 patients received palliative chemotherapy. The median score was 10.2% for TS and 35% for ERCC1. There was no correlation between TS expression and OS (13.7 vs. 21.6 months for low and high levels, respectively; P = .32). There was a trend between high ERCC1 expression and longer OS (27.6 vs. 10.3 months; P = .06). CONCLUSION: In this series of patients with MPM undergoing EPP, TS expression was not associated with prolonged survival, but there was a trend for longer survival in patients with high ERCC1 expression.

Validation of tissue microarray technology in malignant pleural mesothelioma.

AIMS: Tissue microarray (TMA) technology has been utilised for assessment of cancers including malignant pleural mesothelioma (MPM). Given the intralesional heterogeneity of MPM, it is questionable if TMAs can adequately represent MPMs. We here investigate the validity of TMAs for MPM. METHODS: TMAs were constructed from at least five cores for each of 80 archival tumours processed by two centres between 1994 and 2009. The percentage of cases correctly subtyped on TMAs compared with whole sections, in relation to the number of cores analysed, was calculated. Immunohistochemical labelling for calretinin and D2-40 was performed on TMAs and whole sections. To evaluate the validity of quantitative immunohistochemistry, percentages of positive cells were recorded and two-way analysis of variance (ANOVA) performed. RESULTS: Five cores were assessable for 91% of patients. Four cores were sufficient to reach concordance with the whole-section result in 98% of cases for calretinin and 99% for D2-40. The correlation of the quantitative scores between the whole section and TMA cores was statistically significant (D2-40, rho = 0.84, p < 2.2e-16; calretinin, rho = 0.65, p = 7.9e-11). Neither the origin nor age of the blocks affected the results. CONCLUSION: If a minimum of four cores is used, TMA is an appropriate method for immunohistochemistry in MPM.

Patient and oncologist estimates of survival in advanced cancer patients.

OBJECTIVE: There is little information about the accuracy of patient perceptions of their life expectancy. Here, we compare patient perceptions of their outlook and their oncologist's estimates of life expectancy to actual survival. METHODS: The Unmet Needs Study recruited patients with metastatic cancer. Oncologists were asked to estimate patient survival as: (1) weeks; (2) months; (3) <1 year; (4)<2 years; and (5) >2 years. Patients were asked to estimate their outlook on a numerical scale from 1-7. Patient and oncologist estimates were compared with actual survival. RESULTS: Complete survival data were available for 50 patients: median age 63.5 years; 48% male; tumor types: 32% colorectal, 24% lung, 10% upper gastrointestinal cancer, 12% unknown primary; and median survival 6.8 months. The oncologists were 32% accurate in predicting survival and overestimated survival 42% of the time (weighted kappa=0.34). The correlation between self-reported patient outlook and survival was modest (Spearman's rho=0.36, p=0.01). The median survival for categories of outlook of 1-3, 4-5, and 6-7 were 4.4, 5.4, and 14.8 months, respectively (p=0.01). Overseas-born patient was the only independent predictor for the oncologists' accurate estimates (p=0.01). CONCLUSIONS: Oncologists were relatively poor at predicting survival and tended to be optimistic in their prognostication. The probability of survival significantly decreased with worse self-reported patient outlook.

High blood neutrophil-to-lymphocyte ratio is an indicator of poor prognosis in malignant mesothelioma patients undergoing systemic therapy.

PURPOSE: Asbestos-induced chronic inflammation is implicated in the pathogenesis of malignant mesothelioma (MM). We have investigated blood neutrophil-to-lymphocyte ratio (NLR), an index of systemic inflammation, as a prognostic factor in MM patients. EXPERIMENTAL DESIGN: Patients with MM who had systemic therapy at participating institutes were studied. Potential prognostic factors such as age, gender, performance status, histologic subtype, and baseline laboratory parameters, including NLR, were analyzed. Overall survival from commencement of therapy was determined by the Kaplan-Meier method. Multivariate analyses using Cox Regression model were performed with significant factors (P ≤ 0.05) to determine their independent effect. RESULTS: A total of 173 MM patients undergoing systemic therapy including 119 patients receiving first-line therapy and 54 patients receiving second- or third-line therapy were included in this retrospective evaluation. Forty-two percent of patients had an elevated NLR at baseline. The following variables were predictive of survival: female gender (P = 0.044), epithelioid histologic subtype (P < 0.001), baseline white blood cell count less than 8.3 × 109/L (P = 0.008), baseline platelet count 400 × 109/L or less (P = 0.05), and NLR of 5 or less (P < 0.001). After multivariate analysis, histologic epithelioid subtype [hazard ratio (HR) = 2.0; 95% confidence interval (CI) = 1.3-2.9; P = 0.001], and NLR less than 5 (HR = 2.7; 95% CI = 1.8-3.9; P < 0.001) remained independent predictors. The 1-year survival rate was 60% versus 26%, whereas the 2-year survival rate was 34% versus 10% for NLR less than 5 and 5 or greater, respectively. In the separate analyses of chemotherapy-naive and previously treated patient groups, NLR was an independent predictor of survival in both groups. CONCLUSION: Our results indicate that NLR is an independent predictor of survival for patients with MM undergoing systemic therapy.